Prasugrel

Class: Platelet-Aggregation Inhibitors
Brands: Effient

• Bleeding


• 
  

  Potential risk of serious (including fatal) bleeding.^{1 2 6 10} (See Bleeding under Cautions.)

  
  


• 
  

  Avoid use in patients with active pathological bleeding, history of stroke/ TIA, or in those likely to undergo CABG.¹

  
  


• 
  

  Generally not recommended in patients ≥75 years of age because of increased risk of fatal and intracranial bleeding, except in certain high-risk patients (e.g., those with diabetes, history of MI) who may experience a greater net clinical benefit.^{1 5 18 70} (See Geriatric Use under Cautions.)

  
  


• 
  

  Consider additional risk factors for bleeding such as body weight <60 kg, concomitant use of drugs that increase risk of bleeding, or other underlying conditions that may increase risk of bleeding.¹

  
  


• 
  

  Discontinue prasugrel at least 7 days prior to any surgery.¹

  
  


• 
  

  Suspect bleeding in any patient receiving prasugrel who is hypotensive and has recently undergone an invasive (e.g., PCI, coronary angiography) or surgical (e.g., CABG) procedure.¹

  
  


• 
  

  If bleeding occurs, attempt to manage without discontinuing therapy; increased risk of subsequent cardiovascular events possible with premature discontinuance, particularly in first few weeks following an acute coronary event or in patients with intracoronary stents.^{1 43 44 45 46 47 48 49 54 70} (See Discontinuance of Therapy under Cautions.)

  
  

REMS:

FDA approved a REMS for prasugrel to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of prasugrel and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Platelet-activation and aggregation inhibitor; thienopyridine derivative.^{1 2 3 4 5 6 8 13 14 15 28 30}

Uses for Prasugrel

Acute Coronary Syndromes: Patients Undergoing PCI

Used in conjunction with aspirin to reduce the risk of thrombotic cardiovascular events (e.g., stent thrombosis, MI) in patients with acute coronary syndromes (ACS) undergoing PCI.^{1 2}

Used in patients with unstable angina or non-ST-segment-elevation MI (NSTEMI) undergoing PCI and in patients with ST-segment elevation MI (STEMI) managed with primary or delayed (after medical treatment) PCI.^{1 2}

Current standard of care in patients with ACS includes dual antiplatelet therapy with a thienopyridine derivative (e.g., clopidogrel, prasugrel) and aspirin.^{3 6 9 16 17 23 27 64 67 70} Increased inhibition of platelet aggregation associated with prasugrel appears to produce greater reductions in ischemic outcomes (e.g., stent thrombosis, MI) compared with standard dosages of clopidogrel in patients with ACS undergoing PCI; however, such benefits have been accompanied by an increased risk of bleeding.^{1 3 5 6 7 8 9 11 13 14 15 17 18 62}

Some evidence suggests that certain patient populations (e.g., those with diabetes, previous MI) may be more likely to benefit from prasugrel’s greater inhibition of platelet aggregation, while others (e.g., patients ≥75 years, those weighing <60 kg, those with previous TIA/stroke) may experience harm;^{2 5 14 16 17 19} additional studies needed to confirm these findings.^{2 5 13 19}

Precise role of prasugrel versus clopidogrel in the management of ACS remains to be fully established.^{13 14 17 20 70} When considering use, balance anticipated greater benefits against increased risk of bleeding.^{1 2 8 9 13 14 17 70}

Prasugrel Dosage and Administration

General

• 
  

  It is generally recommended that antiplatelet agents be administered promptly upon presentation or diagnosis in patients with ACS.^{1 2 64 66 67}

  
  


• 
  

  Pretreatment with prasugrel may be considered prior to determining coronary anatomy in patients who are not likely to undergo CABG surgery; weigh benefits of pretreatment against risk of surgical bleeding in patients who may require urgent CABG.¹

  
  


• 
  

  In patients with STEMI who will undergo primary PCI, ACC and AHA currently recommend administration of a loading dose of either clopidogrel or prasugrel as early as possible before PCI or at the time of the procedure.⁷⁰

  
  

Administration

Administer orally without regard to meals.¹

Dosage

Available as prasugrel hydrochloride; dosage expressed in terms of prasugrel.¹

Adults

Acute Coronary Syndromes

Patients Undergoing PCI

Oral

60-mg initial loading dose followed by maintenance dosage of 10 mg daily; give in conjunction with aspirin (75–325 mg daily).¹ ACC and AHA recommend that the loading dose of prasugrel be administered as soon as possible in patients with STEMI undergoing primary PCI.⁷⁰ In patients with STEMI undergoing nonprimary PCI who have not received thrombolytic therapy and in whom coronary anatomy has been determined and PCI is planned, ACC and AHA recommend administering a 60-mg loading dose of prasugrel promptly and no later than 1 hour after PCI, followed by a maintenance dosage of 10 mg once daily.⁷⁰ Majority of patients in TRITON-TIMI 38 study received loading dose after first coronary guidewire was placed or within 1 hour of PCI.^{1 2 3}

Consider reduced maintenance dosage in patients weighing <60 kg.^{1 6 18} (See Low Body Weight under Dosage and Administration: Special Populations.)

Optimum duration of maintenance therapy not known; premature discontinuance in patients with intracoronary stents associated with thrombotic events, sometimes fatal.^{1 43 44 45 46 47 48 49 54 70} (See Discontinuance of Therapy under Cautions.) Long-term antiplatelet therapy with a thienopyridine derivative is recommended in patients with intracoronary stents to prevent ischemic events.^{65 66 70} In patients who receive a bare-metal or drug-eluting stent during PCI, ACC and AHA recommend daily maintenance therapy with clopidogrel or prasugrel for at least 12 months; earlier discontinuance may be considered if risk of morbidity from bleeding is thought to outweigh the anticipated benefit of such therapy.⁷⁰ ACC and AHA suggest consideration of extending thienopyridine therapy beyond 15 months in patients with ACS and drug-eluting stents.⁷⁰

Special Populations

Hepatic Impairment

No dosage adjustments required in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B).¹ Not studied in patients with severe hepatic disease.¹

Renal Impairment

No dosage adjustments required.¹

Low Body Weight

May reduce maintenance dosage to 5 mg daily in patients who weigh <60 kg, although safety and efficacy of such lower dosages not established.^{1 6 18} (See Bleeding under Cautions.)

Cautions for Prasugrel

Contraindications

• 
  

  Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).¹

  
  


• 
  

  History of stroke or TIA.¹

  
  

Warnings/Precautions

Warnings

Bleeding

Risk of serious, sometimes fatal bleeding.^{1 2 6 10} Major and minor bleeding events, including life-threatening and fatal bleeding reported more frequently in patients receiving prasugrel than those who received clopidogrel in pivotal clinical study.^{1 2 6 10}

Greater risk of bleeding observed in patients ≥75 years of age, those weighing < 60 kg, and those with prior stroke or TIA.^{1 2} Additional risk factors include recent trauma, recent surgery (e.g., CABG), recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment, and concurrent use of drugs that increase risk of bleeding (e.g., oral anticoagulants, NSAIAs, thrombolytic agents).¹

Do not use in patients who are actively bleeding and/or who have a history of stroke or TIA.^{1 17 18} Not recommended in patients likely to undergo emergent CABG.¹ (See CABG under Cautions.)

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or any other surgical procedure, even if there are no overt manifestations of bleeding.¹

If possible, manage bleeding without discontinuing prasugrel; premature discontinuance is associated with an increased risk of subsequent cardiovascular events.¹ (See Discontinuance of Therapy under Cautions.) May treat bleeding with platelet transfusions; however, transfusions within 6 hours of a loading dose or 4 hours of a maintenance dose may be less effective.¹ Withholding a dose not likely to resolve or prevent bleeding.¹

Cerebrovascular Events

Higher incidence of stroke (thrombotic and hemorrhagic) and no evidence of clinical benefit reported among patients with a history of stroke or TIA receiving prasugrel compared with clopidogrel in TRITON-TIMI 38 study.^{1 2} Use not recommended in patients with a history of stroke or TIA; in general, discontinue prasugrel in those who experience such cerebrovascular events during therapy.^{1 18}

CABG

Increased risk of bleeding in patients who undergo CABG surgery.^{1 2} (See Bleeding under Cautions.) CABG-related major and minor bleeding events occurred substantially more frequently in patients who received prasugrel versus clopidogrel in pivotal clinical study.^{1 2}

Discontinue prasugrel at least 7 days prior to CABG.¹ Do not initiate in patients who are likely to undergo urgent CABG.¹ May treat CABG-related bleeding with blood product transfusions (e.g., packed red blood cells, platelets).¹

Discontinuance of Therapy

Discontinue prasugrel in patients who develop active bleeding, stroke, or TIA during therapy.¹ Discontinue drug at least 7 days prior to elective surgery.^{1 70}

Avoid premature discontinuance of thienopyridine treatment because of the subsequent increased risk of ischemic complications.^{1 6 45} Premature discontinuance of dual antiplatelet therapy with clopidogrel and aspirin in patients with intracoronary stents has been associated with an increased risk of stent thrombosis, MI, and/or death.^{43 44 45 46 47 48 49 54} Advise patients to never discontinue such therapy without consulting their prescribing clinician.^{1 45} (See Advice to Patients.) If prasugrel must be temporarily discontinued because of an adverse event, reinstitute therapy as soon as possible.¹

Thrombotic Thrombocytopenic Purpura (TTP)

Reported rarely with use of other thienopyridine derivatives, sometimes after brief exposure (<2 weeks); potentially fatal.^{1 31} Characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on peripheral blood smear), neurologic findings, renal dysfunction, and fever.^{1 31} Requires urgent treatment (e.g., plasmapheresis).¹

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use during nursing only if potential benefits outweigh risks.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

Geriatric patients, particularly those ≥75 years of age, appear to be at greater risk of bleeding (including fatal bleeding) with prasugrel therapy compared with younger patients.¹ Fatal bleeding and symptomatic intracranial hemorrhage occurred more often in patients ≥75 years of age receiving prasugrel compared with that in clopidogrel-treated patients in a large clinical study.¹

In general, avoid use in patients ≥75 years of age, but may consider use in certain geriatric patients with high-risk conditions (e.g., diabetes, previous MI) in whom a greater net clinical benefit has been demonstrated.^{1 5 18 70}

Hepatic Impairment

In patients with mild to moderate hepatic impairment (Child-Pugh Class A and B), inhibition of platelet aggregation was similar to that of healthy individuals.¹ Not specifically studied in patients with severe hepatic impairment; such patients generally are at higher risk of bleeding.¹

Renal Impairment

Inhibition of platelet aggregation similar in patients with moderate renal impairment (Cl_cr of 30–50 mL/minute) and healthy individuals.¹

Low Body Weight

Patients with low body weight (< 60 kg) have increased exposure to the active metabolite of prasugrel and appear to be at increased risk of bleeding.¹ (See Bleeding under Cautions.)

Common Adverse Effects

Bleeding, including life-threatening and fatal bleeding events.^{1 2}

Interactions for Prasugrel

Metabolized principally by CYP3A4 and CYP2B6; to a lesser extent by CYP2C9 and CYP2C19.^{1 13 14 22 23 30} Not likely to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6 or 3A4 nor induce isoenzymes 1A2 or 3A4.^{1 13} Weak inhibitor of CYP2B6.^{1 25}

Does not inhibit P-glycoprotein (Pgp) transport system.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions mediated by CYP enzymes unlikely.^{1 13 25}

CYP3A4 inhibitors: No substantial effect on systemic exposure or antiplatelet activity of prasugrel’s active metabolite.^{1 22}

CYP3A4 inducers: Not expected to substantially alter pharmacokinetic or pharmacodynamic response to prasugrel.^{1 25}

Drugs metabolized by CYP2B6: Potential for increased plasma concentrations and exposure to concomitantly administered drug; however, clinically important interactions not expected because of weak inhibition of CYP2B6.^{1 25}

Other Antiplatelet or Antithrombotic Agents

Manufacturer states that prasugrel may be administered concomitantly with aspirin, heparin, and GP IIb/IIIa-receptor inhibitors.¹ While evidence from drug interaction studies with other antiplatelet or antithrombotic agents generally is lacking, increased risk of bleeding likely with concomitant use of such agents.^{13 14}

Specific Drugs or Foods

Drug	Interaction	Comments
Aspirin	Possible increased bleeding time and greater levels of platelet inhibition1 26	May be administered concomitantly1
Carbamazepine	Pharmacokinetic/pharmacodynamic response to prasugrel not expected to be substantially altered1 25
Ciprofloxacin	Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22
Clarithromycin	Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22
Cyclophosphamide	Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25
Digoxin	Concurrent administration not expected to affect digoxin clearance1	May be administered concomitantly1
Diltiazem	Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22
Grapefruit juice	Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22
Halothane	Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1
Heparin	Possible increased bleeding time, but no associated changes in coagulation or platelet inhibition1	May be administered concomitantly1
HMG-CoA reductase inhibitors (e.g., atorvastatin)	Minor effect on exposure to active prasugrel metabolite, but no effect on inhibition of platelet aggregation1 17 23	May be used concomitantly; no dosage adjustments necessary.1 23
Histamine H2-receptor antagonists (e.g., ranitidine )	Decreased plasma concentrations of active prasugrel metabolite by approximately 14%, but systemic exposure unaffected	May be administered concomitantly1
Indinavir	Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22
Ketoconazole	Decreased plasma concentrations of prasugrel’s active metabolite by 34–46%; no change in systemic exposure or platelet inhibition1 14 17 22
Nevirapine	Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25
NSAIAs	Increased risk of bleeding with concomitant long-term use of NSAIAs1
Propofol	Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25
Proton-pump inhibitors (e.g., lansoprazole)	Possible decreased systemic exposure and peak plasma concentrations of prasugrel’s active metabolite, but no effect on platelet inhibition1 13 17 24	May be administered concomitantly1
Rifampin	Pharmacokinetic/pharmacodynamic response to prasugrel not expected to be substantially altered1 25
Thrombolytic agents	Increased risk of bleeding1
Warfarin	Increased risk of bleeding; prolonged bleeding time observed with concomitant use1

Prasugrel Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration.^{1 13 27 28 62}

Onset

Peak plasma concentrations of active metabolite attained approximately 30 minutes following oral administration; no evidence of accumulation with repeated administration.^{1 13 25 28}

Following a 60-mg loading dose, approximately 90% of patients achieve at least 50% inhibition of platelet aggregation by 1 hour; maximum platelet inhibition was approximately 80%.¹ Steady-state platelet inhibition (70%) occurs within 3–5 days following maintenance therapy with repeated dosages of 10 mg daily.¹

Duration

Following discontinuance, platelet aggregation gradually returns to baseline values in about 5–9 days.¹

Food

In healthy individuals, food (high-fat or high-caloric meal) decreased peak plasma concentrations by 49% but did not alter exposure to active metabolite.¹

Special Populations

In patients with end-stage renal impairment, exposure to active metabolite was decreased to approximately half that in healthy individuals and those with moderate renal impairment.¹

In low-weight individuals (weight <60 kg), increased exposure to active metabolite observed.¹ Clearance of active metabolite appears to increase exponentially with increasing body weight.³⁰

In patients ≥75 years of age, mean exposure to active metabolite increased by 19% compared with younger patients.¹

Distribution

Plasma Protein Binding

Approximately 98% for active metabolite.¹

Elimination

Metabolism

Rapidly hydrolyzed by esterases to an inactive thiolactone; subsequently metabolized to active metabolite by CYP isoenzymes (primarily by 3A4 and 2B6, and to a lesser extent by 2C9 and 2C19).^{1 13 14 22 23 28 30} Requires a single step for metabolic activation compared with clopidogrel, which undergoes a 2-step oxidative process.^{13 14 22 29 30 31}

Elimination Route

Excreted in urine (68%) and feces (27%) as inactive metabolites.^{1 14 28} Active metabolite not expected to be removed by dialysis.¹

Half-life

Manufacturer reports half-life of active metabolite about 7 hours (range 2–15 hours);¹ half-life of about 3.7 hours also reported.^{13 14}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Dispense and store in original container; keep container closed and do not remove dessicant from bottle.¹

Actions

• 
  

  Prodrug; platelet inhibitory activity is dependent on hepatic transformation to an active metabolite.^{1 2 14 22 30 31}

  
  


• 
  

  Active metabolite binds irreversibly to P2Y12 class of ADP receptors on platelet surfaces, thereby inhibiting ADP-dependent platelet activation and aggregation.^{1 13 14 15}

  
  


• 
  

  ADP receptor is irreversibly modified; platelets exposed to prasugrel remain affected for the remainder of their lifespan (about 7–10 days).^{1 22}

  
  


• 
  

  Prasugrel is a thienopyridine derivative that is structurally and pharmacologically related to clopidogrel.^{1 2 3 4 5 6 8 13 14 15 28 30} Exhibits more rapid, consistent, and greater inhibition of ADP-mediated platelet aggregation than clopidogrel.^{2 3 8 9 11 12 13 14 15 27} Increased potency appears to be a result of more efficient conversion of the prodrug to its active metabolite.^{2 3 9 14 15 22 27 30}

  
  

  Genetic polymorphisms of CYP isoenzymes (e.g., CYP2B6, CYP2C9, CYP2C19, CYP3A5) do not appear to affect pharmacologic or clinical response to prasugrel.^{1 29}

  
  

Advice to Patients

• 
  

  Importance of counseling patients about potential risks versus benefits of prasugrel.¹

  
  


• 
  

  Importance of informing patients that they will bruise and/or bleed more easily and that a longer than usual time will be required to stop bleeding when taking prasugrel.¹ Importance of informing clinicians about any unexpected, prolonged, or excessive bleeding, or blood in urine or stool.¹

  
  


• 
  

  Importance of patients taking prasugrel exactly as prescribed and not discontinuing therapy without first consulting the prescribing clinician.¹

  
  


• 
  

  Importance of informing clinicians (e.g., physicians, dentists) about prasugrel therapy before any invasive procedure or surgery is scheduled.^{1 45} Clinician performing invasive procedure should consult with prescribing clinician before discontinuing prasugrel.^{1 45}

  
  


• 
  

  Risk of thrombotic thrombocytopenic purpura (TTP); importance of advising patients to immediately seek medical attention if they experience manifestations such as fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or otherwise unexplained neurologic changes.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly drugs that affect bleeding (e.g., warfarin, NSAIAs).¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Prasugrel Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	5 mg (of prasugrel)	Effient	Eli Lilly and Company (also promoted by Daiichi Sankyo, Inc.)
		10 mg (of prasugrel)	Effient	Eli Lilly and Company (also promoted by Daiichi Sankyo, Inc.)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Effient 10MG Tablets (LILLY): 30/$215.26 or 90/$608.03

Effient 5MG Tablets (LILLY): 30/$218.00 or 90/$622.00

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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3. Wiviott SD, Antman EM, Gibson CM et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006; 152:627-35. [PubMed 16996826]

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5. Wiviott SD, Braunwald E, Angiolillo DJ et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation. 2008; 118:1626-36. [PubMed 18757948]

6. 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; 51:2028-33. [PubMed 18498956]

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16. Calatzis A. Another view on prasugrel. Thromb Haemost. 2009; 101:12-3. [PubMed 19132183]

17. Schafer JA, Kjesbo NK, Gleason PP. Critical review of prasugrel for formulary decision makers. J Manag Care Pharm. 2009; 15:335-43. [PubMed 19422273]

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24. Small DS, Farid NA, Payne CD et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol. 2008; 48:475-84. [PubMed 18303127]

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30. Ernest CS, Small DS, Rohatagi S et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn. 2008; 35:593-618. [PubMed 19023649]

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43. Pfisterer M, Brunner-La Rocca HP, Buser PT et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents. JACC. 2006; 48:2584-91. [PubMed 17174201]

44. Eisenstein EL, Anstrom KJ, Kong DF et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159-168.

45. Grines CL, Bonow RO, Casey DE et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stenosis. A science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation. 2007; 115:813-8. [PubMed 17224480]

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