Heart with stent intersected by a timeline, balancing stent thrombosis and mortality.

Stent Thrombosis & Mortality: Unpacking the Debate Around Timing and Treatment

Beau Callahan in Health & Wellness December 2025 • 5 min read.

"Explore the complexities of antiplatelet therapy in acute coronary syndromes, dissecting the ATLANTIC trial and its implications for stent thrombosis and mortality. What does this mean for future treatment strategies?"

In the treatment of acute coronary syndromes (ACS), current medical guidelines strongly advocate for the administration of P2Y12 inhibitors. This recommendation frequently translates into pre-treatment with the respective P2Y12 inhibitor, initiated before the coronary anatomy is even fully understood. This approach stems from earlier studies with clopidogrel that hinted at significant benefits in reducing major adverse cardiac events when administered prior to knowing the extent of coronary artery disease. Pre-treatment aims to kickstart the antiplatelet effect, crucial for preventing thrombus formation during percutaneous coronary intervention (PCI).

However, these initial clopidogrel studies were not without their critics. Concerns were raised about the study designs, particularly regarding prolonged pre-treatment intervals before PCI and the use of clopidogrel dosages lower than what is currently recommended. Despite these criticisms, the concept of clopidogrel pre-treatment gained traction, particularly in Europe, fueled by observational studies suggesting increased mortality risk in ST-segment elevation patients who did not receive pre-treatment.

One of the key limitations associated with clopidogrel is the variability in how effectively it inhibits platelets. This variability leads to instances of high on-treatment platelet reactivity, which has been linked to an increased risk of both stent thrombosis and mortality. The debate around high on-treatment platelet reactivity has centered on its definition, how it's measured, and its overall usefulness in clinical practice. Newer P2Y12 inhibitors such as prasugrel and ticagrelor were developed to overcome clopidogrel's limitations. These agents offer faster and more predictable platelet inhibition, which led to significant reductions in cardiovascular mortality, myocardial infarction, and stroke in ACS patients during pivotal clinical trials.

The ATLANTIC Trial: Challenging Pre-Treatment Norms

Heart with stent intersected by a timeline, balancing stent thrombosis and mortality.

Given the quicker action of prasugrel and ticagrelor compared to clopidogrel, the critical question arose: Should these newer agents also be administered at first medical contact, or could their administration be safely postponed until after coronary anatomy is determined and the decision for PCI is confirmed? The ACCOAST trial explored the use of prasugrel pre-treatment in non-ST elevation acute coronary syndrome (NSTE-ACS) patients. The trial revealed no significant reduction in the composite ischemic endpoint of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy. More concerningly, the pre-treatment arm, which used a reduced prasugrel loading dose of 30 mg, showed a significant increase in major bleeding events. This outcome led current guidelines to advise against using prasugrel before coronary angiography in NSTE-ACS patients.

Following ACCOAST, the ATLANTIC trial investigated ticagrelor administration, comparing pre-hospital versus in-hospital initiation in patients with ST-segment elevation myocardial infarction (STEMI). The primary goal was to assess whether earlier administration of ticagrelor improved surrogate endpoints. The results showed no significant difference in the co-primary surrogate endpoints between the two study arms, nor in the combined ischemic secondary endpoint. However, a notable finding was a significant reduction in acute and early definite stent thrombosis with pre-hospital ticagrelor administration.

Surrogate Endpoints: No difference observed in primary surrogate endpoints between pre-hospital and in-hospital ticagrelor administration.
Stent Thrombosis: Significant reduction in acute and early definite stent thrombosis with pre-hospital ticagrelor.
Mortality Paradox: No reduction in all-cause mortality with pre-hospital ticagrelor; a numerically higher risk was observed (3.3% vs 2.0%, p=0.08).

Interestingly, this reduction in stent thrombosis did not translate into a decrease in overall mortality. In fact, there was a numerically higher mortality risk in the group that received pre-hospital ticagrelor (3.3% vs. 2.0%, p=0.08). These conflicting results prompted critical analysis regarding the interpretation and implications of the ATLANTIC trial. It's important to note that the ATLANTIC trial was a timing trial for ticagrelor, unlike the PLATO trial, which compared ticagrelor to clopidogrel. Therefore, direct comparisons between these trials should be approached with caution.

Reconciling Stent Thrombosis and Mortality: A Broader Perspective

While reducing stent thrombosis remains a crucial goal in interventional cardiology, it's becoming increasingly clear that it doesn't automatically guarantee improved survival. Modern drug-eluting stents and advanced intracoronary imaging techniques have significantly decreased the risk of stent thrombosis. As a result, stent thrombosis may no longer be the dominant factor influencing overall mortality. Other factors, such as bleeding complications, arrhythmias, and non-cardiac events, may now play a more significant role in determining patient outcomes. The focus needs to shift towards a more holistic approach, considering all potential risks and benefits when tailoring antiplatelet therapy for ACS patients.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1160/th15-02-0159, Alternate LINK

Title: Atlantic: Another Reason To Investigate The Disconnect Between Stent Thrombosis And Mortality?

Subject: Hematology

Journal: Thrombosis and Haemostasis

Publisher: Georg Thieme Verlag KG

Authors: Dirk Sibbing, Daniel Aradi

Published: 2015-01-01

Everything You Need To Know

Why is pre-treatment with P2Y12 inhibitors recommended in Acute Coronary Syndromes (ACS)?

In treating Acute Coronary Syndromes (ACS), current guidelines emphasize using P2Y12 inhibitors, often before fully understanding the coronary anatomy. This pre-treatment strategy aims to quickly initiate the antiplatelet effect, preventing thrombus formation during Percutaneous Coronary Intervention (PCI). Early studies with clopidogrel suggested benefits in reducing major adverse cardiac events when given preemptively. However, pre-treatment does carry potential risks, and the effectiveness of this approach continues to be a topic of investigation and refinement in clinical practice.

What is high on-treatment platelet reactivity, and why is it a concern?

Clopidogrel's effectiveness in inhibiting platelets varies, leading to high on-treatment platelet reactivity in some patients. High on-treatment platelet reactivity is associated with increased risks of stent thrombosis and mortality. Newer P2Y12 inhibitors, like prasugrel and ticagrelor, were developed to provide faster and more predictable platelet inhibition, reducing cardiovascular mortality, myocardial infarction, and stroke in ACS patients. Addressing high on-treatment platelet reactivity is vital for optimizing patient outcomes after PCI.

What was the ATLANTIC trial about, and what did it find?

The ATLANTIC trial investigated whether administering ticagrelor to patients with ST-segment elevation myocardial infarction (STEMI) before arriving at the hospital improved outcomes compared to in-hospital administration. The trial's primary goal was to determine if earlier administration of ticagrelor could improve surrogate endpoints. The results showed a significant reduction in stent thrombosis with pre-hospital ticagrelor, but this did not translate into a decrease in overall mortality. The ATLANTIC trial plays a pivotal role in shaping strategies around antiplatelet therapy timing in ACS.

What was the ACCOAST trial about and what did it discover?

The ACCOAST trial examined the use of prasugrel pre-treatment in non-ST elevation acute coronary syndrome (NSTE-ACS) patients. It found no significant reduction in the composite ischemic endpoint. More concerningly, the pre-treatment arm showed a significant increase in major bleeding events. As a result, current guidelines advise against using prasugrel before coronary angiography in NSTE-ACS patients. The ACCOAST trial highlights the importance of carefully evaluating the risks and benefits of pre-treatment strategies in specific ACS patient populations.

Why doesn't reducing stent thrombosis always lead to improved survival?

While reducing stent thrombosis is important in interventional cardiology, it does not automatically guarantee improved survival. Modern drug-eluting stents and advanced intracoronary imaging techniques have decreased the risk of stent thrombosis. Consequently, other factors, such as bleeding complications, arrhythmias, and non-cardiac events, now play a more significant role in determining patient outcomes. Balancing the risks and benefits when choosing antiplatelet therapy for ACS patients is the new approach.