Similar risk of NACE when comparing two P2Y12 inhibitors in patients with ACS after PCI

Association of Ticagrelor vs Clopidogrel With Net Adverse Clinical Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Literature - You SC, Rho Y, Bikdeli B, et al. - JAMA. 2020;324(16):1640-1650. doi:10.1001/jama.2020.16167

Introduction and methods

The P2Y12 inhibitor ticagrelor is a more potent platelet inhibitor than clopidogrel [1]. Guidelines from the ACC, AHA, ESC, and EACTS recommend ticagrelor in combination with aspirin for patients with acute coronary syndrome (ACS) [2,3]. The recommendations are based on the PLATO-trial, which demonstrated that ticagrelor had a more profound effect in patients with ACS compared to clopidogrel [4-7]. However, in this trial the efficacy of ticagrelor was not observed in patients from North-America and Asia [8]. Also safety concerns in regards to ticagrelor-induced dyspnea and increased hemorrhagic events observed with use of ticagrelor in routine practice have been raised [9].

This study assessed the association of ticagrelor (n=31,290) compared to clopidogrel (n=31,290) with clinical outcomes in patients from the United States and South-Korea diagnosed with ACS who underwent PCI.

This retrospective cohort study used the electronic health record (EHR)-based databases, US Optum EHR (n=32,828) and US IQVIA Hospital (n=7996) from the United States and the nationwide claims database Health Insurance Review and Assessment service (HIRA; n=21,756) from South-Korea. Adult patients (≥20 years) who underwent PCI for the first time after an ACS diagnosis were selected for the study. The index date was the date of PCI. Patients were matched using a large-scale propensity score algorithm resulting in 31,290 matched pairs. The primary outcome was net adverse clinical events (NACE) that included ischemic events (recurrent acute MI, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding) from the index date to 1 year after PCI. Secondary outcomes were a broader definition of NACE (NACE or mortality), all-cause mortality, composite ischemic events, composite hemorrhagic events, and individual outcomes from the primary endpoint within 1 year. The 1-year risk of dyspnea was also evaluated. A post-hoc analysis for CV-related mortality and MACE (CV mortality, recurrent acute MI, and stroke) was conducted using only the US Optum EHR and South-Korean HIRA databases. Follow-up period was from November 2011 to March 2019.

Main results

  • The 1-year incidence of NACE in patients with ACS who underwent PCI was 15.1% (3484/23116 person-years) in the ticagrelor group compared to 14.6% (3290/22587 person-years) in the clopidogrel group (HR 1.05, 95% CI: 1.00-1.10, P=0.06).
  • The incidence rate of NACE or mortality was comparable between patients treated with ticagrelor or clopidogrel (16.8% vs. 16.6%, respectively, HR 1.03, 95% CI: 0.98-1.08). There were also no differences observed in the risk for an ischemic event, ischemic stroke, acute MI, revascularization, or all-cause mortality.
  • Patients treated with ticagrelor had, compared to patients receiving clopidogrel, a significantly higher risk of an hemorrhagic event (HR 1.35, 95% CI: 1.13-1.61, P=0.001), hemorrhagic stroke (HR 1.60, 95% CI: 1.10-2.33, P=0.01), or gastrointestinal bleeding (HR 1.32, 95% CI: 1.05-1.66, P=0.02).
  • The 1-year risk of dyspnea was significantly increased in patients treated with ticagrelor compared to those on clopidogrel (HR 1.21, 95% CI: 1.17-1.26, P<0.001).
  • There was no difference in CV-related mortality (HR 0.98, 95% CI: 0.76-1.26) and MACE (HR 1.05, 95% CI: 0.90-1.22) between the ticagrelor and clopidogrel groups.


Risk of NACE in patients using ticagrelor was comparable to that in patients on clopidogrel among patients from the US and South-Korea, who underwent a first time PCI after ACS diagnosis. Patients on ticagrelor had a higher risk of an hemorrhagic stroke or gastrointestinal bleeding and dyspnea compared to patients using clopidogrel.


1. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585. doi:10.1161/CIRCULATIONAHA.109.912550

2. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68(10):1082-1115. doi:10.1016/j.jacc.2016.03.513

3. Valgimigli M, Bueno H, Byrne RA, et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213-260. doi:10.1093/eurheartj/ehx419

4. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. doi:10.1056/NEJMoa0904327

5. Yudi MB, Clark DJ, Farouque O, et al; Melbourne Interventional Group. Clopidogrel, prasugrel or ticagrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention. Intern Med J. 2016;46(5):559-565. doi:10.1111/imj.13041

6. Sahlén A, Varenhorst C, Lagerqvist B, et al. Contemporary use of ticagrelor in patients with acute coronary syndrome: insights from Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Eur Heart J Cardiovasc Pharmacother. 2016;2(1):5-12. doi:10.1093/ehjcvp/pvv034

7. Dayoub EJ, Seigerman M, Tuteja S, et al. Trends in platelet adenosine diphosphate P2Y12 receptor inhibitor use and adherence among antiplatelet-naive patients after percutaneous coronary intervention, 2008-2016. JAMA Intern Med. 2018;178(7):943-950. doi:10.1001/jamainternmed.2018.0783

8. Mahaffey KW,Wojdyla DM, Carroll K, et al; PLATO Investigators. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124(5):544-554. doi:10.1161/CIRCULATIONAHA.111.047498

9. Turgeon RD, Koshman SL, Youngson E, et al. Association of ticagrelor vs clopidogrel with major adverse coronary events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. JAMA Intern Med. 2020;180(3):420-428. doi:10.1001/jamainternmed.2019.6447

Find this article online at JAMA

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