An Efficacy and Safety Comparison of Oral P2Y Inhibitors

An Efficacy and Safety Comparison of Oral P2Y12 Inhibitors
Alexandra Vecchia, Pharm.D., M Health Fairview

Background: Oral P2Y12 inhibitors are a key component of antiplatelet therapy after acute coronary syndromes (ACS). The three commonly used agents, clopidogrel, prasugrel, and ticagrelor, function by binding to the P2Y12 receptor on platelets and inhibiting adenosine diphosphate platelet activation. Although these agents produce the same result, there are key differences between them. Clopidogrel irreversibly inhibits P2Y12, but it must be converted to its active metabolite. This conversion primarily occurs via CYP2C19 which leads to patient-to-patient variability and drug-drug interactions. Prasugrel is also a prodrug whose active metabolite irreversibly inhibits P2Y12. However, its conversion is primarily driven by CYP3A4 and CYP2B6, and inter-person variability is of less concern than with clopidogrel. Finally, ticagrelor is a reversible inhibitor that does not require CYP450 activation. The 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes recommends that either clopidogrel or ticagrelor be added to aspirin for up to 12 months in medically treated patients, with a slight preference given to ticagrelor. If coronary stenting is performed, all three agents are reasonable options although a slight preference is given to ticagrelor and prasugrel.

Objective: This network meta-analysis aimed to compare the efficacy and safety of clopidogrel, prasugrel, and ticagrelor in patients with ACS.

Study Design: Investigators performed a search of Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, TCTMD,, and major congress proceedings to identify randomized trials of clopidogrel, prasugrel, and ticagrelor in patients with ACS published prior to October 19, 2019. Trials were included if they reported cardiovascular (CV) outcomes and followed patients beyond 30 days. Nonrandomized, crossover, and pharmacokinetic/pharmacodynamic trials were excluded. A network meta-analysis was completed to compare the three agents using evidence from direct comparisons trials as well as indirect evidence generated from multiple trials with one common intervention. The primary outcomes included CV mortality, myocardial infarction (MI), stroke, definite or probable stent thrombosis (ST), and major bleeding.

Results: The search led to the inclusion of 12 trials with a total of 52,816 patients. Ticagrelor significantly lowered CV mortality when compared to clopidogrel (HR 0.82 [95% CI 0.72 – 0.92]). However, prasugrel was not found to be significantly different from clopidogrel (HR 0.90 [95% CI 0.80 – 1.01]). Prasugrel and ticagrelor were not significantly different (HR 1.10 [95% CI 0.94 – 1.29]). Prasugrel significantly reduced MI events when compared to clopidogrel (HR 0.81 [95% CI 0.67 – 0.98]), but prasugrel and ticagrelor were not significantly different (HR 0.83 [95% CI 0.64 – 1.07]). Ticagrelor did not significantly reduce MI events in comparison with clopidogrel (HR 0.97 [95% CI 0.78 – 1.22]). However, when assessing only re-MI (excluding periprocedural MI), ticagrelor did significantly reduce events when compared to clopidogrel (HR 0.85 [95% CI 0.73 – 0.98]). Ticagrelor significantly reduced occurrence of definite or probable ST when compared to clopidogrel (HR 0.72 [95% CI 0.58 – 0.90]) as did prasugrel (HR 0.50 [95% CI 0.38 – 0.64]). Prasugrel significantly reduced occurrence of ST compared to ticagrelor (HR 0.68 [95% CI 0.50 – 0.93]). There were no significant differences between ticagrelor, prasugrel, or clopidogrel regarding the outcome of total strokes, hemorrhagic strokes, or ischemic strokes. In the safety analysis, both prasugrel (HR, 1.26 [95% CI, 1.01–1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04–1.55]) resulted in significantly more major bleeding events than clopidogrel, but no difference was found between prasugrel and ticagrelor (HR 0.99 [95% CI 0.79-1.24]). 

Conclusions: This large network meta-analysis suggests that ischemic events may be reduced by using ticagrelor or prasugrel rather than clopidogrel. However, only ticagrelor significantly reduced CV mortality in comparison to clopidogrel. These benefits are offset by an increase in major bleeding events that was seen with both ticagrelor and prasugrel. One limitation of this study is a high level of heterogeneity that was found in the analysis of MI (I2=58.7%) and a moderate level of heterogeneity that was found in the analysis of major bleeding (I2=35.3%).

Key Point: Although ticagrelor and prasugrel may provide superior efficacy to clopidogrel, both agents led to significantly more major bleeding events. These findings are consistent with the 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes.


  1. Navarese EP, Khan SU, Kolodziejczak M, et al. Comparative efficacy and safety of oral P2Y12 inhibitors in acute coronary syndrome: network meta-analysis of 52,816 patients from 12 randomized trials. Circulation. 2020;142(2):150-160. doi:10.1161/CIRCULATIONAHA.120.046786.

  1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139–e228. doi:10.1016/jjacc.2014.09.017.