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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

Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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Page 1: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 2: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Anticoagulant Pharmacology Update

Margaret Baldwin, PharmD, BCPSCritical Care Clinical PharmacistShock Trauma ICUIntermountain Medical Center

Page 3: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Objectives

Review new antithrombotics on the market

List new antithrombotics in the pipeline

Discuss how these new medications will impact patient care

Page 4: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Nature Reviews Cardiology Volume: 11, Pages: 290–303 Year published: (2014)

Page 5: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Warfarin

Approved in 1954 Most widely prescribed oral anticoagulant Drug interactions Genetics Diet Compliance

Page 6: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 7: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Direct Thrombin Inhibitors (DTIs)

Binds directly to thrombin Parenteral

Argatroban Bivalirudin (Angiomax®) Leprudin

Oral Dabigatran (Pradaxa®)

Advantages Reversal

Cardiovascular Therapeutics 2010;28:278–286

Page 8: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Nature Reviews Cardiology Volume: 11, Pages: 290–303 Year published: (2014)

Page 9: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 10: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 11: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 12: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Nature Reviews Cardiology Volume: 11, Pages: 290–303 Year published: (2014)

Page 13: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 14: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 15: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 16: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 17: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 18: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 19: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Antiplatelet

Bind to P2Y12 adenosine diphosphate receptors, reducing platelet activation and aggregation Clopidogrel (Plavix®)

• Irreversible Prasugrel (Effient®)

• Irreversible Ticagrelor (Brilinta®)

• Reversible

Monitoring P2Y12 assay

Page 20: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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.

Page 21: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 22: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 23: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 24: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 25: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 26: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 27: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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

Page 28: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

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 $$$$$$$

Page 29: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Questions

Page 30: Anticoagulation Pharmacology Update Margaret Baldwin ... · Anticoagulation Pharmacology Update Margaret Baldwin, PharmD, BCPS Pharmacist, Intermountain Medical Center, Intermountain

Anticoagulant Pharmacology Update

Margaret Baldwin, PharmD, BCPSCritical Care Clinical PharmacistShock Trauma ICUIntermountain Medical Center