II. Mechanism: Thienopyridine Class

  1. Inhibits Platelet signal transduction
  2. Inhibits Platelet aggregation
  3. Reversibly binds Adenosine Diphosphate (ADP) P2Y12-Class Receptors
    1. Inhibits G Protein
    2. Inhibits Adenyl Cyclase

III. Indications: Prevention of Thrombotic Events

  1. Cerebrovascular Accident Prevention
  2. Coronary Artery Disease Prevention (especially if Aspirin Allergy)
  3. Post-ST Elevation MI (with or without reperfusion)

IV. Contraindications

  1. Active Bleeding

V. Preparations

  1. Clopidogrel (Plavix)
    1. Generic as of May 2012
    2. Less GI Bleeding than Aspirin or Prasugrel
      1. Option if GI Bleeding occurs with Aspirin
      2. Switch to Plavix does not prevent recurrent GI Bleed
        1. GI Bleed occurs in 8% of those switched to Plavix
        2. Consider adding PPI to Aspirin instead of Plavix
  2. Prasugrel (Effient)
    1. More effective than Plavix in cardiovascular event reduction
    2. Higher risk of bleeding than Plavix in age >75 years, weight <60 kg, CVA history
    3. Avoid in prior Cerebrovascular Accident (CVA) or Transient Ischemic Attack (TIA)
    4. Typically initiated in the catheter lab
      1. Do not initiate in emergency department due to bleeding risk
    5. References
      1. Wiviott (2007) N Engl J Med 357(20):2001-15 [PubMed]
  3. Ticagrelor (Brilinta)
    1. Recommended by ACA (2016) over Clopidogrel in Acute Coronary Syndrome and stenting
    2. Per 1000 ACS patients, Ticagrelor prevents more adverse CV events than Clopidogrel
      1. Prevents 11 more cardiovascular deaths
      2. Prevents 11 more Myocardial Infarctions
      3. Prevents 6 more stent thromboses
    3. Majority of cardiovascular benefit is within first few weeks after Acute Coronary Syndrome
      1. Patients on Clopidogrel already will be unlikely to benefit from switch to Ticagrelor
      2. Discuss antiplatelet agent choice with cardiology at time of Acute Coronary Syndrome
    4. Adverse Effects and disadvantages
      1. Similar bleeding risk to Clopidogrel
      2. Dyspnea occurs with Brilinta use for 1 in 27 patients
      3. Requires twice daily dosing
    5. Dosing Adjustments
      1. No dosing adjustment needed in renal and mild hepatic Impairment
      2. Use caution in moderate liver disease and avoid in severe liver disease
    6. Adverse Effects
      1. Dyspnea
      2. Bleeding
      3. Dizziness or Syncope
      4. Acute Kidney Injury
      5. Other less common effects include Angioedema or Hypersensitivity, AV Block, Bradycardia, skin rash
    7. Safety
      1. Pregnancy Category C
      2. Lactation Unknown
    8. Drug Interactions: CYP3A4
    9. References
      1. (2012) Presc Lett 19(5): 27

VI. Disadvantages

  1. Clopidogrel (Plavix) is now generic ($10/month compared with $300/month for other agents)

VII. Dosing: Clopidogrel (Plavix)

  1. Standard dosing
    1. Plavix 75 mg orally daily
  2. Acute Myocardial Infarction
    1. Loading dose: Plavix 300 mg (if age <75 years)
    2. Then initiate standard 75 mg daily Plavix dose with Aspirin 81 mg
  3. Impending Percutaneous Coronary Intervention (PCI)
    1. Plavix 600 mg orally once
    2. Then initiate standard 75 mg daily Plavix dose after PCI

VIII. Dosing: Ticagrelor (Brilinta)

  1. Standard dosing
    1. Brilanta 90 mg orally twice daily
  2. Acute Myocardial Infarction with or without impending PCI
    1. Loading dose: Brilanta 180 mg orally once
    2. Then initiate standard 90 mg twice daily Brilanta dose
    3. Used with Aspirin 81 mg (Dual Antiplatelet Therapy) after PCI

IX. Dosing: Prasugrel (Effient)

  1. Impending Percutaneous Coronary Intervention (PCI)
    1. Effient 60 mg orally once
    2. Then initiate standard 10 mg daily Effient dose after PCI

X. Drug Interactions: General

  1. Morphine (and presumed other Opioids)
    1. Morphine decreased (35%) and delayed (2 hours) Ticagrelor absorption
    2. May affect acute STEMI management
    3. Kubica (2016) Int J Cardiol 215:201-8 [PubMed]

XI. Drug Interactions: Proton Pump Inhibitors interacting with Clopidogrel (Plavix)

  1. Agents that reduce conversion of Plavix to active metabolite (unclear clinical impact)
    1. Omeprazole
    2. Esomeprazole
  2. Safe agents that do not appear to interact with Plavix
    1. Lansoprazole
    2. Dexlansoprazole
    3. Pantoprazole
    4. Famotidine (high dose)
  3. Limit Proton Pump Inhibitors to high risk patients
    1. Prior GI Bleed
    2. Advanced age
    3. Concurrent Aspirin, NSAIDs, Corticosteroids, or Warfarin
  4. Application
    1. Avoid Proton Pump Inhibitors unless clear indication
    2. If a Proton Pump Inhibitor is needed
      1. Choose one that that does not interfere with Cloipidogrel (e.g. Lansoprazole)
      2. Consider agent that does not interact with PPIs such as Ticagrelor (Brilanta) in place of Clopidogrel
    3. Best data suggests no increased risk of cardiovascular events with PPI and Clopidogrel
  5. References
    1. (2013) Presc Lett 20(6): 36
    2. Mehta (2011) Clin Cardiol 34(9): 528-31 [PubMed]

XII. Management: Reversal

  1. Platelet Transfusion 2 units (12 pack)
  2. Consider Desmopressin (DDAVP) 0.3 mcg/kg (expert opinion)
  3. Consider Recombinant activated Clotting Factor VII (rFVIIa) 30-90 mcg/kg (expert opinion)

XIII. References

  1. Filler and Lovecchio (2017) Crit Dec Emerg Med 31(7): 24
  2. Switaj (2017) Am Fam Physician 95(4): 232-40 [PubMed]

Images: Related links to external sites (from Bing)

Related Studies

Cost: Medications

clopidogrel (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
CLOPIDOGREL 75 MG TABLET Generic $0.07 each
plavix (on 1/18/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
PLAVIX 75 MG TABLET Generic $0.07 each
effient (on 5/2/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
EFFIENT 10 MG TABLET $14.66 each
EFFIENT 5 MG TABLET $14.68 each
brilinta (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BRILINTA 60 MG TABLET $5.33 each
BRILINTA 90 MG TABLET $5.32 each

Ontology: clopidogrel (C0070166)

Definition (CHV) a kind of anti-clotting drug
Definition (CSP) inhibits platelet aggregation
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C055162
SnomedCT 108979001, 386952008
LNC LP171391-8
English clopidogrel, clopidogrel [Chemical/Ingredient], methyl 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno(3,2-c)pyridin-5-yl)acetate, CLOPIDOGREL, Clopidogrel, Clopidogrel (product), Clopidogrel (substance)
Spanish clopidogrel (producto), clopidogrel (sustancia), clopidogrel

Ontology: Thiophene (C0599532)

Definition (CSP) 5-membered aromatic ring structure with a sulfur heteroatom.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
SnomedCT 12878005
English thiophene, thiofuran, thiole, Thiophene (substance), Thiophene
Spanish tiofeno (sustancia), tiofeno

Ontology: Plavix (C0633084)

Definition (CHV) a drug that prevents heart attack
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C055162
English Plavix, clopidogrel bisulfate (Plavix), BMS brand 1 of clopidogrel bisulfate, plavix

Ontology: prasugrel (C1620287)

Definition (NCI) A novel platelet inhibitor approved for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome. Prasugrel produces inhibition of platelet aggregation by binding to receptors for ADP on the surface of platelets.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C408153
SnomedCT 443312008, 443129001
English Prasugrel (product), Prasugrel, Prasugrel (substance), prasugrel (medication), antiplatelet prasugrel, PRASUGREL, prasugrel
Spanish prasugrel (producto), prasugrel, prasugrel (sustancia)

Ontology: Ticagrelor (C1999375)

Concepts Pharmacologic Substance (T121) , Nucleic Acid, Nucleoside, or Nucleotide (T114)
MSH C503700
SnomedCT 698805004
English Ticagrelor, TICAGRELOR, ticagrelor, (1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, antiplatelet ticagrelor, antiplatelet ticagrelor (medication), Ticagrelor (substance)
Spanish ticagrelor (sustancia), ticagrelor

Ontology: Effient (C2718746)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
English Effient

Ontology: Adenosine Receptor Antagonists [MoA] (C2917195)

Concepts Molecular Function (T044)
English Adenosine Receptor Antagonists, Adenosine Receptor Antagonists [MoA]

Ontology: Thienopyridines (C2936588)

Definition (MSH) Heterocyclic compounds that contain 4H,5H,6H,7H-thieno[2,3-c]pyridine as part of their structure.
Definition (NCI) A class of agents that target at platelet ADP receptor or purinergic receptor P2RY12 with antiplatelet activity.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH D058924
English Platelet ADP Receptor Antagonist, Thienopyridine Antiplatelet Agent, Thienopyridine Derivatives, Derivatives, Thienopyridine, Thienopyridines [Chemical/Ingredient], Thienopyridines
French Dérivés de la thiéno-pyridine, Thiénopyridines, Thiéno-pyridines, Dérivés de la thiénopyridine
German Thienopyridin-Derivate, Thienopyridine
Czech thienopyridinové deriváty, thienopyridiny, deriváty thienopyridinu
Italian Tienopiridine
Spanish Tienopiridinas
Portuguese Tienopiridinas
Polish Tienopirydyny pochodne, Tienopirydyny
Croatian Not Translated[Thienopyridines]

Ontology: P2Y12 Receptor Antagonists [MoA] (C2962193)

Concepts Molecular Function (T044)
English P2Y12 Receptor Antagonists [MoA], P2Y12 Receptor Antagonists

Ontology: Brilinta (C3163571)

Concepts Nucleic Acid, Nucleoside, or Nucleotide (T114) , Pharmacologic Substance (T121)
MSH C503700
English Brilinta