Comparison of Clopidogrel and Prasugrel for Prevention of Ischemic Events in Acute Coronary Syndrome

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.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiac Surgery, Dyslipidemia, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Anticoagulation Management and ACS, Aortic Surgery, Cardiac Surgery and Heart Failure, Statins, Interventions and ACS, Hypertension

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


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