Coumadin

Historical Nomenclature

  • The Term Warfarin was Derived from the Wisconsin Alumni Research Foundation (“warf”) and “arin” from Coumarin

Indications for Anticoagulation

Cardiovascular

Pulmonary

Other


Pharmacology

Origin

  • 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]])
  • xxx
  • xxx
  • xxx
  • xxx
  • xxx
  • xxx

Agents Which Inhibit the Effect of Coumadin

  • Green, Leafy Vegetables
  • xxx
  • xxx
  • xxx
  • 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)
  • Anticoagulation for Venous Thromboembolism (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]] and Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])
    • High Risk for Perioperative Thromboembolism
      • Venous Thromboembolism ≤3 mo Ago
      • 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)

Reversal of Anticoagulation

Factor VIIa (see Factor VIIa, [[Factor VIIa]])

  • 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)

Fresh Frozen Plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])

  • 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

Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])

  • Pharmacology:
  • Advantages
    • Rapid Correction of the INR
  • Disadvantages
    • Expensive
  • Clinical Efficacy
    • 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

Vitamin K (see Vitamin K, [[Vitamin K]])

  • Adverse Effects
    • Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]): risk is low (only 3 per 10k doses)
      • Decreasing the Infusion Rate May Decrease the Risk of Anaphylaxis, But This is Controversial
  • Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Coumadin Anticoagulation with INR 4.5-10 without Associated Hemorrhage
      • Vitamin K is Not Recommended (Grade 2B Recommendation)
    • Coumadin Anticoagulation with INR >10 without Associated Hemorrhage
      • Vitamin K (Oral) is Recommended (Grade 2C Recommendation)
    • Coumadin Anticoagulation with Associated Hemorrhage
      • Vitamin K (5-10 mg Slow IV Infusion) is Recommended, In Addition to Prothrombin Complex Concentrate-4 Factor (Grade 2C Recommendation)

Adverse Effects

Hemorrhagic Adverse Effects

Types of Hemorrhage

Dermatologic Adverse Effects

  • Coumadin-Induced Skin Necrosis

Other Adverse Effects

  • Calcification of Arteries and Valves
  • Osteoporosis (see Osteoporosis, [[Osteoporosis]])
  • Purple Toe Syndrome

References

  • 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]