Medicine · November 17, 2022

Comparing Clopidogrel Versus Prasugrel – Med Ed 101

Post-MI there are a lot of medications most patients will be started on, and it can get confusing for both patients and providers. Today, we’re clearing up some of the confusion surrounding the choice behind which platelet aggregation inhibitors should be used. We’ll be focusing on a comparison of prasugrel versus clopidogrel.

Both medications work via similar mechanisms, selectively and irreversibly inhibiting the binding of adenosine diphosphate to P2Y12 receptors, stopping platelet aggregation. The reduction of platelet aggregation leads to a decreased risk of thrombotic events, which can specifically reduce the complications associated with ACS and PCI.

In a head-to-head study conducted by Wiviott et al comparing clopidogrel versus prasugrel, there was no significant difference in overall mortality between the two treatments. However, when looking more closely there were some differences. Prasugrel is considered to be a more potent antiplatelet agent with a faster onset of action that is thought to reduce major cardiovascular events more so than clopidogrel. This was shown to hold true in the clinical trials, in which primary composite endpoints were significantly reduced with prasugrel compared to clopidogrel. Those primary endpoints were comprised of death from cardiovascular causes, nonfatal MI, and nonfatal stroke, however, the majority of the benefit came from a decrease in nonfatal MIs.. However, major bleeding was also observed significantly more often in the prasugrel treatment arm, leading to the addition of a boxed warning for bleeding.

In the same trial, it was noted that patients who had experienced a transient ischemic attack (TIA) or stroke had a higher rate of stroke on prasugrel than on clopidogrel. In patients without this history, similar rates of stroke occurred between the two treatment arms. Notably, the patients on clopidogrel that experienced strokes only experienced thrombotic strokes, while the patients on prasugrel experienced a mix of thrombotic strokes and intracranial hemorrhages. Due to this, a history of TIA or stroke is a contraindication to prasugrel use.

Another important aspect to consider is cost. Clopidogrel is older than prasugrel and may be much more affordable for patients compared to the newer prasugrel.

Pharmacokinetic and Pharmacogenomic Comparison of Clopidogrel Versus Prasugrel

One situation in which clopidogrel may not be an option is if a patient is a known CYP2C19 poor metabolizer (a very common board certification/pharmacology question!). This means that they carry two no-function alleles and clopidogrel cannot be formed into the active metabolite. In the case of a known CYP2C19 poor metabolizer, CPIC (Clinical Pharmacogenetics Implementation Consortium) guidelines recommend avoiding clopidogrel and using prasugrel or ticagrelor as long as no contraindications exist. Due to the metabolism by CYP2C19, there are also some notable drug interactions. Proton pump inhibitors (PPIs) are the main drug class that interferes with metabolism of clopidogrel, including omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole. Some PPIs may have less impact on CYP2C19 compared to others. Omeprazole and esomeprazole are considered to have more significant impacts. In the case of a patient using a PPI, prasugrel may be preferred over clopidogrel. Some possible interactions have also been identified with clopidogrel and calcium channel blockers, including amlodipine and nifedipine, although this interaction has not shown clinical significance. If you’d like our free 18-page PDF on common drug interactions, you can get that by subscribing via email here.

Prasugrel has notably fewer interactions relating to its metabolism, despite both clopidogrel and prasugrel being prodrugs. While clopidogrel is primarily metabolized into its active metabolite by CYP2C19, prasugrel undergoes processing by esterases and then CYP3A4 and CYP2B6. Due to the difference in metabolism, few clinically relevant CYP drug interactions have been noted with prasugrel.

Bleed Risk – Clopidogrel Versus Prasugrel

One last item that may be important to consider relates to prasugrel’s black box warning for bleeding. Prasugrel, unlike clopidogrel, is also on the Beers list, indicating that it should be used cautiously in patients 75 years of age or older. Due to the increased risk of bleeding with increased age, the use of prasugrel should only occur after a risk versus benefit consideration. Older adults may be at higher risk of bleeding, although some patients may still benefit if they have a high risk of a thrombotic event.

Clopidogrel Versus Prasugrel Comparison Table

Clopidogrel Prasugrel
FDA Indications Thrombosis prophylaxis for STEMI, CVA, MI, NSTEMI post PCI, NSTEMI, peripheral arterial occlusive disease, and post PCI Thrombosis prophylaxis for ACS post PCI
Usual Dosing in ACS Loading Dose: 300-600 mg
Maintenance Dose: 75 mg
Loading Dose: 30-60 mg
Maintenance Dose: 10 mg
Contraindications Active bleeding, Hypersensitivity Active bleeding, Hypersensitivity, History of stroke or TIA
Adverse Effects Hemorrhage – both non-major and major, Pancytopenia, Hepatotoxicity Hypertension, Nose bleeds, Atrial Fibrillation, Hemorrhage
Beers List Criteria Not on the Beers List. On Beers List: Use caution in patients 75 years or older due to increased risk of bleeding. Risk versus benefit consideration is necessary.
Other Notes: CYP2C19 metabolism is prominent Black Box Warning: Bleeding
Comparison Table – Clopidogrel Versus Prasugrel

This article was written by Jordyn Erkel, PharmD, Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP.

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References

Wiviott, S. D., Braunwald, E., McCabe, C. H., Montalescot, G., Ruzyllo, W., Gottlieb, S., … & Antman, E. M. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 357(20), 2001-2015.

Jackson, L. R., Ju, C., Zettler, M., Messenger, J. C., Cohen, D. J., Stone, G. W., … & Wang, T. Y. (2015). Outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a comparison of clopidogrel versus prasugrel from the TRANSLATE-ACS study. JACC: Cardiovascular Interventions, 8(14), 1880-1889.

Lee, C. R., Luzum, J. A., Sangkuhl, K., Gammal, R. S., Sabatine, M. S., Stein, C. M., … & Shuldiner, A. R. (2022). Clinical pharmacogenetics implementation consortium guideline for CYP2C19 genotype and clopidogrel therapy: 2022 update. Clinical Pharmacology & Therapeutics.

Prasugrel [package insert]. Accord Healthcare Durham, NC, Revised 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd6bf899-06b7-4f52-96c5-ffc94a7288ff. Accessed: 11/14/2022.

Clopidogrel [package insert]. Accord Healthcare Durham, NC, Revised 2022.https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8b84d00e-9aac-4da2-b9aa-17e5ddf9b922. Accessed: 11/14/2022.

Clopidogrel Hydrogen Sulfate. IBM Micromedex ® Drug Summary [online]. Updated periodically. IBM Watson Health, Greenwood Village, Colorado, USA. Accessed at: https://www-micromedexsolutions-com.ezp3.lib.umn.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=topHome&isToolPage=true#. Accessed: 11/15/22.