An overlooked risk in heart surgery: The perioperative question insufficiently addressed for too long

For most patients undergoing heart surgery with cardiopulmonary bypass (CPB), the blood thinner heparin is a routine safeguard, preventing dangerous clots during extracorporeal circulation. However, for a significant minority, heparin is ineffective – creating a critical situation in which the attending physicians in the operating theatre must act quickly, often with limited tools.

An estimated one in ten cardiac surgery patients develops heparin resistance, frequently caused by low levels of antithrombin, a protein essential for heparin to work. When heparin resistance occurs, it places additional strain on hospital resources.

Despite the seriousness of the problem, the condition has received relatively little focused clinical attention. A major international trial now aims to address this gap.

Sponsored by Octapharma, the ongoing Phase 3 ATN-108 study is testing whether an intravenous antithrombin concentrate can restore heparin responsiveness in patients with acquired antithrombin deficiency undergoing complex cardiac surgery requiring cardiopulmonary bypass.

Designed for speed, clarity and real-world relevance

The ATN-108 study is a randomised, double-blind, placebo-controlled Phase 3 study which will enroll approximately 120 heparin-resistant patients across 37 sites in 11 countries across Europe and North America.

Patients are randomised to receive one of two doses of antithrombin concentrate or a placebo, administered shortly before employing CPB. The primary objective is to assess whether treatment can restore and maintain heparin responsiveness without the need for additional antithrombin-containing rescue therapies, such as fresh frozen plasma, during cardiopulmonary bypass.

The Phase 3 trial was launched in 2024 and progressed significantly in 2025, with early enrolment indicating the need to refine dosing based on emerging data.

“This indication requires rapid intervention,” explains Cristina Solomon, Global Vice President, Head of CRD Lachen. “The study is designed to generate clear and clinically meaningful efficacy and safety data in an acquired antithrombin deficiency indication.”

The trial has expanded Octapharma’s collaboration with anaesthesia and cardiac surgery teams worldwide, both in countries where perioperative use of coagulation factor concentrates is well established and in those where use is still developing.

A blueprint for future global trials

For Sylvia Werner, Senior Director, Clinical R&D, who leads the programme, ATN-108 reflects how Octapharma intends to conduct other complex global studies. “For trials such as this, a broad international footprint is essential,” she says. “It enhances patient diversity, supports recruitment timelines and allows us to operate across multiple regulatory systems.”

Sylvia adds that close collaboration with individual centres is critical in less common indications such as heparin resistance.

Learning from early signals

The study placed emphasis on real-time data monitoring from the start, allowing early review of patient outcomes. That close monitoring proved decisive when early data suggested the initial dosing regimen might not be sufficient for some patients with severe antithrombin depletion. Recruitment was paused, the dosing strategy revised and the updated protocol was submitted for regulatory approval.

The revised design now evaluates two higher active doses versus placebo, with dosing linked directly to activated clotting time, which is routinely measured during cardiac surgery.

“This approach allows us to understand dose response while balancing efficacy and safety,” Sylvia explains. Recruitment for the trial is expected to continue until early 2028.

Reaching multiple indications

While antithrombin concentrates are widely approved for congenital antithrombin deficiency, ATN-108 focuses on acquired deficiency – a far larger and more heterogeneous patient population.

Strategically, Cristina sees the study as a foundation for further development in surgical bleeding management and critical care indications. Future applications could extend beyond cardiac surgery to other high-risk settings where heparin resistance is a concern, including extracorporeal membrane oxygenation (ECMO), major vascular surgery and potentially within intensive care units.

Shifting standards and access

Beyond trial endpoints, the study aims to change how acquired antithrombin deficiency is managed globally. “Lasting success would mean moving the clinical benchmark away from fresh frozen plasma in countries and hospitals where frozen plasma is still the standard-of-care,” says Sylvia. “It could also support dialogue with regulatory authorities in markets such as the United States.”

Cristina believes the focused design of the study could enable rapid translation into regulatory and clinical decision-making. For patients facing high-risk heart surgery – and for clinicians managing one of its high-risk complications – ATN-108 could help align treatment standards and access to care.

For Octapharma, the implications of ATN-108 extend beyond clinical data, aligning with a broader strategy to expand access to therapies worldwide. “Generating robust evidence in areas of unmet medical need is how we create the foundation for broader patient access,” says Oliver Hegener, Senior Vice President, IBU Critical Care.

If successful, ATN-108 could support a significantly wider and more consistent access to antithrombin therapy in perioperative and critical-care settings around the world.