What is the role of ticagrelor (ticagrelor) in patients with clopidogrel (clopidogrel) resistance in ischemic stroke?

Role of Ticagrelor in Clopidogrel Resistance for Ischemic Stroke

Ticagrelor is recommended as an effective alternative antiplatelet therapy for patients with ischemic stroke who demonstrate clopidogrel resistance, particularly in those with CYP2C19 loss-of-function alleles, as it provides more consistent platelet inhibition and reduces the risk of recurrent stroke compared to clopidogrel.

Mechanism and Clinical Rationale

• Ticagrelor is a direct-acting, reversible P2Y12 receptor antagonist with more rapid onset and more consistent inhibition of platelet aggregation compared to clopidogrel, which is a prodrug requiring metabolism by the cytochrome P450 enzyme system 1, 2
• Clopidogrel resistance, often due to CYP2C19 loss-of-function alleles, can lead to inadequate platelet inhibition and increased risk of recurrent ischemic events 3
• Unlike clopidogrel, ticagrelor does not require metabolic activation, making it effective in patients with genetic polymorphisms affecting clopidogrel metabolism 2, 3

Evidence Supporting Ticagrelor in Clopidogrel Resistance

• The CHANCE-2 trial demonstrated that among patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, ticagrelor plus aspirin significantly reduced the risk of recurrent stroke at both 90 days and 1 year compared to clopidogrel plus aspirin (HR 0.80; 95% CI 0.68-0.95; p=0.007) 3
• A 2023 meta-analysis showed that ticagrelor was superior to clopidogrel or aspirin in reducing the risk of subsequent stroke in patients with a history of acute ischemic stroke or TIA (HR 0.79; 95% CI 0.71-0.89, p<0.0001) 4
• In patients with atherosclerotic stenosis, the SOCRATES subgroup analysis found ticagrelor to be superior to aspirin in preventing stroke, myocardial infarction, or death at 90 days (HR 0.68; 95% CI 0.53-0.88; p=0.003) 5

Dosing Recommendations

• For patients switching from clopidogrel to ticagrelor due to resistance, a loading dose of 180 mg ticagrelor is recommended, followed by 90 mg twice daily 1
• When used with ticagrelor, the aspirin maintenance dose should be limited to ≤100 mg daily (preferably 81 mg) to optimize efficacy and minimize bleeding risk 1, 2

Safety Considerations and Contraindications

• Ticagrelor is associated with an increased risk of non-CABG major bleeding compared to clopidogrel 1, 6
• Ticagrelor is contraindicated in patients with a history of intracranial hemorrhage 2
• Special caution is needed in:
  • Patients ≥75 years of age 1
  • Patients with low body weight (<60 kg) 1
  • Patients with prior stroke or TIA who may have increased risk of intracranial bleeding 2

Duration of Therapy

• For patients with ischemic stroke receiving ticagrelor due to clopidogrel resistance, treatment should typically be continued for at least 90 days based on clinical trial evidence 6, 3
• The CHANCE-2 trial showed continued benefit at 1 year, suggesting potential value in longer treatment for high-risk patients 3

Practical Considerations

• Ticagrelor requires twice-daily dosing, which may affect patient adherence compared to once-daily clopidogrel 1, 2
• Ticagrelor should be discontinued at least 5 days before planned surgical procedures to reduce bleeding risk 1, 2
• Patients should be monitored for dyspnea, which is a known side effect of ticagrelor 1

Algorithm for Decision-Making

1. Identify clopidogrel resistance:

   • Consider genetic testing for CYP2C19 loss-of-function alleles in high-risk patients 3
   • Evaluate for recurrent ischemic events despite clopidogrel therapy 4

2. Assess patient risk factors:

   • Check for contraindications (history of intracranial hemorrhage) 2
   • Evaluate bleeding risk (age ≥75, weight <60 kg, prior bleeding) 1

3. Initiate ticagrelor therapy:

   • Loading dose: 180 mg 1
   • Maintenance: 90 mg twice daily 1
   • If used with aspirin, limit aspirin to 81 mg daily 1, 2

4. Monitor for:

   • Bleeding complications 6
   • Dyspnea 1
   • Medication adherence (twice-daily dosing) 1, 2