Coumarin is a Sweet-Smelling Chemical with No Anticoagulant Properties: found in sweet clover, tonka beans (cumaru), and other plants
Dicoumarol is a Mycotoxin Anticoagulant Which is Derived from Coumarin: originally isolated from sweet clover-based animal feeds
Warfarin is a Synthetic Derivative of Dicoumarol
Warfarin Functions to Inhibit Vitamin K Epoxide Reductase
Vitamin K Epoxide Reductase Recycles Vitamin K1 to its Reduced Form
Inhibition of Vitamin K Epoxide Reductase Results in Vitamin K Depletion
Impaired Carboxylation of Vitamin K-Dependent Coagulation Factors
Prothrombin (Factor II)
Factor VII
Factor IX
Factor X
Protein C
Protein S
Protein Z
Impaired Bone Metabolism
Administration
PO:
Monitor
Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time, [[Prothrombin Time]])
Dose Adjustment
Hepatic: xxx
Renal: xxx
Genotype-Guided Coumadin Dosing
Clinical Efficacy
Systematic Review and Meta-Analysis of Genoptye-Guided Coumadin Dosing (Br J Clin Pharmacol, 2015) [MEDLINE]: 9 studies evaluated genotype-guided coumadin dosing
Genotype-Guided Coumadin Dosing Demonstrated Improved Time Within the Therapeutic INR Range
Genotype-Guided Coumadin Dosing Decreased Coumadin-Related Minor Bleeding, Major Bleeding, and Thromboembolism
Evaluation of the Efficacy of Genotype-Guided Dosing for Other Medications was not Possible in this Study
Drug Interactions
Agents Which Enhance the Effect of Coumadin
Ceftaroline (Teflaro, Zinfloro) (see Ceftaroline, [[Ceftaroline]])
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Agents Which Inhibit the Effect of Coumadin
Green, Leafy Vegetables
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xxx
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xxx
Effect on Anticoagulation Tests
Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time, [[Prothrombin Time]]): prolonged
Partial Thromboplastin Time (PTT)b (see Partial Thromboplastin Time, [[Partial Thromboplastin Time]]): no change-slightly increased
However, Coumadin Enhances the PTT-Prolonging Effect of Heparin
Thrombin Time (TT) (see Thrombin Time, [[Thrombin Time]]): no change
Anti-Factor Xa Activity (see Anti-Factor Xa Activity, [[Anti-Factor Xa Activity]]): no change
Management of Coumadin for Surgery/Major Procedures (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
Risk for Perioperative Thromboembolism
Anticoagulation for Mechanical Heart Valve
High Risk for Perioperative Thromboembolism
Any Mitral Valve Prosthesis
Caged-Ball or Tilting Disc Aortic Valve Prosthesis
History of Thromboembolism During Prior Temporary Interruption of Anticoagulation
Recent (Within 6 mo) Stroke or Transient Ischemic Attack (TIA)
Surgery Associated with Increased Risk of Stroke or Thromboembolism (Cardiac Valve Replacement, Carotid Endarterectomy, Major Vascular Surgery)
Moderate Risk for Perioperative Thromboembolism
Bileaflet Aortic Valve Prosthesis and ≥1 of the Following Risk Factors
Age >75 y/o
Atrial Fibrillation
Congestive Heart Failure
Diabetes Mellitus
History of Stroke or Transient Ischemic Attack
Hypertension
Low Risk for Perioperative Thromboembolism
Bileaflet Aortic Valve Prosthesis without Atrial Fibrillation and No Other Risk Factors for Stroke
Anticoagulation for Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])
High Risk for Perioperative Thromboembolism
CHADS2 Score 5-6
History of Stroke or Transient Ischemic Attack Within 3 mo (and Also Possibly History of Stroke or Transient Ischemic Attack >3 mo Ago with CHADS2 Score <5)
History of Thromboembolism During Prior Temporary Interruption of Anticoagulation
Rheumatic Valvular Heart Disease
Surgery Associated with Increased Risk of Stroke or Thromboembolism (Cardiac Valve Replacement, Carotid Endarterectomy, Major Vascular Surgery)
Moderate Risk for Perioperative Thromboembolism
CHADS2 Score 3-4
Low Risk for Perioperative Thromboembolism
CHADS2 Score 0-2 (Assuming No History of Stroke or Transient Ischemic Attack)
Severe Thrombophilia (Protein C Deficiency, Protein S Deficiency, Antithrombin Deficiency, Antiphospholipid Antibody Syndrome)
Surgery Associated with Increased Risk of Stroke or Thromboembolism (Cardiac Valve Replacement, Carotid Endarterectomy, Major Vascular Surgery)
Moderate Risk for Perioperative Thromboembolism
Active Cancer (Treated Within 6 mo or Palliative)
Non-Severe Thrombophilia (Heterozygous Factor V Leiden, Prothrombin Gene Mutation)
Recurrent Venous Thromboembolism
Venous Thromboembolism Within the Past 3-12 mo
Low Risk for Perioperative Thromboembolism
Venous Thromboembolism >12 mo Ago and No Other Risk Factors
Clinical Efficacy
BRIDGE Trial Studying Peri-Operative Low Molecular Weight Heparin Bridge Therapy in Atrial Fibrillation Patients on Coumadin with Planned Interruption for Surgery/Procedures (NEJM, 2015) [MEDLINE]
In Atrial Fibrillation with Coumadin Interruption for Elective Surgery/Invasive Procedure, Forgoing Low Molecular Weight Heparin Bridge Therapy Decreased the Rate of Bleeding and was Non-Inferior to Using Low Molecular Weight Heparin Bridge Therapy for the Prevention of Arterial Thromboembolism
Recommendations
Discontinue Coumadin 5 Days Prior to Surgery/Major Procedure (Grade 1C Recommendation)
In Patients with Mechanical Heart Valve, Atrial Fibrillation, or Venous Thromboembolism at Low Risk for Perioperative Thromboembolism, Bridging Anticoagulation is Not Recommended (Grade 2C Recommendation)
In Patients with Mechanical Heart Valve, Atrial Fibrillation, or Venous Thromboembolism at High Risk for Perioperative Thromboembolism, Bridging Anticoagulation is Recommended (Grade 2C Recommendation)
When Coumadin is Discontinued for Surgery/Major Procedure, Resume 12-24 hrs After Surgery/Major Procedure (Evening of or Next Morning) or When There is Adequate Hemostasis (Grade 2C Recommendation)
Management of Coumadin for Minor Dental Procedures
Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
Discontinue Coumadin 2-3 Days Prior to Procedure or Continue Coumadin with an Oral Prohemostatic Agent (Grade 2C Recommendation)
Management of Coumadin for Minor Dermatologic Procedures
Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
Continue Coumadin and Optimize Local Hemostasis (Grade 2C Recommendation)
Management of Coumadin for Cataract Surgery
Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
Continue Coumadin and Optimize Local Hemostasis (Grade 2C Recommendation)
Recommendations (Neurocritical Care Society and Society of Critical Care Medicine Guidelines for Reversal of Antithrombotics in the Setting of Intracranial Hemorrhage, 2016) [MEDLINE]
Factor VIIa is Not Recommended in this Setting (Strong Recommendation, Low Quality Evidence)
Pharmacology: contains all of the coagulation factors which are present in whole blood
The Amount of FFP Required to Correct the INR Individually Varies Due to the Non-Linear Exponential Relationship Between Coagulation Factor Levels and Coagulation Test Results
Advantages
Low Cost: $200-400 per dose
Widely Available
Disadvantages
Fluid Load
Long Latency to Correction of the INR: may take >30 hrs
Recommendation
May Be Considered if Prothrombin Complex Concentrate-4 Factor is Not Available or if Patient Cannot Tolerate Prothrombin Complex Concentrates
Trial Comparing PCC to FFP in the Correction of INR in Coumadin-Associated Hemorrhage (Circulation, 2013) [MEDLINE]: PCC-4 factor was superior to FFP in terms of achieving rapid INR correction
Randomized, Non-Inferiority Trial Comparing Prothrombin Complex Concentrate-4 Factor vs Fresh Frozen Plasma in Reversing Coumadin (Lancet, 2015) [MEDLINE]: prothrombin complex concentrate-4 factor achieved effective hemostasis in 90% of subjects, as compared to 75% in the plasma group
Safety Profile (Thromboembolic Events, Fluid Overload, and Late Bleeding Events): similar in the two groups
Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
For Coumadin Anticoagulation with Associated Major Hemorrhage, Prothrombin Complex Concentrate-4 Factor is Recommended Over Fresh Frozen Plasma (Grade 2C Recommendation)
Intravenous Vitamin K (5-10 mg IV) is Also Recommended: see below
Recommendations (Neurocritical Care Society and Society of Critical Care Medicine Guidelines for Reversal of Antithrombotics in the Setting of Intracranial Hemorrhage, 2016) [MEDLINE]
Prothrombin Complex Concentrate-3 Factor or Prothrombin Complex Concentrate-3 Factor are Recommended Over FFP or Factor VIIa (Conditional Recommendation, Low Quality Evidence)
Prothrombin Complex Concentrate-4 Factor is Recommended Over Prothrombin Complex Concentrate-3 Factor (Conditional Recommendation, Low Quality Evidence)
Intravenous Vitamin K (5-10 mg IV) is Also Recommended: see below
Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3 [MEDLINE]
A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369(24):2294-2303 [MEDLINE]
A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369(24):2283-2293 [MEDLINE]
Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma- controlled, phase IIIb study. Circulation. 2013;128:1234–43 [MEDLINE]
Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation. 2013 Jul 23;128(4):360-4. doi: 10.1161/CIRCULATIONAHA.113.001875. Epub 2013 Jun 14 [MEDLINE]
Genotype-guided drug prescribing: a systematic review and meta-analysis of randomized control trials. Br J Clin Pharmacol. 2015 Oct;80(4):868-77. doi: 10.1111/bcp.12475. Epub 2015 Jul 22 [Epub ahead of print] [MEDLINE]
Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015 May 23;385(9982):2077-87. doi: 10.1016/S0140-6736(14)61685-8. Epub 2015 Feb 27 [MEDLINE]
Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015;373(9):823 [MEDLINE]
Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]
Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016 Feb;24(1):6-46. doi: 10.1007/s12028-015-0222-x [MEDLINE]
