In a patient with an ischemic stroke or transient ischemic attack that occurred more than five years ago, is clopidogrel the preferred P2Y12 inhibitor after PCI for acute coronary syndrome, and are prasugrel and ticagrelor contraindicated?

Prior Stroke/TIA and Clopidogrel Use After PCI for ACS

In patients with acute coronary syndrome undergoing PCI who have a history of stroke or TIA—regardless of how remote—clopidogrel is the mandatory P2Y12 inhibitor choice, and prasugrel is absolutely contraindicated with no time limitation on the stroke/TIA history. 1

Prasugrel: Absolute Contraindication

• Prasugrel should not be administered to any patient with a history of stroke or TIA, regardless of when it occurred (Class III: Harm recommendation). 1
• This contraindication applies to all prior ischemic strokes or TIAs, with no temporal exclusion—a stroke 5 years ago, 10 years ago, or 20 years ago all constitute absolute contraindications. 1
• The evidence base demonstrates that prasugrel increases cerebrovascular bleeding events and worsens net clinical outcomes in this population, leading to the FDA black-box warning and guideline prohibition. 2, 3

Ticagrelor: Safe and Effective Alternative

• Ticagrelor remains a valid and preferred option over clopidogrel even in patients with remote stroke/TIA history (Class IIa recommendation). 1
• The PLATO trial specifically evaluated 1,152 ACS patients with prior stroke/TIA and found that ticagrelor versus clopidogrel showed consistent efficacy (hazard ratio 0.87 for the primary composite outcome) and similar bleeding rates (14.6% vs 14.9%), with only 4 intracranial bleeds in each arm. 4
• Among patients with prior stroke/TIA, ticagrelor reduced total mortality compared to clopidogrel (7.9% vs 13.0%; hazard ratio 0.62), demonstrating a favorable net clinical benefit. 4
• Ticagrelor is contraindicated only in patients with prior intracranial hemorrhage or ongoing active bleeding—a history of ischemic stroke or TIA does not preclude its use. 3, 1

Clopidogrel: Default When Potent P2Y12 Inhibitors Are Contraindicated

• Clopidogrel (600 mg loading dose, then 75 mg daily) is recommended when ticagrelor or prasugrel are unavailable, not tolerated, or contraindicated. 1
• For patients with prior stroke/TIA who cannot receive ticagrelor (e.g., due to prior intracranial hemorrhage), clopidogrel becomes the only viable P2Y12 inhibitor option. 3

Clinical Decision Algorithm for ACS Patients with Prior Stroke/TIA

Step 1: Determine stroke/TIA type and timing

• If prior intracranial hemorrhage → Use clopidogrel only; both ticagrelor and prasugrel are contraindicated. 3
• If prior ischemic stroke or TIA (any timeframe) → Proceed to Step 2.

Step 2: Select P2Y12 inhibitor

• First-line: Ticagrelor 180 mg loading, then 90 mg twice daily (superior efficacy, similar bleeding to clopidogrel in this population). 4, 1
• Second-line: Clopidogrel 600 mg loading, then 75 mg daily (if ticagrelor unavailable or not tolerated). 1
• Never use: Prasugrel—absolute contraindication regardless of stroke/TIA timing. 1

Step 3: Maintain DAPT for 12 months

• Continue aspirin 75-100 mg daily plus the selected P2Y12 inhibitor for 12 months unless high bleeding risk warrants shortening to 6 months. 1
• Prescribe a proton pump inhibitor to all patients on DAPT (Class I recommendation). 3, 1

Common Pitfalls to Avoid

• Never assume that a remote stroke history (>5 years) makes prasugrel acceptable—the contraindication has no temporal limitation and applies to all prior strokes/TIAs. 1
• Do not confuse ischemic stroke with intracranial hemorrhage—ticagrelor is safe after ischemic stroke but contraindicated after intracranial hemorrhage. 3, 4
• Do not discontinue DAPT within the first 30 days after stent placement in any patient, as this dramatically increases stent thrombosis risk. 3, 1
• Do not use aspirin doses >100 mg daily with ticagrelor, as higher doses diminish ticagrelor's antiplatelet efficacy. 3

Evidence Strength and Nuances

The prohibition against prasugrel in stroke/TIA patients is based on the TRITON-TIMI 38 trial, which demonstrated net clinical harm in this subgroup, leading to consistent Class III (Harm) recommendations across all major guidelines. 1, 2 In contrast, the PLATO trial's prespecified subgroup analysis of 1,152 patients with prior stroke/TIA provides robust evidence that ticagrelor maintains its efficacy advantage over clopidogrel without excess intracranial bleeding in this high-risk population. 4 The 2021 ACC/AHA/SCAI and 2020 ESC guidelines both explicitly state that prior stroke/TIA is not a contraindication to ticagrelor, only to prasugrel. 1