What is the difference between P2Y12 inhibitors?

Differences Between P2Y12 Inhibitors

The newer P2Y12 inhibitors prasugrel and ticagrelor provide more rapid, potent, and consistent platelet inhibition than clopidogrel, resulting in reduced major adverse cardiovascular events (MACE) in acute coronary syndrome patients, though with increased bleeding risk. 1

Pharmacological Differences

Mechanism of Action and Metabolism

• Clopidogrel:

  • Prodrug requiring two-step hepatic conversion to active metabolite
  • Irreversibly binds to P2Y12 receptor
  • Significant variability in response due to CYP2C19 genetic polymorphisms
  • Slower onset of action (several hours to maximal effect) 1, 2

• Prasugrel:

  • Prodrug requiring single-step conversion to active metabolite
  • Irreversibly binds to P2Y12 receptor
  • More rapid and consistent conversion to active metabolite than clopidogrel
  • Faster onset (significant effect within 30 minutes) 1, 2

• Ticagrelor:

  • Direct-acting agent (not a prodrug)
  • Reversibly binds to P2Y12 receptor
  • No biotransformation required
  • Rapid onset (significant effect within 30 minutes) 1, 2

Potency and Duration

• Clopidogrel: Least potent, effect lasts 5-7 days
• Prasugrel: More potent than clopidogrel, effect lasts 7-10 days
• Ticagrelor: More potent than clopidogrel, effect lasts 3-5 days (shorter due to reversible binding) 2

Clinical Efficacy and Safety Considerations

Efficacy

• Prasugrel and ticagrelor have demonstrated superior reduction in MACE and stent thrombosis compared to clopidogrel in ACS patients 1
• Clopidogrel remains effective but has more variable response and higher rates of treatment failure 1

Bleeding Risk

• Prasugrel: Highest bleeding risk, especially in:

  • Patients ≥75 years old
  • Patients <60 kg
  • Patients with history of stroke/TIA (contraindicated) 3

• Ticagrelor: Intermediate bleeding risk, but higher than clopidogrel 1

• Clopidogrel: Lowest bleeding risk among the three agents 1

Specific Contraindications and Cautions

• Prasugrel: Contraindicated in patients with:

  • History of stroke or TIA
  • Active pathological bleeding
  • Generally not recommended in patients ≥75 years unless high-risk (diabetes or prior MI) 3

• Ticagrelor:

  • Can cause dyspnea in 10-15% of patients
  • Is a CYP3A4 substrate/inhibitor (multiple drug interactions)
  • Requires twice daily dosing 2

• Clopidogrel:

  • Affected by CYP2C19 genetic polymorphisms
  • Reduced efficacy with certain proton pump inhibitors 4

Perioperative Management

Discontinuation Before Surgery

• Clopidogrel: Discontinue 5 days before elective surgery
• Prasugrel: Discontinue 7 days before elective surgery
• Ticagrelor: Discontinue 3-5 days before elective surgery 1

For urgent surgery, all agents should ideally be interrupted for at least 24 hours if possible 1

Clinical Selection Algorithm

1. For STEMI patients managed with primary PCI:

   • First choice: Prasugrel or ticagrelor (superior efficacy)
   • Second choice: Clopidogrel (if prasugrel/ticagrelor unavailable or contraindicated) 1

2. For NSTE-ACS patients undergoing PCI:

   • First choice: Prasugrel or ticagrelor
   • Second choice: Clopidogrel (if prasugrel/ticagrelor unavailable or contraindicated) 1

3. For NSTE-ACS patients managed medically (without PCI):

   • First choice: Ticagrelor
   • Second choice: Clopidogrel 1

4. For patients with high bleeding risk:

   • First choice: Clopidogrel (lowest bleeding risk)
   • Avoid prasugrel in patients ≥75 years, <60 kg, or with history of stroke/TIA 3

5. For patients with CYP2C19 poor metabolizer status:

   • Avoid clopidogrel
   • Use prasugrel or ticagrelor 4, 5

Common Pitfalls and Caveats

• Genetic variability: CYP2C19 polymorphisms significantly affect clopidogrel efficacy but have minimal impact on prasugrel or ticagrelor 5
• Drug interactions: Ticagrelor has significant interactions with CYP3A4 inhibitors/inducers 2
• Switching between agents: Requires careful consideration of pharmacodynamics to avoid periods of inadequate platelet inhibition 6
• Aspirin dose: When using ticagrelor, aspirin doses should be ≤100 mg daily 1
• Discontinuation risk: Premature discontinuation of any P2Y12 inhibitor increases risk of stent thrombosis, MI, and death 4