What are the differences between prasugrel, ticagrelor, and clopidogrel?

Differences Between Prasugrel, Ticagrelor, and Clopidogrel

All three are P2Y12 inhibitors used to prevent platelet aggregation in acute coronary syndromes, but prasugrel and ticagrelor provide superior reduction in cardiovascular events compared to clopidogrel, at the cost of increased bleeding risk. 1

Mechanism of Action and Pharmacokinetics

Clopidogrel

• Irreversibly binds to the P2Y12 receptor as a thienopyridine prodrug 2
• Requires two-step hepatic conversion via CYP450 enzymes to its active metabolite 1
• Delayed onset of action with peak effect occurring hours after loading 2
• Exhibits significant interpatient variability due to CYP2C19 genetic polymorphisms, creating "hyporesponders" at higher risk for adverse cardiovascular events 2, 3
• Proton pump inhibitors may interfere with its metabolism 1

Prasugrel

• Irreversibly binds to the P2Y12 receptor as a thienopyridine prodrug 1
• Requires only single-step hepatic conversion via CYP450 enzymes 1
• Achieves more rapid onset with peak active metabolite concentrations within 30 minutes 1
• Provides more consistent and complete platelet inhibition than clopidogrel 1
• No evidence that CYP2C19 polymorphisms or proton pump inhibitors interfere with its metabolism 1

Ticagrelor

• Reversibly and directly binds to the P2Y12 receptor without requiring metabolic activation 1
• Achieves platelet inhibition within 30 minutes of administration 2
• Has a plasma half-life of 12 hours, requiring twice-daily dosing 1
• Provides faster recovery of platelet function after discontinuation due to reversible binding 1
• No interpatient variability related to genetic polymorphisms 2, 4

Clinical Efficacy in Acute Coronary Syndromes

Prasugrel vs. Clopidogrel

• In the TRITON-TIMI 38 trial (13,608 ACS patients undergoing PCI), prasugrel reduced the composite endpoint (cardiovascular death, MI, stroke) from 12.1% to 9.9% (HR 0.81, p<0.001) 1
• The benefit was driven primarily by reduction in nonfatal MI (9.5% to 7.3%, p<0.001) 1
• Stent thrombosis was reduced from 2.4% to 1.1% (p<0.001) 1
• No significant reduction in cardiovascular death (2.4% vs 2.1%, p=0.31) or stroke 1
• Greatest benefits occurred in ST-elevation MI patients and those with diabetes 1

Ticagrelor vs. Clopidogrel

• In the PLATO trial (18,624 ACS patients), ticagrelor reduced the composite endpoint (vascular death, MI, stroke) from 11.7% to 9.8% (HR 0.84, p<0.001) 1
• All-cause mortality was reduced with ticagrelor 1
• Benefit was consistent in both invasively and medically managed patients 1
• Ticagrelor was studied in "all-comer" ACS patients, not limited to those undergoing PCI 1

Prasugrel vs. Ticagrelor (Indirect Comparison)

• No significant differences in major efficacy outcomes in head-to-head comparison terminated early for futility 1
• Network meta-analysis suggests prasugrel may reduce stent thrombosis more effectively than ticagrelor (OR 0.63,95% CI 0.42-0.94) 5
• In patients with high on-clopidogrel platelet reactivity, ticagrelor produces significantly higher platelet inhibition than prasugrel (32.9 vs 101.3 PRU, p<0.001) 6, 7

Bleeding Risk Profile

Clopidogrel

• Lowest bleeding risk among the three agents 1, 2
• TIMI major or minor non-CABG bleeding: 3.4% 1, 8

Prasugrel

• Highest bleeding risk with FDA boxed warning 1
• TIMI major or minor non-CABG bleeding: 4.5% (vs 3.4% for clopidogrel, p<0.001) 1, 8
• Fatal bleeding increased (0.4% vs 0.1% for clopidogrel, p=0.002) 1, 8
• Life-threatening bleeding increased (1.3% vs 0.8% for clopidogrel) 8
• CABG-related major bleeding: 11.3% (vs 3.6% for clopidogrel) 8
• Particularly high bleeding risk in patients ≥75 years (9.0% vs 6.9% for clopidogrel) and <60 kg body weight (10.1% vs 6.5% for clopidogrel) 8

Ticagrelor

• Intermediate bleeding risk between clopidogrel and prasugrel 5, 9
• Overall major bleeding not significantly increased compared to clopidogrel 1
• Non-procedure-related major bleeding: 3.1% (vs 2.3% for clopidogrel, p=0.05) 1
• Network meta-analysis shows less major or minor bleeding than prasugrel (OR 0.81,95% CI 0.69-0.96) 5

Unique Side Effects and Contraindications

Clopidogrel

• Thrombotic thrombocytopenic purpura (TTP) is rare but serious, typically occurring within first 2 weeks 3

Prasugrel

• Contraindicated in patients with prior stroke or TIA due to net harm (increased bleeding without benefit) 1
• No net clinical benefit in patients ≥75 years or <60 kg body weight 1
• FDA approval includes boxed warning for bleeding risk 1

Ticagrelor

• Dyspnea occurs in 10-15% of patients within first week, rarely severe enough to cause discontinuation 1, 2
• Bradycardia and ventricular pauses ≥3 seconds may occur, though largely asymptomatic 1, 2
• Benefit over clopidogrel limited to patients taking 75-100 mg aspirin; no benefit seen with higher aspirin doses in US subgroup 1

Guideline Recommendations

ACC/AHA Guidelines

• Class IIa recommendation for ticagrelor or prasugrel preferred over clopidogrel in ACS 1, 2
• Prasugrel should only be administered after coronary anatomy is defined and decision to proceed with PCI is made 1
• Ticagrelor can be given upfront to all ACS patients regardless of management strategy 1

ESC Guidelines

• Class I recommendation for ticagrelor or prasugrel preferred over clopidogrel in ACS 1
• Stronger recommendation than ACC/AHA guidelines 1

When to Choose Each Agent

Choose Clopidogrel When:

• Patient has prior stroke or TIA (prasugrel contraindicated) 1, 2
• Patient has high bleeding risk 1, 2, 4
• Patient is ≥75 years old or <60 kg (prasugrel shows no net benefit) 1
• Contraindications or intolerance to newer agents exist 2
• Cost considerations are paramount 1
• Patient has aspirin intolerance (ticagrelor not studied without aspirin) 1

Choose Prasugrel When:

• Patient has ST-elevation MI undergoing PCI (greatest benefit demonstrated) 1
• Patient has diabetes mellitus (subgroup with particular benefit) 1
• Patient has high risk of stent thrombosis 5, 9
• Patient is <75 years, ≥60 kg, no prior stroke/TIA 1
• Coronary anatomy is known and PCI is planned 1

Choose Ticagrelor When:

• Patient has ACS managed medically without planned PCI 1
• Patient requires upfront treatment before coronary anatomy is known 1
• All-cause mortality reduction is priority 1
• Patient has high on-clopidogrel platelet reactivity 6, 7
• Patient can tolerate twice-daily dosing 1

Surgical Timing Considerations

• Clopidogrel: Discontinue at least 5 days before CABG 1, 2
• Prasugrel: Discontinue at least 7 days before CABG 1
• Ticagrelor: Discontinue at least 5 days before CABG due to faster platelet function recovery 1, 2

Common Pitfall to Avoid

Do not administer prasugrel before coronary angiography in undifferentiated ACS patients. The ACCOAST trial demonstrated that pre-treatment with prasugrel before angiography in NSTEMI patients increased bleeding complications without reducing ischemic events compared to administration only at time of PCI. 1 This contrasts with ticagrelor, which can be safely administered upfront. 1