Dual antiplatelet therapies with a P2Y₁₂ inhibitor and aspirin have shown to reduce ischemic events and stent thrombosis in patients with acute coronary syndromes (ACS) undergoing revascularization.¹ Clopidogrel (Plavix), a P2Y₁₂ inhibitor, in combination with aspirin was the standard of care in the management of ACS for several years until the development of newer agents. The first of the newer agents was prasugrel (Effient), a third generation thienopyridine with irreversible binding to the P2Y₁₂ class of adenosine diphosphate (ADP) receptors. Prasugrel offered alternative antiplatelet options for certain patient population experiencing diminished response from clopidogrel. Clopidogrel is a pro-drug which is converted to its active drug moiety by CYP450 2C19 isoenzyme. Certain patients who carry genetic alleles or are taking medications that inhibit this 2C19 isoenzyme may experience a diminished antiplatelet effect from clopidogrel. Similar to clopidogrel, prasugrel is also a pro-drug, but it undergoes conversion to its active metabolite via hydrolysis in the intestine and then oxidation by CYP450 2B6 and 3A4 isoenzymes. It therefore did not carry a similar clinical concern of diminished antiplatelet activity. While approval of prasugrel offered alternative antiplatelet therapy options for ACS patients, its use in patients ≥75 years of age, <60 kg in weight, or with prior transient ischemic attack (TIA) or stroke is not recommended due to increased risk of bleeding as seen in the subgroup analyses of the TRITON-TIMI 38 (Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel- Thrombolysis in Myocardial Infarction 38) study.²

Despite these differences, both clopidogrel and the newer P2Y₁₂ inhibitors such as prasugrel remain an integral part of drug therapies in the management of ACS. The table below further lists the similarities and differences between clopidogrel and prasugrel:

Comparison of Two Antiplatelet Therapies3,4
	Clopidogrel	Prasugrel
Drug class	Thienopyridine; Inhibitor of P2Y12 ADP receptors	Thienopyridine; Inhibitor of P2Y12 ADP receptors
Mechanism of Action	Inhibits platelet activation and aggregation through irreversible binding of its active metabolite to P2Y12 ADP receptors on platelets	Inhibits platelet activation and aggregation through irreversible binding of its active metabolite to P2Y12 ADP receptors on platelets
Metabolism	Two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative and one mediated by multiple cytochrome P450 enzymes, mostly 2C19	Two main metabolic pathways: Undergoes hydrolysis in the intestine to thiolactone, which is then converted to the active metabolite, primarily by CYP3A4 and CYP2B6
Return to baseline platelet activity	5 days upon discontinuation	7 days upon discontinuation
FDA indication	To reduce the rate of myocardial infarction and stroke in patients with ACS	To reduce thrombotic cardiovascular events, including stent thrombosis in patients with ACS who are to be managed with percutaneous coronary intervention (PCI)
Dosing recommendation	Single 300-mg loading dose followed by 75-mg once every day with or without food No dose adjustment required in hepatic impairment Limited experience in patients with moderate to severe renal impairment	Single 60-mg oral loading dose followed by 10-mg once every day with or without food For patients <60 kg, consider 5-mg once every day; however, the effectiveness of 5-mg dose has not been prospectively studies No dose adjustment required in patients with mild to moderate hepatic impairment or renal impairment The risk of bleeding is increased in end-stage renal disease
Boxed warning	Diminished antiplatelet effect in patients with two loss-of-function alleles of CYP2C19 gene Effectiveness of clopidogrel is depended on conversion to an active metabolite by CYP2C19 Tests are available to identify patients who are CYP2C19 poor metabolizers Consider use of another P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers	Prasugrel can cause significant, sometimes fatal bleeding Do not use in patients with active pathological bleeding or a history of TIA or stroke Do not use in patients ≥75 years of age unless patient has a history of diabetes or myocardial infarction then it's use can be considered Do not initiate therapy with prasugrel in patients likely to undergo coronary artery bypass graft (CABG) surgery Discontinue prasugrel at least 7 days before surgery Additional risk factors for bleeding include: weight <60 kg; propensity to bleed; concomitant use of medications that increase the risk of bleeding
Contraindications	Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage Hypersensitivity to clopidogrel or any component of the product	Active pathological bleeding Prior transient ischemic attack or stroke Hypersensitivity to prasugrel or any component of the product
Adverse events (includes ≥5% occurrence post- marketing)	Bleeding Thrombotic thrombocytopenic purport Hypotension Pruritis	Bleeding, including life-threatening and fatal bleeding Hypertension Hyperlipidemia Headache Back pain
Drug interactions	Increased risk of bleeding when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin or serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs)	Increased risk of bleeding when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDs), or warfarin Can be administered with drugs that inhibitors or inducers of CYP450 enzymes
Pregnancy category	Category B	Category B

Clopidogrel remains an integral component of ACS drug therapy management despite availability of third generation thienopyridine agents. Prasugrel provides clinicians with additional antiplatelet options for consideration in management of ACS. The 2011 ACCF/AHA/SCAI Guideline endorses clopidogrel, prasugrel and the newest of the third generation thienopyridine, ticagrelor (Brilinta) in patients undergoing stent placement during PCI for the management of ACS. Healthcare professionals should recognize the similarities and differences between these agents in selecting the most appropriate therapy for ACS patients.

References

1. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guidelines for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
2. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON–TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008;51P:2028-33.
3. Plavix [package insert]. Bridgewater, NJ: Bristol Myers Squibb/Sanofi Pharmaceuticals Partnership, 2016.
4. Effient [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.

Keywords: Acute Coronary Syndrome, Adenosine, Adenosine Diphosphate, Alleles, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Blood Platelets, Carboxylic Acids, Coronary Artery Bypass, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Diabetes Mellitus, Drug Interactions, Drug Labeling, Hydrolysis, Hyperlipidemias, Hypertension, Hypotension, Intracranial Hemorrhages, Ischemic Attack, Transient, Isoenzymes, Kidney Failure, Chronic, Medication Therapy Management, Myocardial Infarction, Norepinephrine, Peptic Ulcer, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation Inhibitors, Polyethylene Glycols, Pruritus, Receptors, Purinergic P2, Risk Factors, Serotonin Uptake Inhibitors, Serotonin, Norepinephrine, Purinergic P2Y Receptor Antagonists, Stents, Stroke, Thrombosis, Ticlopidine, Warfarin, Geriatrics

< Back to Listings