Which P2Y12 (purinergic receptor P2Y12) inhibitor has the least bleeding risk?

From the Guidelines

Among the P2Y12 inhibitors, clopidogrel generally has the least bleeding risk compared to prasugrel and ticagrelor. Clopidogrel (typically dosed at 75 mg daily after a 300-600 mg loading dose) is associated with lower rates of major bleeding events while still providing effective platelet inhibition, as seen in the TRITON-TIMI 38 study 1 and the PLATO trial 1. This reduced bleeding risk is due to clopidogrel's more moderate antiplatelet effect compared to the more potent P2Y12 inhibitors. The trade-off is that clopidogrel has a slower onset of action and provides less consistent platelet inhibition due to genetic variability in its metabolism. Some patients are "poor metabolizers" who convert less of the prodrug to its active form. For patients at high bleeding risk but requiring antiplatelet therapy, clopidogrel is often preferred, particularly in elderly patients, those with low body weight, prior bleeding history, or requiring concomitant anticoagulation.

Key Considerations

• The 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease recommends using ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy in patients with ACS, but notes that prasugrel should not be administered to patients with a prior history of stroke or TIA due to increased bleeding risk 1.
• The choice between P2Y12 inhibitors should balance the individual patient's thrombotic risk against their bleeding risk, with clopidogrel representing the safest option from a bleeding perspective.
• It's worth noting that a lower dose of ticagrelor (60 mg twice daily) may have a more favorable benefit/risk ratio compared to the higher dose (90 mg twice daily), as seen in the PEGASUS-TIMI 54 study 1. However, clopidogrel still has the least bleeding risk among the P2Y12 inhibitors.

Patient-Specific Factors

• Elderly patients
• Patients with low body weight
• Prior bleeding history
• Requiring concomitant anticoagulation These factors should be taken into consideration when choosing a P2Y12 inhibitor, with clopidogrel being the preferred option for patients at high bleeding risk.

From the FDA Drug Label

5 WARNINGS AND PRECAUTIONS

5.1 Bleeding Drugs that inhibit platelet P2Y12 function, including KENGREAL, increase the risk of bleeding. In CHAMPION PHOENIX bleeding events of all severities were more common with KENGREAL than with clopidogrel [see Adverse Reactions (6.1)].

• The FDA drug label for cangrelor (KENGREAL) does not provide a direct comparison of bleeding risk with other P2Y12 inhibitors.
• Bleeding risk is increased with KENGREAL compared to clopidogrel.
• The label does not identify a specific P2Y12 inhibitor with the least bleeding risk 2. The FDA drug label does not answer the question.

From the Research

P2Y12 Inhibitors and Bleeding Risk

• The available evidence suggests that cangrelor, an intravenously administered P2Y12 receptor antagonist, may have a lower bleeding risk compared to other P2Y12 inhibitors 3.
• In the CHAMPION PHOENIX trial, cangrelor provided improved anti-ischemic protection compared with clopidogrel, without increasing the risk of severe bleeding 3.
• Cangrelor's rapid and reversible action may contribute to its lower bleeding risk, as it can be quickly discontinued if bleeding occurs 4.

Comparison of P2Y12 Inhibitors

• Ticagrelor, a reversible P2Y12 inhibitor, has been shown to have a faster and more consistent antiplatelet effect compared to clopidogrel, but its bleeding risk is not directly compared to cangrelor in the available evidence 5, 4.
• Prasugrel, an irreversible P2Y12 inhibitor, has a faster and more consistent antiplatelet effect compared to clopidogrel, but its bleeding risk is not directly compared to cangrelor in the available evidence 4, 6.
• The available evidence does not provide a direct comparison of the bleeding risks of all P2Y12 inhibitors, including cangrelor, ticagrelor, and prasugrel 5, 3, 4, 6, 7.

Clinical Considerations

• The choice of P2Y12 inhibitor should be based on individual patient characteristics, clinical presentation, and treatment goals, as well as the potential for drug-drug interactions and bleeding risk 5, 4, 6.
• Clinicians should consider the pharmacokinetic and pharmacodynamic properties of each P2Y12 inhibitor when selecting a treatment regimen and monitoring patients for bleeding complications 4, 7.