Recently we’ve discussed the differences between clopidogrel and prasugrel as antiplatelet medications. However, there are additional medications included in the P2Y12 inhibitor drug class. Today, we’ll be comparing all of the P2Y12 inhibitors: clopidogrel, prasugrel, ticagrelor, and cangrelor. For your convenience, we’ve put together a free PDF of our P2Y12 Comparison Table that is available for download at the end of this post.

The medications in this class work by selectively and irreversibly inhibiting adenosine diphosphate to P2Y12 receptors, leading to decreased platelet aggregation. Reduced platelet aggregation in turn leads to a lowered risk of thrombotic events. Oftentimes, this is particularly helpful post-MI or as prophylaxis during a PCI for an ACS.

Overall, newer agents such as prasugrel, ticagrelor, and cangrelor have fewer drug interactions, fewer gene interactions, and overall improved cardiovascular outcomes. Two well-known trials in ACS patients include the PLATO and TRITON-TIMI trials. PLATO demonstrated the potential benefit of ticagrelor over clopidogrel. TRITON-TIMI demonstrated improved outcomes of prasugrel over clopidogrel. However, prasugrel has been shown to cause higher rates of bleeding. According to a meta-analysis conducted by Briasoulis et al., ticagrelor use is associated with significantly reduced major adverse cardiovascular events, and all-cause mortality, with similar rates of stroke and major bleeding to clopidogrel.

While the efficacy of prasugrel in ACS has been demonstrated to be superior to clopidogrel, two major drawbacks of prasugrel exist. Prasugrel should generally be avoided in patients over 75 years of age and does show up on the Beers list. Patients with a history of TIA or stroke should avoid prasugrel. There are two crucial clinical pearls that I have seen show up on pharmacology and board exams throughout my career. 

The unique clinical pearl regarding ticagrelor involves coadministration with aspirin. Maintenance doses of aspirin greater than 100 mg daily reduce ticagrelor effectiveness. While most cardiologists are well aware of this boxed warning, it may slip by some primary care folks. In addition, I have come across a handful of patients in clinical practice who use aspirin regularly for analgesic purposes. This needs to be reviewed with patients when going over OTC medication use in a patient taking ticagrelor. 

The major benefit to consider with clopidogrel is the cost-benefit and once-daily dosing (ticagrelor is dosed twice daily). Newer agents are more costly in comparison. However, it must be noted that clopidogrel is not recommended in patients that are known to be CYP2C19-poor metabolizers. There are also known interactions between clopidogrel and PPIs that might make newer agents a better choice.

Cangrelor is an interesting agent as it is the only P2Y12 inhibitor that is available as an intravenous solution. Cangrelor has the unique benefit of acting extremely quickly, reaching peak concentrations within 2 minutes and having a rapid offset with a half-life of 3 to 6 minutes. For these reasons, it can play an excellent role in preventing ischemic attacks while patients are undergoing a PCI. Afterward, patients would then need to be transitioned to oral therapy as appropriate.

P2Y12 Comparison Table

	Clopidogrel (Podcast)	Prasugrel (Podcast)	Ticagrelor (Podcast)	Cangrelor
FDA Indications	Thrombosis prophylaxis for STEMI, CVA, MI, NSTEMI post PCI, NSTEMI, peripheral arterial occlusive disease, and post PCI	Thrombosis prophylaxis for ACS post PCI	Acute Coronary Syndrome, Prophylaxis for Ischemic Stroke or TIA with Cerebrovascular Accident, MI, Coronary Arteriosclerosis with High Risk of MI	Thrombosis Prophylaxis for PCI
Usual Dosing in ACS	*ONLY ORALLoading Dose: 300-600 mg Maintenance Dose: 75 mg daily	*ONLY ORALLoading Dose: 30-60 mg Maintenance Dose: 10 mg daily	*ONLY ORAL Loading Dose: 180 mgMaintenance:60-90 mg twice daily	*ONLY IV*30 mcg/kg bolus prior to PCI, followed by 4 mcg/kg/min for 2 hours or length of PCI, whichever is longer
Contraindications	Active bleeding, Hypersensitivity	Active bleeding, Hypersensitivity, History of stroke or TIA	History of intracranial hemorrhage, Active bleeding, Hypersensitivity	Significant Active Bleeding, Hypersensitivity
Adverse Effects	Hemorrhage – both non-major and major, Pancytopenia, Hepatotoxicity	Hypertension, Nose bleeds, Atrial Fibrillation, Hemorrhage	Hemorrhage, Increased serum creatinine, dyspnea, Bradyarrhytmia	Hemorrhage
Beers List Criteria	Not on the Beers List.	On Beers List: Use caution in patients 75 years or older due to increased risk of bleeding. Risk versus benefit consideration is necessary.	Not on the Beers List.	Not on the Beers List.
Other Notes:	CYP2C19 metabolism is prominent.	Black Box Warning: Bleeding	Black Box Warning: Bleeding Maintenance doses of aspirin greater than 100 mg daily reduce ticagrelor effectiveness.	Avoid use with clopidogrel or prasugrel.

Comparison Table – Free Download

This article was written by Jordan Erkel, PharmD Candidate in Collaboration with Eric Christianson, PharmD, BCPS, BCGP

References:

Wiviott, S. D., Braunwald, E., McCabe, C. H., Montalescot, G., Ruzyllo, W., Gottlieb, S., … & Antman, E. M. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 357(20), 2001-2015.

Jackson, L. R., Ju, C., Zettler, M., Messenger, J. C., Cohen, D. J., Stone, G. W., … & Wang, T. Y. (2015). Outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a comparison of clopidogrel versus prasugrel from the TRANSLATE-ACS study. JACC: Cardiovascular Interventions, 8(14), 1880-1889.

Lee, C. R., Luzum, J. A., Sangkuhl, K., Gammal, R. S., Sabatine, M. S., Stein, C. M., … & Shuldiner, A. R. (2022). Clinical pharmacogenetics implementation consortium guideline for CYP2C19 genotype and clopidogrel therapy: 2022 update. Clinical Pharmacology & Therapeutics.

Prasugrel [package insert]. Accord Healthcare Durham, NC, Revised 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd6bf899-06b7-4f52-96c5-ffc94a7288ff. Accessed: 11/14/2022.

Clopidogrel [package insert]. Accord Healthcare Durham, NC, Revised 2022.https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8b84d00e-9aac-4da2-b9aa-17e5ddf9b922. Accessed: 11/14/2022.

Clopidogrel Hydrogen Sulfate. IBM Micromedex ® Drug Summary [online]. Updated periodically. IBM Watson Health, Greenwood Village, Colorado, USA. Accessed at: https://www-micromedexsolutions-com.ezp3.lib.umn.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=topHome&isToolPage=true#. Accessed: 11/15/22.

Ticagrelor [package insert]. Amneal Pharmaceuticals: Bridgewater, NJ, 2020. Accessed at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cee944f-e2ca-4fc8-bb97-f46ca28728c5. Accessed: 12/13/2022.

Kengreal [package insert]. Chiesi USA: Cary, NC, 2022. Accessed at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=88b434fa-8891-4fd5-9d86-7ea64667c08f. Accessed: 12/13/2022.

Briasoulis, A., Telila, T., Palla, M., Siasos, G., & Tousoulis, D. (2016). P2Y12 Receptor Antagonists: Which One to Choose? A Systematic Review and Meta-Analysis. Current pharmaceutical design, 22(29), 4568–4576.

De Luca, L., Steg, P. G., Bhatt, D. L., Capodanno, D., & Angiolillo, D. J. (2021). Cangrelor: Clinical Data, Contemporary Use, and Future Perspectives. Journal of the American Heart Association, 10(13), e022125.