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Antiplatelet Therapy Reversal
Navigating the Bleeding Risks: Essential Insights for Surgeons Managing Antiplatelet Therapy in Urgent Surgery

Released: January 02, 2025

Expiration: January 01, 2026

Deepak L. Bhatt
Deepak L. Bhatt, MD, MPH, MBA, FACC, FAHA, FESC, MSCAI
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Key Takeaways
  • Managing patients on dual antiplatelet therapy requiring urgent or emergent surgery poses challenges due to increased bleeding risks, with limited options to mitigate bleeding complications.
  • Clearance times for P2Y12 antagonists vary and are prolonged, which require a careful balance of increasing bleeding risk or delaying surgery. Although platelet transfusions may be an option for clopidogrel and prasugrel, they are less effective with reversible agents like ticagrelor due to ongoing inhibition of transfused platelets, highlighting the need for tailored approaches.
  • Bentracimab, a monoclonal antibody currently in development, shows promise for reversing ticagrelor’s antiplatelet effects rapidly and effectively, as evidenced by interim trial data, offering potential solutions for urgent surgical cases.

The management of patients requiring urgent or emergent surgery while taking antiplatelet therapy presents several clinical challenges in surgical practice. Although there is established comfort with performing surgeries on patients taking aspirin alone, particularly in cardiac procedures, the complexity increases substantially when managing patients on dual antiplatelet therapy (DAPT). DAPT typically consists of aspirin combined with an oral P2Y12 receptor antagonist, also known as adenosine diphosphate antagonist. Evidence from landmark randomized clinical trials, including the CURE trial with clopidogrel, the TRITON trial with prasugrel, and the PLATO trial with ticagrelor, has demonstrated increased bleeding risk for patients undergoing cardiac and noncardiac surgeries. This includes higher rates of bleeding complications due to the potential need for reoperation and surgical re-exploration to identify and control bleeding, which can significantly complicate outcomes.

Cangrelor: A Bridging Solution
The challenge is further compounded by the increasing number of patients receiving DAPT as well as receiving P2Y12 receptor antagonist monotherapy. Cangrelor, a short-acting intravenous P2Y12 inhibitor, offers potential flexibility due to its rapid offset of biologic activity after discontinuation in approximately 1 hour. In certain scenarios, it can be used off-label as a bridging therapy, allowing patients to transition to surgery without completely discontinuing an antiplatelet agent. However, this approach is not viable in true emergency situations where immediate surgical intervention is required. Delaying surgery is occasionally considered, but this strategy carries risks, including prolonged hospital stays, increased healthcare costs, and potential ischemic events due to antiplatelet therapy interruption. Cangrelor has shown promise as a short-acting intravenous P2Y12 inhibitor in bridging strategies for patients on DAPT requiring surgery, but there is no current randomized clinical trial to support routine use of bridging strategies like cangrelor for ischemic risk reduction.

Antiplatelet Agent Clearance Times
Another critical consideration that often complicates management is drug clearance times, which can vary significantly among antiplatelet agents. Oral P2Y12 receptor antagonists generally require between 3 to 7 days to clear. Prasugrel has the longest clearance time of approximately 7 days, while ticagrelor, due to its reversible binding properties and shorter half-life, can clear within 3 days. Clopidogrel falls somewhere in the middle at around 5 days, though this can vary based on individual patient response patterns.

Platelet Transfusion Strategies
In some cases, platelet transfusions are administered prophylactically, while in others, they are given only in response to active surgical bleeding. The approach often varies based on the type and complexity of surgery and the patient’s overall comorbidities. When considering transfusions, it is important to recognize that their efficacy depends on the specific antiplatelet agent involved. For irreversible agents such as aspirin, clopidogrel, and prasugrel, transfusions provide fresh platelets that can clot effectively. However, ticagrelor, a reversible agent, presents a unique challenge. Because ticagrelor does not clear quickly from a patient’s system and binds reversibly to the adenosine diphosphate receptor, the active drug can inhibit both transfused platelets and those already present, reducing the efficacy of platelet transfusions.

Ticagrelor: Benefits and Risks
Ticagrelor is often the preferred P2Y12 agent of choice due to its demonstrated efficacy in reducing ischemic events. In the PLATO trial, ticagrelor demonstrated superior outcomes compared with clopidogrel in patients with acute coronary syndromes (ACS), including reduced mortality rates. Beyond ACS, ticagrelor demonstrated superiority against placebo in patients with a history of myocardial infarction in the PEGASUS trial and showed benefits in patients with diabetes and chronic coronary artery disease in the THEMIS and THEMIS-PCI trials. These findings have led to expanded FDA-approved indications, making ticagrelor therapy applicable across a broad range of patient populations. Given these expanded indications, it is inevitable that some patients treated with ticagrelor will experience major bleeding episodes or require urgent or emergent surgery. These scenarios highlight the critical need for effective strategies to manage bleeding and facilitate timely surgical intervention without compromising patient outcomes.

Bentracimab: Reversal of Ticagrelor
One promising emerging option is bentracimab, a monoclonal antibody specifically developed to reverse the effects of ticagrelor. It binds with high affinity to both ticagrelor and its major active metabolite. Although still an investigational agent, phase I trial data demonstrated rapid and thorough reversal of ticagrelor’s antiplatelet effects in healthy volunteers. Interim analysis from the ongoing phase III REVERSE-IT trial has also shown promising results in patients, with reversal achieved within 5 to 10 minutes and sustained over 24 hours. In addition, the trial reported approximately 90% adjudicated hemostasis success rates in urgent surgical cases, with no significant adverse reactions. If approved, bentracimab could provide a vital tool for managing the bleeding risks associated with ticagrelor in patients requiring emergent surgery, offering a safe and effective option without the need to wait for the antiplatelet to clear naturally. 

Conclusion
Understanding the complexities of managing patients on antiplatelet therapy is important, as these agents are increasingly prescribed for a wide range of indications. Emerging targeted reversal agents like bentracimab represent a significant advancement in addressing longstanding challenges in this field. As the use of antiplatelet therapy grows, particularly with the impending generic availability of ticagrelor, these strategies will become even more important in surgical practice. The ability to safely and effectively reverse antiplatelet therapy in emergent situations could significantly improve surgical outcomes and patient care in this challenging clinical scenario.

Your Thoughts?
How often do you encounter challenges in managing patients on antiplatelet therapy requiring urgent or emergent surgery? Learn more by attending a live in-person and virtual satellite symposium from the Society of Thoracic Surgeons meeting on January 25, 2025 at 6:00 AM PST or join the discussion by posting a comment below!

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