Evaluation of Protamine Sulfate for Heparin Reversal to Mitigate Neurologic and Hemorrhagic Events Post-Transcatheter Aortic Valve Implantation in Aortic Stenosis

The primary objective of the ATLANTIS Protamine study is to demonstrate the **superiority** of systematic antagonization with **protamine sulfate** over usual care in reducing in-hospital mortality, vascular/bleeding complications, stroke and transient ischemic attack (TIA), myocardial infarction, or the need for red blood cell transfusion from randomization to hospital discharge. This is clinically relevant as it aims to improve patient outcomes following transcatheter aortic valve implantation (TAVI) for aortic stenosis, a procedure associated with significant risks of neurologic and hemorrhagic events.

Secondary objectives include: - To demonstrate whether systematic heparin antagonization is associated with a shorter hospital stay. - To assess if systematic heparin antagonization reduces the risk of bleeding, vascular or ischemic complications, and acute kidney injury. - To evaluate whether there is an interaction based on the use of echo-guided femoral puncture and/or radial approach as the secondary arterial access site.

The clinical trial involves **participants** aged 18 years and older, both male and female, who are eligible for transfemoral transcatheter aortic valve implantation (**TAVI**). The study population is required to have medical insurance coverage and be registered with the French social healthcare system. Participants are selected based on their eligibility for TAVI, regardless of their chronic antithrombotic treatment, and must provide written informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **protamine sulfate** in reducing neurologic ischemic and hemorrhagic events following transcatheter aortic valve implantation (TAVI) for aortic stenosis. This is a Phase III, randomized, double-blind, controlled trial. The trial aims to demonstrate the superiority of systematic antagonization with protamine sulfate over the usual care in reducing in-hospital mortality, vascular and bleeding complications, stroke, transient ischemic attack (TIA), myocardial infarction, or the need for red blood cell transfusion from randomization to hospital discharge. The trial is expected to commence on November 2, 2023, and conclude by January 2, 2026.

Participants will be involved in the study from the time of randomization until hospital discharge. The inclusion visit will involve screening to ensure participants meet the criteria, including being 18 years or older, eligible for transfemoral TAVI, and having provided written informed consent. Follow-up visits will occur during the hospital stay to monitor for the primary endpoint, which includes the first occurrence of any event from a composite of all-cause mortality, type 2, 3, or 4 bleeding, major or minor vascular complications, stroke or TIA, myocardial infarction, or any red-blood transfusion. The primary endpoint will be assessed by a clinical event committee using the Valve Academic Research Consortium-3 (VARC-3) classifications. Secondary endpoints include the assessment of in-hospital stay length and the occurrence of specific complications from the procedure to discharge.

The expected length of participant involvement is from the procedure to hospital discharge, with the possibility of early termination if the participant experiences any adverse events that necessitate withdrawal or if they withdraw consent. The trial will employ stratification at randomization to assess the impact of systematic antagonization based on the use of echo-guided femoral puncture and/or arterial radial access. The study will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the trial outcomes.

The clinical trial involves the administration of **PROTAMINE CHOAY 1000 U.A.H./ml**, a **solution for injection** containing the active substance **protamine sulfate**. This experimental medication is provided in the form of an injectable solution and is administered via **intravenous administration**. The maximum daily dose is set at 50 mg, with a total maximum dose of 50 mg, and the treatment period is limited to one day. The medication is produced by CHEPLAPHARM ARZNEIMITTEL GMBH and is classified under the ATC code V03AB14, indicating its role as a protamine. The substance is of chemical origin, and the formulation is not specifically designed for pediatric use.

In this study, the experimental treatment with protamine sulfate is compared against the usual standard-of-care therapy. The objective is to demonstrate the superiority of systematic antagonization with protamine sulfate over the standard care in reducing in-hospital mortality and complications such as vascular/bleeding events, stroke, transient ischemic attack (TIA), myocardial infarction, or the need for red blood cell transfusion. The trial does not involve the use of a placebo or any other comparator treatment. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol.

Efficacy in the clinical trial titled "ATLANTIS Protamine - Antagonization of heparin with protamine sulfate to reduce all neurologic ischemic and hemorrhagic events after transcatheter aortic valve implantation for aortic stenosis" will be assessed using both primary and secondary endpoints. The primary endpoint is defined as the first occurrence, from procedure to hospital discharge, of any event within the composite of all-cause mortality, type 2, 3, or 4 bleeding, major or minor vascular complications, stroke or **transient ischemic attack (TIA)**, myocardial infarction, or any red blood cell transfusion. This endpoint will be determined blindly by a clinical event committee according to the Valve Academic Research Consortium-3 (VARC-3) classifications.

Secondary endpoints include the assessment of the length of in-hospital stay in days post-transcatheter aortic valve implantation (TAVI) procedure, and the occurrence of type 2, 3, or 4 bleeding or any red blood cell transfusion from procedure to hospital discharge. Additionally, the trial will assess the impact of systematic antagonization based on the use of echo-guided femoral puncture and/or arterial radial access, with subgroups defined at randomization by stratification. Other secondary endpoints involve the occurrence of death, type 2, 3, or 4 bleedings, any kidney injury (stage 2 to 4 according to the KDIGO definition), myocardial infarction, stroke, TIA, and access site and access-related vascular injury according to VARC-3 criteria.