Clopidogrel (Plavix)

J. Comin; D. Kallmes

doi:10.3174/ajnr.A2913

Abstract

SUMMARY: Clopidogrel is an inhibitor of platelet aggregation, indicated for the prevention of ischemic stroke and in-stent thrombosis. However, it has a number of drawbacks, including an increased risk of hemorrhage; a clinical effect that is slow in onset and irreversible; a genetically determined variability in its clinical potency; and interactions with other commonly administered drugs.

ABBREVIATIONS

Act-Met: active metabolite of clopidogrel
ADP: adenosine diphosphate
AHA: American Hospital Association
GI: gastrointestinal
GPIIb/IIIa: glycoprotein IIb/IIIa
PPI: proton pump inhibitor
VWF: von Willebrand factor

Clopidogrel (Plavix, Bristol-Myers Squibb, Washington, DC; Sanofi Aventis, Bridgewater, New Jersey) is a prodrug of the thienopyridine family, which has little, if any, platelet inhibitory effect in its original state. Its active form (Act-Met) is produced by metabolism of the prodrug through the cytochrome P450 system of the liver, most particularly by the enzyme CYP2C19.

Act-Met permanently and irreversibly disables the G protein−coupled platelet receptor known as P2Y12. P2Y12, normally activated by ADP, brings about conformational change of the surface molecule GPIIb/IIIa. This conformational change increases the affinity of GPIIb/IIIa for the divalent bridging molecules fibrinogen and VWF, thereby allowing platelet aggregation (Fig 1). As such, activated clopidogrel-mediated disabling of this G protein−coupled receptor leads to diminished aggregation of platelets.

Fig 1.

Production of clopidogrel active metabolite and its effect on platelet aggregation. Clopidogrel is metabolized in the liver by cytochrome P450 enzymes, producing Act-Met. Act-Met irreversibly binds and disables the platelet receptor P2Y12. ADP-induced P2Y12 activation causes downstream G-protein signaling, which in turn results in conformational change and activation of the platelet receptor GPIIb/IIIa. This activated GPIIb/IIIa receptor can bind to similarly activated receptors on other platelets via divalent bridging molecules such as VWF and fibrinogen, resulting in platelet aggregation.

Clinical Indication

According to the most recent AHA/American Stroke Association Council “Guidelines for the Prevention of Stroke,”¹ clopidogrel is indicated to prevent noncardioembolic stroke in patients with known atherosclerotic disease, though it is not definitely superior to aspirin or aspirin/dipyridamole for this purpose. The same guidelines asserted that, currently, insufficient evidence exists to recommend its administration in the acute treatment of ischemic stroke.

Clopidogrel is familiar to the neurointerventionalist in the setting of intracranial or extracranial carotid/vertebral stent placement. The evidence to support its use in this circumstance is primarily extrapolation from trials of coronary arterial stent placement.

Administration

Plavix is commercially available only in an oral form. Trials validating its effectiveness in the setting of secondary prevention of ischemic stroke have used once-daily doses of 75 mg. This dose is expected to result in a steady-state effect on platelet aggregation after approximately 5–6 days.² This dose is, however, arbitrary, and may not be sufficient to produce optimal platelet inhibition in all patients.

In the acute setting of emergent arterial stent placement, the optimal loading dose has not been clearly established in the cardiology literature; there is some evidence to suggest that 600- or 900-mg loading doses are more efficacious than the traditionally used 300-mg loading dose.³ A loading dose of 900 mg may result in the same level of platelet inhibition after just 2 hours as a loading dose of 300 mg achieves after 6 hours.⁴

Side Effects

The most clinically significant side effect of clopidogrel is hemorrhage. The observed risk with clopidogrel is significantly lower than that observed with aspirin for GI bleeding (2% versus 2.66% for clopidogrel and aspirin, respectively) and is similar for intracranial hemorrhage (0.31% versus 0.42% for clopidogrel and aspirin, respectively).⁵ Other side effects include pruritus and rash⁶ and, rarely, thrombotic thrombocytopenic purpura.⁷

Poor Responders

It is believed that a subset of approximately one-third of patients are “poor responders” to clopidogrel,⁸ with diminished in vitro reduction of ADP-induced platelet aggregation and proved increased risk of in-stent and native arterial thrombosis.⁹

The most important intrinsic determinant of this variable response is likely to be related to polymorphisms within the genes that regulate CYP2C19 activity,¹⁰ and these are particularly common in Asian populations.¹¹

A further likely intrinsic determinant is variable intestinal absorption, thought to be related to polymorphisms of the ABCB1 gene.¹⁰

There are various commercially available tests of in vitro platelet function, including ADP-stimulated platelet aggregation and vasodilator-stimulated phosphoprotein phosphorylation. Their clinical utility in determining clopidogrel clinical response and dosing is controversial.

Interactions

With regard to pharmacokinetic interactions, the most important are with drugs that inhibit CYP2C19 activity and thereby reduce conversion of the prodrug to its active form. The most important of these is the PPI group; these medications are both ubiquitous (available over-the-counter in many countries) and are often deliberately coadministered to patients receiving clopidogrel to reduce the risk of GI hemorrhage.

There is definite reduced ex vivo inhibition of platelet aggregation by clopidogrel when PPIs are coadministered.¹² However, the current position of the AHA is that there is no conclusive evidence that this translates to an increased risk of clinically significant thrombosis.¹³

Strategies suggested to minimize PPI-induced inhibition include substituting the less inhibitory pantoprazole for omeprazole,¹⁴ and spacing clopidogrel and PPI doses 12 hours apart from each other.¹⁵ The entire subject remains controversial.

Economic Issues

The cost of Plavix was estimated at US $103 per month in 2007 inflation-adjusted terms, compared with US $6 per month for aspirin, in a study comparing the cost-effectiveness of the 2 agents.¹⁶ This does, however, compare favorably with the newer thienopyridines, and with the direct GPIIb/IIIa antagonists. Clopidogrel is protected by US patent until May 2012¹⁷; generic versions may further reduce the cost of treatment.

Summary

Clopidogrel remains a front-line drug in the prevention of arterial thrombosis in high-risk patients, such as those with arterial stents and those with atherosclerotic disease. However, its problematic pharmacokinetics mean that it may be supplanted by the newer P2Y12 antagonists, which have fewer clinically significant drug interactions, a faster onset, reversibility, and more predictable and greater clinical potency.

View this table:

Clopidogrel summary

Footnotes

Disclosures: David Kallmes—UNRELATED: Grants/Grants Pending: ev3, Penumbra, MicroVention, Sequent, NFocus, Payment for Development of Educational Presentations: ev3, CareFusion, Travel/Accommodations/Meeting Expenses Unrelated to Activities Listed: MicroVention.

References

1.↵
1. Sacco RL,
2. Adams R,
3. Albers G,
4. et al
. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke—co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 2006;37:577–617
Abstract/FREE Full Text
2.↵
1. Reinhart KM,
2. White CM,
3. Baker WL
. Prasurgel: a critical comparison with clopidogrel. Pharmacotherapy 2009;29:1441–51
CrossRef PubMed
3.↵
1. King SB,
2. Smith SC,
3. Hirshfeld JW,
4. et al
. 2007 focused update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines—2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 2008;117:261–95. Epub 2007 Dec 13
FREE Full Text
4.↵
1. Montalescot G,
2. Sideris G,
3. Meuleman C,
4. et al
. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48:931–38. Epub 2006 Aug 17
CrossRef PubMed
5.↵
1. Harker LA,
2. Boissel JP,
3. Pilgrim AJ,
4. et al
. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE—CAPRIE Steering Committee and Investigators. clopidogrel versus aspirin in patients at risk of ischemic events. Drug Saf 1999;21:324–35
6.↵
Plavix [package insert]. http://products.sanofi-aventis.us/plavix/plavix.html. Accessed October 18, 2011
7.↵
1. Bennett CL,
2. Connors JM,
3. Carwile JM,
4. et al
. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342:1773–77
CrossRef PubMed
8.↵
1. Angiolillo DJ,
2. Fernandez-Ortiz A,
3. Bernardo E,
4. et al
. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–16
CrossRef PubMed
9.↵
1. Cuisset T,
2. Frere C,
3. Quilici J,
4. et al
. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542–49. Epub 2005 Dec 22
CrossRef PubMed
10.↵
1. Simon T,
2. Verstuyft C,
3. Mary-Krause M,
4. et al
. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363–75
CrossRef PubMed
11.↵
NDA 20–839 S-044. Plavix label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s0511b1.pdf. Accessed October 18, 2011
12.↵
1. Gilard M,
2. Arnaud B,
3. Cornily C,
4. et al
. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256–60
CrossRef PubMed
13.↵
1. Abraham N,
2. Hlatky M,
3. Antman E,
4. et al
. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2010;56:2533–49
14.↵
1. Sibbing D,
2. Morath T,
3. Stegherr J,
4. et al
. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. J Thromb Haemost 2009;101:714–19
15.↵
1. Laine L,
2. Hennekens C
. Proton pump inhibitor and clopidogrel interaction: fact or fiction? Am J Gastroenterol 2010;105:34–41
CrossRef PubMed
16.↵
1. Chen J,
2. Bhatt DL,
3. Schneider Dunn E,
4. et al
. Cost-effectiveness of clopidogrel plus aspirin versus aspirin alone for secondary prevention of cardiovascular events: results from the CHARISMA trial. Value Health 2009;12:872–79
CrossRef PubMed
17.↵
1. Pierson R,
2. Bansal P
. U.S. judge upholds Bristol, Sanofi patent on Plavix. Reuters. June 19. 2007. http://www.reuters.com/article/2011/10/18/sanofi-apotex-patent-idUSN1E79H1NL20111018. Accessed 18 October 2011

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[1] 1.↵
Sacco RL,
Adams R,
Albers G,
et al
. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke—co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 2006;37:577–617
Abstract/FREE Full Text

[2] Sacco RL,

[3] Adams R,

[4] Albers G,

[5] et al

[6] 2.↵
Reinhart KM,
White CM,
Baker WL
. Prasurgel: a critical comparison with clopidogrel. Pharmacotherapy 2009;29:1441–51
CrossRef PubMed

[7] Reinhart KM,

[8] White CM,

[9] Baker WL

[10] 3.↵
King SB,
Smith SC,
Hirshfeld JW,
et al
. 2007 focused update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines—2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 2008;117:261–95. Epub 2007 Dec 13
FREE Full Text

[11] King SB,

[12] Smith SC,

[13] Hirshfeld JW,

[14] et al

[15] 4.↵
Montalescot G,
Sideris G,
Meuleman C,
et al
. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48:931–38. Epub 2006 Aug 17
CrossRef PubMed

[16] Montalescot G,

[17] Sideris G,

[18] Meuleman C,

[19] et al

[20] 5.↵
Harker LA,
Boissel JP,
Pilgrim AJ,
et al
. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE—CAPRIE Steering Committee and Investigators. clopidogrel versus aspirin in patients at risk of ischemic events. Drug Saf 1999;21:324–35

[21] Harker LA,

[22] Boissel JP,

[23] Pilgrim AJ,

[24] et al

[25] 6.↵
Plavix [package insert]. http://products.sanofi-aventis.us/plavix/plavix.html. Accessed October 18, 2011

[26] 7.↵
Bennett CL,
Connors JM,
Carwile JM,
et al
. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342:1773–77
CrossRef PubMed

[27] Bennett CL,

[28] Connors JM,

[29] Carwile JM,

[30] et al

[31] 8.↵
Angiolillo DJ,
Fernandez-Ortiz A,
Bernardo E,
et al
. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–16
CrossRef PubMed

[32] Angiolillo DJ,

[33] Fernandez-Ortiz A,

[34] Bernardo E,

[35] et al

[36] 9.↵
Cuisset T,
Frere C,
Quilici J,
et al
. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542–49. Epub 2005 Dec 22
CrossRef PubMed

[37] Cuisset T,

[38] Frere C,

[39] Quilici J,

[40] et al

[41] 10.↵
Simon T,
Verstuyft C,
Mary-Krause M,
et al
. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363–75
CrossRef PubMed

[42] Simon T,

[43] Verstuyft C,

[44] Mary-Krause M,

[45] et al

[46] 11.↵
NDA 20–839 S-044. Plavix label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s0511b1.pdf. Accessed October 18, 2011

[47] 12.↵
Gilard M,
Arnaud B,
Cornily C,
et al
. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256–60
CrossRef PubMed

[48] Gilard M,

[49] Arnaud B,

[50] Cornily C,

[51] et al

[52] 13.↵
Abraham N,
Hlatky M,
Antman E,
et al
. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2010;56:2533–49

[53] Abraham N,

[54] Hlatky M,

[55] Antman E,

[56] et al

[57] 14.↵
Sibbing D,
Morath T,
Stegherr J,
et al
. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. J Thromb Haemost 2009;101:714–19

[58] Sibbing D,

[59] Morath T,

[60] Stegherr J,

[61] et al

[62] 15.↵
Laine L,
Hennekens C
. Proton pump inhibitor and clopidogrel interaction: fact or fiction? Am J Gastroenterol 2010;105:34–41
CrossRef PubMed

[63] Laine L,

[64] Hennekens C

[65] 16.↵
Chen J,
Bhatt DL,
Schneider Dunn E,
et al
. Cost-effectiveness of clopidogrel plus aspirin versus aspirin alone for secondary prevention of cardiovascular events: results from the CHARISMA trial. Value Health 2009;12:872–79
CrossRef PubMed

[66] Chen J,

[67] Bhatt DL,

[68] Schneider Dunn E,

[69] et al

[70] 17.↵
Pierson R,
Bansal P
. U.S. judge upholds Bristol, Sanofi patent on Plavix. Reuters. June 19. 2007. http://www.reuters.com/article/2011/10/18/sanofi-apotex-patent-idUSN1E79H1NL20111018. Accessed 18 October 2011

[71] Pierson R,

[72] Bansal P

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American Journal of Neuroradiology

Clopidogrel (Plavix)

Abstract