Network meta-analysis compares P2Y₁₂ inhibitors after PCI

In a network meta-analysis of 15 RCTs, prasugrel provided the best balance between efficacy and safety compared with ticagrelor and clopidogrel in patients after PCI.

This summary is based on the publication of Maqsood MH, Feit F, Kaul U, et al. - Efficacy and Safety of Prasugrel, Ticagrelor, or Clopidogrel After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis. JAMA Cardiol. 2026 Jul 1;11(7):651-658. doi: 10.1001/jamacardio.2026.1128.

Introduction and methods

Background

The 2025 ACC/AHA and 2023 ESC guidelines for ACS recommend prasugrel or ticagrelor to reduce MACE or stent thrombosis in patients undergoing PCI [1-2]. The 2023 ESC guidelines additionally recommend prasugrel over ticagrelor, based on the ISAR-REACT 5 trial, in which prasugrel was associated with lower MACE compared with ticagrelor without a difference in major bleeding [2-3]. More recently, the TUXEDO-2 trial showed that ticagrelor was not noninferior to prasugrel for the primary outcome, with point estimates favoring prasugrel for most endpoints [4-5]. These findings highlight the need to further evaluate the comparative efficacy and safety of currently used oral P2Y₁₂ inhibitors.

Aim of the study

The aim of this systematic review and network meta-analysis was to compare the efficacy and safety of prasugrel, ticagrelor, and clopidogrel in patients who underwent PCI.

Methods

PubMed and Embase were searched through November 15, 2025 for RCTs comparing at least 2 of the 3 oral P2Y₁₂ inhibitors. Trials enrolling adults with ACS or chronic coronary syndrome undergoing an invasive management strategy were eligible.

A total of 15 RCTs comprising 48,904 patients were included. Of these, 12,120 patients (24.8%) received prasugrel, 16,049 (32.8%) ticagrelor, and 20,735 (42.4%) clopidogrel. Mean age was 63.2 years, 27.3% of participants were women, 28.2% had diabetes, and 93.9% had ACS. Mean follow-up was 12.1 months.

Outcomes

The primary efficacy outcome was MACE, and the primary safety outcome was major bleeding. Secondary outcomes included all-cause mortality, MI, ischemic stroke, cardiovascular mortality, stent thrombosis, intracranial hemorrhage, and drug discontinuation due to adverse events.

Main results

• Compared with clopidogrel, prasugrel was associated with a lower risk of MACE (OR: 0.80; 95%CI: 0.69-0.93), MI (OR: 0.71; 95%CI: 0.62-0.82), and stent thrombosis (OR: 0.48; 95%CI: 0.37-0.62).
• Compared with clopidogrel, ticagrelor did not significantly reduce MACE (OR: 0.97; 95%CI: 0.84-1.12) or MI (OR: 0.91; 95%CI: 0.79-1.05), but was associated with a lower risk of stent thrombosis (OR: 0.73; 95%CI: 0.59-0.91).
• Compared with ticagrelor, prasugrel was associated with a lower risk of MACE (OR: 0.83; 95%CI: 0.70-0.98), MI (OR: 0.78; 95%CI: 0.65-0.94), and stent thrombosis (OR: 0.66; 95%CI: 0.49-0.88).
• There were no significant differences between the 3 P2Y₁₂ inhibitors in all-cause mortality, ischemic stroke, or cardiovascular mortality.
• Ticagrelor was associated with a higher risk of major bleeding compared with clopidogrel (OR: 1.24; 95%CI: 1.01-1.52), whereas no significant difference was observed between prasugrel and clopidogrel (OR: 1.08; 95%CI: 0.84-1.38) or between ticagrelor and prasugrel (OR: 1.15; 95%CI: 0.88-1.49).
• The risk of intracranial hemorrhage was higher with ticagrelor than with clopidogrel (OR: 1.89; 95%CI: 1.08-3.33).
• Drug discontinuation due to adverse events was more frequent with ticagrelor than with clopidogrel (OR: 2.07; 95%CI: 1.20-3.56).
• In the treatment rankings, prasugrel ranked first for MACE, MI, and stent thrombosis, whereas clopidogrel ranked first for major bleeding, intracranial hemorrhage, and discontinuation due to adverse events.
• Cluster analyses combining MACE, MI, and stent thrombosis with major bleeding showed that, overall, prasugrel provided the best balance between efficacy and safety.

Conclusion

In this systematic review and network meta-analysis of patients who underwent PCI, prasugrel was associated with a lower risk of MACE compared with both clopidogrel and ticagrelor, driven by reductions in MI and stent thrombosis. Ticagrelor was associated with a higher risk of major bleeding and intracranial hemorrhage compared with clopidogrel. Overall, prasugrel provided the most favorable balance between efficacy and safety among the 3 oral P2Y₁₂ inhibitors evaluated.

Find this article online at JAMA Cardiol.

References

1. 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. Circulation. 2025;151(13):e771-e862. doi:10.1161/CIR.0000000000001309
2. Byrne  RA, Rossello  X, Coughlan  JJ,  et al; ESC Scientific Document Group.  2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826. doi:10.1093/eurheartj/ehad191
3. Schüpke  S, Neumann  FJ, Menichelli  M,  et al; ISAR-REACT 5 Trial Investigators.  Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381(16):1524-1534. doi:10.1056/NEJMoa1908973
4. Bangalore  S. TUXEDO-2: ticagrelor vs. prasugrel in patients with diabetes and multivessel disease after PCI. Paper presented at: American Heart Association Late Breaking Trials 2025; November 10, 2025; New Orleans, Louisiana. Accessed April 4, 2026. https://www.acc.org/latest-in-cardiology/articles/2025/11/03/16/19/mon-915am-tuxedo-aha-2025
5. Bangalore  S, Sinha  SK, Singh  R,  et al; TUXEDO-2 India Investigators.  Ticagrelor vs prasugrel in patients with diabetes and multivessel coronary artery disease: the TUXEDO-2 randomized clinical trial. JAMA Cardiol. 2026;11(4):369-377. doi:10.1001/jamacardio.2025.5057