Four late-breaking trials, presented at ESC Congress 2026 focused on post-acute coronary syndrome (ACS) antithrombotic therapy. LIBREXIA ACS examined adding the factor XIa inhibitor milvexian to antiplatelet therapy after ACS, PREMIUM looked at aspirin omission at the time of primary PCI for STEMI, SWITCH SWEDEHEART evaluated whether to switch from ticagrelor to prasugrel in ACS, and A-CLOSE compared clopidogrel monotherapy with extended dual antiplatelet therapy (DAPT) after high-risk PCI.

LIBREXIA ACS: Can Factor XIa Inhibition Improve Outcomes After ACS?

Despite contemporary antiplatelet therapy and revascularization, patients remain at risk of recurrent ischemic events after ACS. Factor XIa inhibition has been proposed as a strategy to reduce pathologic thrombosis while preserving hemostasis better than conventional anticoagulation.

The LIBREXIA ACS has 3 placebo-controlled trial evaluated factor XIa inhibition with milvexian in patients with ACS within seven days. Patients with PCI or medical therapy and ≥2 ischemic risk factors received milvexian 25 mg twice daily or placebo, alongside antiplatelet therapy.¹

Among 14,194 patients, the efficacy endpoint was cardiovascular death, myocardial infarction (MI), or ischemic stroke. The safety endpoint was Bleeding Academic Research Consortium (BARC) type 3c or 5 bleeding.

After an interim analysis based on 556 adjudicated efficacy events, the trial was terminated for futility. At 12.2 months, the outcome occurred in 5.4% with milvexian vs. 5.1% with placebo (hazard ratio [HR], 1.05; 95% CI, 0.91-1.21; p=0.50). BARC type 3c or 5 bleeding occurred in 0.3% vs. 0.3%, respectively (p=0.88).

Why Did the Strategy Fail?

LIBREXIA ACS challenges the hypothesis that additional factor XIa inhibition provides meaningful incremental protection against ischemic events after ACS when added to contemporary antiplatelet therapy and revascularization. Although milvexian did not increase the prespecified serious bleeding endpoint, it also did not reduce ischemic events. These findings emphasize that a favorable bleeding profile alone is insufficient if a novel antithrombotic strategy does not provide meaningful ischemic protection.^2,3

Clinical Perspective

LIBREXIA ACS does not support routine addition of milvexian 25 mg twice daily to antiplatelet therapy after ACS. Milvexian did not reduce cardiovascular death, MI, or ischemic stroke, while BARC type 3c or 5 bleeding was similar to placebo, with no increase in intracranial or fatal bleeding.

Importantly, these findings do not disprove factor XIa inhibition as a therapeutic strategy. Its benefit-risk profile may differ across thrombotic conditions, patient populations, and treatment settings. Ongoing LIBREXIA trials will determine whether factor XIa inhibition can achieve the anticipated separation between thrombosis and hemostasis.²

Bottom Line

LIBREXIA ACS is an important negative trial, showing that the absence of ischemic benefit limits the clinical value of a strategy, even when the prespecified serious bleeding outcome remains low and similar to placebo.

PREMIUM: Can Aspirin Be Safely Omitted During Primary PCI For STEMI?

Aspirin is a cornerstone of antiplatelet therapy during primary PCI for STEMI but increases bleeding risk. This raises the question of whether prasugrel monotherapy can provide adequate protection during and after PCI.

The PREMIUM multicenter, randomized Japanese trial evaluated aspirin omission from the outset in patients with STEMI undergoing primary PCI. The 2,216 patients randomized before PCI received either low-dose prasugrel monotherapy or DAPT with aspirin plus low-dose prasugrel for 12 months. The primary endpoint was all-cause death, MI, or stroke; major bleeding was the key secondary endpoint.⁴

At 12 months, the primary outcome occurred in 11.0% of the monotherapy group vs. 8.5% of the DAPT group (HR, 1.34; 95% CI, 1.02-1.75); prasugrel monotherapy failed to meet the prespecified noninferiority criterion. Major bleeding was lower with monotherapy (5.6% vs. 8.4%; HR, 0.66; 95% CI, 0.47-0.91). MI was more frequent with monotherapy, whereas definite or probable stent thrombosis was similar between groups.

Why Is This Important?

PREMIUM challenges immediate aspirin omission during primary PCI for STEMI. Although prasugrel monotherapy reduced major bleeding, it was associated with a higher incidence of the primary ischemic composite. Importantly, prior trials supporting P2Y12 inhibitor monotherapy generally discontinued aspirin after an initial period of DAPT, rather than before PCI. Thus, PREMIUM does not refute later aspirin discontinuation in selected patients. Generalizability may also be limited by the Japanese population, use of low-dose prasugrel, and extensive use of intravascular imaging. Whether these findings apply to contemporary Western STEMI populations remains uncertain.⁵

Clinical Perspective

For now, PREMIUM does not support routine upfront aspirin omission during primary PCI for STEMI. Current ACS guidance recommends aspirin loading and maintenance therapy with a P2Y12 inhibitor added for patients undergoing PCI.⁶

The broader lesson is that bleeding reduction should not come at the expense of early ischemic protection. In STEMI, the immediate post-PCI period remains particularly vulnerable to thrombotic complications, supporting continued aspirin use during this high-risk phase.

Bottom Line

PREMIUM suggests that aspirin-free low-dose prasugrel therapy initiated before primary PCI is not an adequate substitute for DAPT in STEMI, despite reducing major bleeding.

SWITCH SWEDEHEART: Prasugrel or Ticagrelor After PCI for ACS?

Prasugrel and ticagrelor are potent P2Y12 inhibitors preferred over clopidogrel in patients with ACS undergoing PCI. However, the optimal choice remains uncertain, given ticagrelor’s dyspnea, twice-daily dosing, and potential adherence challenges.

The SWITCH SWEDEHEART trial evaluated whether a default prasugrel policy could maintain ischemic protection while potentially reducing bleeding compared with a default ticagrelor policy after PCI. This registry-based, open-label, stepped-wedge, cluster-randomized trial included 17,095 patients with ACS undergoing PCI across seven Swedish regions between 2021 and 2024. STEMI accounted for 39.4% of presentations.⁷

At one year, death, MI, or stroke occurred in 11.1% with the prasugrel policy vs. 11.8% with the ticagrelor policy (adjusted odds ratio [OR], 0.90; 95% CI, 0.77-1.06), indicating no statistically significant difference in ischemic outcomes. Major bleeding occurred in 4.2% vs. 4.4%, respectively (adjusted OR, 0.80; 95% CI, 0.64-0.99).

What Does This Add?

SWITCH SWEDEHEART complements the ISAR-REACT 5 trial, which reported fewer ischemic events with prasugrel than ticagrelor.⁸ However, the trials addressed different questions. SWITCH SWEDEHEART evaluated pragmatic institutional treatment policies rather than individual randomization to a specific P2Y12 inhibitor.

Importantly, SWITCH SWEDEHEART should not be interpreted as evidence that patients can be routinely switched from ticagrelor to prasugrel without considering clinical context, timing, and appropriate loading therapy. The trial evaluated default treatment strategies rather than a protocolized patient-level switching strategy.

Clinical Perspective

The 2025 ACC/AHA/Multisociety ACS guideline recommends prasugrel or ticagrelor as preferred P2Y12 inhibitors for patients with ACS undergoing PCI, without favoring either agent.⁹ Prasugrel should not be used in patients with prior stroke or transient ischemic attack, and a reduced 5 mg maintenance dose should be considered in patients aged ≥75 years or weighing <60 kg.⁹

Bottom Line

SWITCH SWEDEHEART supports prasugrel as a reasonable first-line alternative to ticagrelor in patients with ACS undergoing PCI, with similar ischemic outcomes and a modestly lower risk of major bleeding. The findings support individualized P2Y12 inhibitor selection rather than assuming universal superiority of either agent.

A-CLOSE: Clopidogrel or Extended DAPT After High-Risk PCI?

The optimal duration of DAPT after PCI remains individualized. Prolonged DAPT may reduce ischemic events but increases bleeding, whereas P2Y12 inhibitor monotherapy reduces bleeding with potential ischemic trade-offs.

The A-CLOSE trial evaluated clopidogrel monotherapy vs. extended DAPT in high-ischemic-risk patients after 12 uneventful months. The trial enrolled 3,203 patients with ≥1 clinical or angiographic high-risk feature who remained free of major ischemic or bleeding events during 12 months of DAPT. Patients were randomized to clopidogrel 75 mg daily monotherapy or continued aspirin plus clopidogrel (DAPT) for an additional 24 months.¹⁰

At 24 months, net adverse clinical events (NACE), including death, MI, stent thrombosis, stroke, or BARC type 2, 3, or 5 bleeding, occurred in 5.0% in the monotherapy group vs. 5.1% in the DAPT group, meeting the prespecified criterion for noninferiority. However, individual outcomes diverged. Ischemic events occurred in 3.7% vs. 1.6%, respectively (HR, 2.33; 95% CI, 1.47-3.69), whereas BARC type 2, 3, or 5 bleeding occurred in 1.8% vs. 4.1% (HR, 0.43; 95% CI, 0.27-0.67).

The Trade-Off Behind the Neutral Composite

A-CLOSE highlights that a neutral composite outcome does not imply equivalent efficacy and safety. Clopidogrel monotherapy reduced bleeding but increased ischemic events, whereas extended DAPT provided greater ischemic protection at the cost of more bleeding. These findings complement OPT-BIRISK and HOST-EXAM Extended trials.^11,12 A-CLOSE therefore addresses a distinct question: whether aspirin can be withdrawn after 12 event-free months in patients with high residual ischemic risk.

Clinical Perspective

A-CLOSE reinforces that antiplatelet therapy beyond 12 months should be individualized according to ischemic and bleeding risk. Patients with complex PCI, prior MI, diabetes, chronic kidney disease, or multivessel disease may have greater residual ischemic risk, whereas prior bleeding, anemia, frailty, or other bleeding-risk features may favor less intensive therapy. A-CLOSE does not support routine extended DAPT or universal preference for clopidogrel monotherapy.

Bottom Line

After 12 uneventful months of DAPT, clopidogrel monotherapy was noninferior to extended DAPT for NACE, but with less bleeding and more ischemic events. Antiplatelet therapy should therefore be individualized according to each patient’s competing ischemic and bleeding risks.

References

1. Gibson CM, Steg PG, Bahit MC, et al. Milvexian with antiplatelet therapy after acute coronary syndrome event. N Engl J Med. Published online August 29, 2026. doi:10.1056/NEJMoa2608717
2. Weitz JI, Harrington RA; LIBREXIA Program Executive Council. Rationale for the milvexian dosing in the phase 3 LIBREXIA program. J Thromb Haemost. 2026;24(6):2158-2169. doi:10.1016/j.jtha.2026.02.020
3. Gibson CM, Bahit MC, Mehran R, et al. Oral factor XIa inhibitor milvexian after a recent acute coronary syndrome: rationale and design of the phase 3 (LIBREXIA ACS). Am Heart J. 2025;285:21-28. doi:10.1016/j.ahj.2025.02.011
4. Takahashi K, Kozuma K, Morino Y, et al. Aspirin omission at the time of primary percutaneous coronary intervention in STEMI. N Engl J Med. Published online August 29, 2026. doi:10.1056/NEJMoa2606997
5. Li M, Zhang G, Liu X. Aspirin after PCI in acute coronary syndromes. N Engl J Med. 2026;394(10):1035-1036. doi:10.1056/NEJMc2518964
6. Kumbhani DJ, Gibson CM, Kinlay S, et al. Antiplatelet therapy in the management of atherosclerotic cardiovascular disease: 2026 ACC scientific statement: a report of the American College of Cardiology. J Am Coll Cardiol. 2026;88(11):1284-1313. doi:10.1016/j.jacc.2026.05.037
7. Omerovic E, Koul S, Andersson J, et al. Prasugrel versus ticagrelor in acute coronary syndromes. N Engl J Med. Published online August 29, 2026. doi:10.1056/NEJMoa2609057
8. Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381(16):1524-1534. doi:10.1056/NEJMoa1908973
9. Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2025;85(22):2135-2237. doi:10.1016/j.jacc.2024.11.009
10. Lee SJ, Lee YJ, Lee K, et al. Clopidogrel or dual antiplatelet therapy in high-ischemic-risk patients. N Engl J Med. Published online August 29, 2026. doi:10.1056/NEJMoa2608533
11. Li Y, Li J, Wang B, et al. Extended clopidogrel monotherapy vs DAPT in patients with acute coronary syndromes at high ischemic and bleeding risk: the OPT-BIRISK randomized clinical trial. JAMA Cardiol. 2024;9(6):523-531. doi:10.1001/jamacardio.2024.
12. Kang J, Park KW, Lee H, et al. Aspirin versus clopidogrel for long-term maintenance monotherapy after percutaneous coronary intervention: the HOST-EXAM Extended study. Circulation. 2023;147(2):108-117. doi:10.1161/CIRCULATIONAHA.122.062770

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiovascular Care Team, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Anticoagulation Management and ACS, Interventions and ACS, Interventions and Vascular Medicine, Chronic Angina

Keywords: ESC Congress, ESC26, Acute Coronary Syndrome, Thrombosis, Anticoagulants, Factor Xa Inhibitors, ST Elevation Myocardial Infarction, Myocardial Infarction, Percutaneous Coronary Intervention, Aspirin, Platelet Aggregation Inhibitors, Ticagrelor, Drug Therapy, Combination, Clopidogrel