What is the difference between Prasugrel and Clopidogrel in patients with a history of cardiovascular disease?

Prasugrel vs Clopidogrel: Key Differences in Cardiovascular Disease

Prasugrel provides superior reduction in cardiovascular death, MI, and stroke compared to clopidogrel (9.9% vs 12.1%, HR 0.81, NNT=46), but carries significantly higher bleeding risk including fatal bleeding (0.4% vs 0.1%), making it contraindicated in patients with prior stroke/TIA and generally not recommended in those ≥75 years or <60 kg. 1, 2

Mechanism and Pharmacology

Prasugrel achieves more potent and consistent platelet inhibition:

• Prasugrel undergoes more efficient prodrug-to-active metabolite conversion, resulting in faster onset (within 60 minutes) and more consistent platelet inhibition compared to clopidogrel's slower, more variable response 3, 4
• Standard dosing: Prasugrel 60 mg loading dose followed by 10 mg daily vs Clopidogrel 300-600 mg loading dose followed by 75 mg daily 1, 2

Efficacy Outcomes from TRITON-TIMI 38

Primary endpoint reduction (cardiovascular death, nonfatal MI, or nonfatal stroke):

• Overall ACS population: 9.9% prasugrel vs 12.1% clopidogrel (HR 0.81, p<0.001) 1
• UA/NSTEMI specifically: 9.9% vs 12.1% (HR 0.82, p=0.002) 1
• STEMI population: 9.8% vs 12.2% (HR 0.81, p=0.019) 1

The benefit was driven primarily by reduction in nonfatal MI:

• Nonfatal MI: 7.3% prasugrel vs 9.5% clopidogrel (HR 0.76, p<0.001) 1
• Stent thrombosis: 1.1% vs 2.4% (50% reduction, p<0.001) 1, 2
• No significant difference in cardiovascular death (2.1% vs 2.4%, p=0.31) or stroke (1.0% vs 1.0%, p=0.93) 1

Bleeding Risk: The Critical Trade-off

Prasugrel significantly increases bleeding complications:

• TIMI major hemorrhage: 2.4% prasugrel vs 1.8% clopidogrel (HR 1.32, NNH=167) 1
• Life-threatening bleeding: 1.4% vs 0.9% (HR 1.52, p=0.01) 1
• Fatal bleeding: 0.4% vs 0.1% (p=0.002) - a four-fold increase 1, 2
• CABG-related major bleeding: 13.4% vs 3.2% (HR 4.73, p<0.001) 1

Absolute Contraindications

Do not use prasugrel in:

• Active pathological bleeding (peptic ulcer, intracranial hemorrhage) 2
• History of TIA or stroke - these patients had net harm with prasugrel (HR 1.54, p=0.04) with stroke rate of 6.5% on prasugrel vs 1.2% on clopidogrel, including 2.3% intracranial hemorrhage 1, 2

High-Risk Populations Requiring Caution

Age ≥75 years:

• Generally not recommended due to increased fatal and intracranial bleeding risk with uncertain benefit (HR 0.99, p=0.92) 1, 5
• Exception: May consider in high-risk elderly with diabetes or prior MI where benefit appears greater 1, 2
• If used, consider reduced 5 mg maintenance dose 5

Body weight <60 kg:

• No net benefit demonstrated (HR 1.03, p=0.89) with increased bleeding risk due to higher drug exposure 1
• Consider 5 mg maintenance dose, though this has not been prospectively studied 2

Timing of Administration

Critical difference in when to give loading dose:

• Prasugrel: Must wait until coronary anatomy is defined (after angiography) in UA/NSTEMI patients 1, 2
• Clopidogrel: Can be given earlier, before angiography 1
• Early prasugrel administration (before PCI) in NSTEMI showed no benefit but increased bleeding risk 1

Surgical Considerations

Pre-operative discontinuation:

• Prasugrel: Discontinue at least 7 days before surgery 5, 2
• Clopidogrel: Discontinue at least 5 days before surgery 1
• Do not start prasugrel in patients likely to undergo urgent CABG 2

Net Clinical Benefit

Overall risk-benefit analysis:

• Net clinical benefit endpoint (death, MI, stroke, or major bleeding): 12.2% prasugrel vs 13.9% clopidogrel (HR 0.87, p=0.004) 1
• This represents a modest overall benefit when balancing efficacy against bleeding risk 1

Clinical Decision Algorithm

Choose prasugrel over clopidogrel when:

• Patient undergoing PCI for ACS with defined coronary anatomy 2
• Age <75 years AND weight ≥60 kg AND no history of stroke/TIA 1, 2
• High thrombotic risk (diabetes, prior MI, prior stent thrombosis) 5

Choose clopidogrel over prasugrel when:

• Age ≥75 years (unless diabetes or prior MI present) 1, 5
• Weight <60 kg 1
• History of stroke or TIA (absolute contraindication for prasugrel) 2
• Active bleeding or high bleeding risk 2
• Need for early antiplatelet therapy before angiography 1
• Planned or likely urgent CABG 2