For an adult with acute coronary syndrome undergoing percutaneous coronary intervention and no contraindications, which P2Y12 inhibitor—ticagrelor, prasugrel, or clopidogrel—is the most appropriate choice?

P2Y12 Inhibitor Selection in Acute Coronary Syndrome with PCI

For adults with acute coronary syndrome undergoing percutaneous coronary intervention without contraindications, ticagrelor (180 mg loading, then 90 mg twice daily) or prasugrel (60 mg loading, then 10 mg daily) should be used instead of clopidogrel, with ticagrelor preferred as first-line therapy. 1, 2

First-Line Agent: Ticagrelor

Ticagrelor is the preferred P2Y12 inhibitor for all ACS patients undergoing PCI because it reduces major adverse cardiovascular events (MACE), stent thrombosis, and all-cause mortality compared to clopidogrel. 1, 2, 3

Dosing Protocol

• Loading dose: 180 mg orally immediately upon ACS diagnosis, before any invasive procedure 1, 3
• Maintenance dose: 90 mg twice daily for 12 months 1, 3
• Critical aspirin interaction: Maintain aspirin at 75-100 mg daily (never exceed 100 mg) because higher aspirin doses reduce ticagrelor's effectiveness 1, 3

Evidence Supporting Ticagrelor

The most recent 2025 ACC/AHA/SCAI guidelines give ticagrelor a Class I recommendation for all ACS patients undergoing PCI, regardless of ST-elevation status. 1 Ticagrelor reduces all-cause mortality by 1.4% absolute risk reduction compared to clopidogrel (4.5% vs 5.9%, P<0.001) at 12 months. 3 Real-world data from 10,793 consecutive ACS patients demonstrated ticagrelor reduced mortality (adjusted HR 0.82,95% CI 0.71-0.96, p=0.01) and stent thrombosis (0.6% vs 1.1%, adjusted HR 0.51, p=0.03) compared to clopidogrel. 4

Second-Line Agent: Prasugrel

Prasugrel is an acceptable alternative to ticagrelor for P2Y12 inhibitor-naïve patients with known coronary anatomy proceeding to PCI. 1

Dosing Protocol

• Loading dose: 60 mg orally at the time of PCI (not before coronary anatomy is known) 1
• Maintenance dose: 10 mg daily for 12 months 1

When to Choose Prasugrel Over Ticagrelor

• Patient cannot tolerate ticagrelor (e.g., dyspnea occurs in 10-15% of ticagrelor patients) 3
• Ticagrelor is unavailable 1
• Patient preference after informed discussion of equivalent efficacy 1

Absolute Contraindications to Prasugrel

Never administer prasugrel to patients with prior stroke or transient ischemic attack because it increases cerebrovascular bleeding and worsens net clinical outcomes. 1, 2 This is a Class III (Harm) recommendation. 1

Additional Prasugrel Cautions

• Age ≥75 years (higher bleeding risk) 1
• Body weight <60 kg (higher bleeding risk) 1
• Do not give prasugrel before coronary anatomy is known (Class III recommendation) 1

Third-Line Agent: Clopidogrel

Clopidogrel should only be used when both ticagrelor and prasugrel are unavailable, cannot be tolerated, or are contraindicated. 1, 2 This represents suboptimal care for ACS patients. 2

Dosing Protocol

• Loading dose: 600 mg orally 1
• Maintenance dose: 75 mg daily 1

Why Clopidogrel is Inferior

Clopidogrel has delayed onset of action, large response variability, and insufficient antiplatelet action in some patients (hyporesponders). 5, 6 It requires hepatic biotransformation to form its active metabolite, resulting in pharmacodynamic variability that increases risk of MACE and stent thrombosis. 1, 5

When Clopidogrel is Preferred

• Patient requires oral anticoagulation (triple therapy): switch from ticagrelor/prasugrel to clopidogrel because clopidogrel has substantially lower bleeding risk in triple-therapy settings 1, 2, 7
• History of intracranial hemorrhage 1
• Active bleeding or very high bleeding risk 1

Standard Duration and Bleeding Mitigation

Duration of Dual Antiplatelet Therapy

All ACS patients should receive 12 months of DAPT (aspirin plus P2Y12 inhibitor) regardless of stent type, ACS type, or completeness of revascularization. 1, 2 This is a Class I recommendation. 1

For patients with high bleeding risk (PRECISE-DAPT score ≥25), consider shortening DAPT to 6 months. 1

Mandatory Bleeding Risk Reduction

Prescribe a proton pump inhibitor (PPI) to all patients on DAPT to reduce gastrointestinal bleeding risk—this is a Class I recommendation. 2, 7 Use pantoprazole 40 mg daily because it has the lowest propensity for CYP2C19 inhibition and does not interfere with clopidogrel metabolism. 2

Use radial artery access over femoral access for PCI when performed by an experienced radial operator. 2, 7

Critical Pitfalls to Avoid

1. Never discontinue DAPT within the first month after stent placement—this dramatically increases risk of stent thrombosis, myocardial infarction, and death. 1, 2

2. Never use clopidogrel as first-line therapy when ticagrelor or prasugrel are available and not contraindicated—this represents suboptimal care. 2

3. Never fail to prescribe a PPI with DAPT—this simple intervention significantly reduces gastrointestinal bleeding. 2, 7

4. Never administer prasugrel to patients with prior stroke or TIA—this is contraindicated due to increased cerebrovascular bleeding risk. 1, 2

5. Never use aspirin >100 mg daily with ticagrelor—higher aspirin doses reduce ticagrelor's effectiveness. 1, 3

6. Never give prasugrel before coronary anatomy is known—wait until PCI is confirmed. 1

Special Clinical Scenarios

STEMI Managed with Primary PCI

Both ticagrelor and prasugrel are recommended over clopidogrel to reduce MACE and stent thrombosis (Class I recommendation). 1 In the STEMI subgroup, both prasugrel (adjusted HR 0.65, p=0.007) and ticagrelor (adjusted HR 0.70, p=0.05) reduced mortality compared to clopidogrel. 4

NSTE-ACS with Delayed Angiography (>24 hours)

Upstream ticagrelor administration may reduce MACE when angiography is delayed beyond 24 hours. 1 Prasugrel should not be given upstream—wait until coronary anatomy is known. 1

Patients Requiring Oral Anticoagulation

Stop aspirin 1-4 weeks after PCI and switch the P2Y12 inhibitor from ticagrelor/prasugrel to clopidogrel because clopidogrel carries substantially lower bleeding risk in triple-therapy settings. 1, 2, 7

Patients Requiring CABG

Resume P2Y12 inhibitor therapy after CABG to complete 12 months of DAPT. 2 For elective CABG, discontinue ticagrelor at least 5 days before surgery to allow adequate platelet function recovery. 3