anticoagulation pharmacology update margaret baldwin ... · anticoagulation pharmacology update...
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Anticoagulation Pharmacology Update
Margaret Baldwin, PharmD, BCPS
Pharmacist, Intermountain Medical Center, Intermountain Healthcare; Salt Lake City, Utah
Objectives: • Review new antithrombotic on the market • List new antithrombotic in the pipeline • Discuss how these new medications will impact patient care
Anticoagulant Pharmacology Update
Margaret Baldwin, PharmD, BCPSCritical Care Clinical PharmacistShock Trauma ICUIntermountain Medical Center
Objectives
Review new antithrombotics on the market
List new antithrombotics in the pipeline
Discuss how these new medications will impact patient care
Nature Reviews Cardiology Volume: 11, Pages: 290–303 Year published: (2014)
Warfarin
Approved in 1954 Most widely prescribed oral anticoagulant Drug interactions Genetics Diet Compliance
New Oral Anticoagulants (NOACs)
Advantages Uniform dosing Consistent anticoagulant effect No monitoring test required
Disadvantages No specific antidote for immediate reversal Very expensive
Cardiovascular Therapeutics 2010;28:278–286
Direct Thrombin Inhibitors (DTIs)
Binds directly to thrombin Parenteral
Argatroban Bivalirudin (Angiomax®) Leprudin
Oral Dabigatran (Pradaxa®)
Advantages Reversal
Cardiovascular Therapeutics 2010;28:278–286
Nature Reviews Cardiology Volume: 11, Pages: 290–303 Year published: (2014)
Dabigatran Approved October 2010
Treatment of acute VTE Prevention of VTE following total knee or hip Prevention of stroke in atrial fibrillation
Prodrug Converted in the liver to its active compound
Dosing 150 mg PO BID 75 mg PO BID (CrCl 15-30 mL/min)
Half-life ~ 12 to 14 hours Renal excretion ~ 80%
Dabigatran. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH.Available at: http://online.lexi.com. Accessed September 6, 2014
Laboratory Testing Activated partial thromboplastin time (aPTT)
Increases with larger doses• Dose response not linear• Plateaus at higher concentrations
PT/INR Variably affected, shown to rise Insensitive measure of activity
Thrombin time (TT) Most sensitive
• Normal value, no drug • Above normal, high concentrations
Ecarin clotting time (ECT) Most sensitive and accurate measure Not widely available
N Engl J Med 2014;370:847-859
Direct Factor Xa Inhibitors
Direct Xa inhibition Rivaroxaban (Xaralto®) Apixaban (Eliquis®) Edoxaban (Lexiana)
Advantages Reversal
Hemodialysis
Ther Drug Monit 2010;32:673–679Thromb Haemost 2010; 103: 815–825Circulation 2011;124:00-00
Nature Reviews Cardiology Volume: 11, Pages: 290–303 Year published: (2014)
Rivaroxaban FDA indications and Dosing
VTE prophylaxis (hip or knee replacement)• 10 mg PO daily (CrCl ≥ 30 mL/min)
VTE treatment• 15 mg PO BID x 21 days, then 20 mg PO daily
Stroke prevention in non-valvular atrial fibrillation• 20 mg PO daily (CrCl > 50 mL/min)• 15 mg PO daily (CrCl 15-50 mL/min)
Half-life ~ 7-9 hours Take with food Reversal
4 factor prothrombin complex concentrate (PCC)
Rivaroxaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed September 6, 2014
Rivaroxaban Creatinine clearance
< 30 mL/min (not recommended) < 15 mL/min (absolute)
Significant hepatic impairment Less than 18 years of age Pregnancy (absolute) Breastfeeding (not recommended) Drug interactions
CYP-3A4 P-glycoprotein efflux transporter
Rivaroxaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed September 6, 2014
Apixaban
FDA indications and dosing Prevention of VTE
• Hip replacement: 2.5 mg PO BID • Knee replacement: 2.5 mg PO BID • Secondary: 2.5 mg BID
Treatment of VTE• Acute: 10 mg PO BID x7 days, then 5 mg PO BID
Stroke prevention in non-valvular atrial fibrillation• 5 mg PO BID
Half-life ~ 8-15 hours 87 % protein bound (not dialyzable) Renal excretion
Apixaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed September 6, 2014
Apixaban
Considerations Patients > 80 years Weight < 60 kg Serum creatinine > 1.5
Drug interactions CYP3A4 and P-glycoprotein inhibitors
• Half dose
Avoid if patient meets 2 of the above criteria and on 2.5 mg PO BID
Hold 24-48 hours prior to elective surgery
Apixaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed September 6, 2014
Edoxaban
Not FDA approved in the United States Phase 3 trials
Studied doses 30 mg or 60 mg PO daily
Once daily dosing Peak concentrations 1.5 hours Half-life 10-14 hours Not affected by food Few drug interactions
Enoxaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed September 6, 2014
Monitoring
No standard laboratory testing to measure the anticoagulant effect Activated partial thromboplastin time (aPTT)
• May be most reliable Prothrombin time (PT) Anti-Xa activity
Antiplatelet
Bind to P2Y12 adenosine diphosphate receptors, reducing platelet activation and aggregation Clopidogrel (Plavix®)
• Irreversible Prasugrel (Effient®)
• Irreversible Ticagrelor (Brilinta®)
• Reversible
Monitoring P2Y12 assay
Clopidogrel FDA indications
Acute coronary syndrome• 300-600 mg PO x1, then 75 mg PO daily
Thrombotic event prevention• 75 mg PO daily
Prodrug Half life ~ 8 hours CYP2C19 primary metabolism
Consider genotyping• Poor metabolizers may not respond to therapy
Precautions Elective surgery within 5 days
Clopidogrel. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed September 6, 2014.
Prasugrel FDA indication
Acute coronary syndrome• 60 mg PO x1, then 10 mg PO daily• 5 mg PO daily if body weight < 60 kg
Prodrug Half-life ~ 7 hours Liver metabolized No monitoring test required Precaution
CABG surgery within 7 days Not recommended in patients over 75 years History of stroke/TIA
Prasugrel. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH.Available at: http://online.lexi.com. Accessed September 6, 2014
Ticagrelor FDA indications
ACS and PCI• 90 mg PO BID• Usually given with aspirin 81 mg PO daily
Half-life ~ 7 hours Liver metabolism through CYP3A4 No routine monitoring required Caution
History of intracranial hemorrhage Elective surgery within 5 days Active bleeding Hepatic impairment
Ticagrelor. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH.Available at: http://online.lexi.com. Accessed September 6, 2014
Vorapaxar (Zontivity™)Protease-activated receptor-1 (PAR-1) antagonist
Inhibits platelet aggregation induced by thrombin and thrombin receptor agonist peptide (TRAP)
http://openi.nlm.nih.gov/detailedresult.php?img=3224753_1756-8722-4-44-1&req=4. Accessed September 7, 2014Zontivity ™[package insert]. Whitehouse Station ,NJ: Merick & Co., Inc.; 2013
Vorapaxar (Zontivity™)
FDA indication Thrombotic event prevention
• 2.08 mg PO daily
Given with aspirin or clopidogrel Half-life ~ 8 days Metabolized by the liver Contraindicated in patients with a history of
intracranial hemorrhage, stroke or TIA
Zontivity ™[package insert]. Whitehouse Station ,NJ: Merick & Co., Inc.; 2013
Antithrombotic ReversalMedication Reversal ProcedureAspirin Platelets +/- DDAVP
P2Y-12 antagonists (clopidogrel, etc) Platelets
Unfractionatedheparin Protamine
LMWH Protamine. Consider recomb activated factor VIIDanaparoid None. Plasmapheresis?Fondaparinux None. Consider recomb activated factor VIIBivalirudin None. Consider hemodialysisArgatroban NoneWarfarin Vitamin K, Prothrombin Complex Concentrate, FFP
DabigatranNone. Consider active charcoal, hemodialysis, Prothrombin Complex Concentrate, and recombactivated factor VII
Rivaroxaban, apixaban, edoxaban
None. Consider active charcoal, hemodialysis, Prothrombin Complex Concentrate, and recombactivated factor VII
N Engl J Med. 2014;370:847-859
Anticoagulants in the Pipeline
Tecarfarin (ATI-5923) A vitamin K antagonist currently in clinical trials Metabolized by esterases rather than the cytochrome
P450 system Not susceptible to have the drug-drug, drug-food,
and genetic alterations common to the other vitamin K antagonists
TB-402 Factor VIII partial inhibitor Human IgG4 monoclonal antibody Long half-life ~ 3 weeks Phase II trial in patients with total knee replacement
Anticoagulants in the Pipeline
ART-123 Recombinant soluble thrombomodulin Phase II trial have shown efficacy for VTE
prophylaxis following hip replacement Half-life ~ 2-3 days Given subcutaneous every 5-6 days
Others in development Factor IXa inhibitor Factor XI inhibitor Factor XIIa inhibitor
New Agents in Trauma
Familiarity Not sure how to monitor or gage therapeutic
affects of the medications Reversal is not clearly defined
Possible delay in time to emergent OR
Increased bleeding risks $$$$$$$
Questions
Anticoagulant Pharmacology Update
Margaret Baldwin, PharmD, BCPSCritical Care Clinical PharmacistShock Trauma ICUIntermountain Medical Center