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
Monitor
- Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time, [[Prothrombin Time]])
Dose Adjustment
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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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
- 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
- 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
- Adrenal Hemorrhage (see Adrenal Insufficiency, [[Adrenal Insufficiency]])
- Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]]
- Epistaxis (see Epistaxis, [[Epistaxis]])
- Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
- Hematuria (see Hematuria, [[Hematuria]])
- Intracerebral Hemorrhage (Hemorrhagic Cerebrovascular Accident) (see Intracerebral Hemorrhage, [[Intracerebral Hemorrhage]])
- Intracranial Epidural Hematoma (see Intracranial Epidural Hematoma, [[Intracranial Epidural Hematoma]])
- Retroperitoneal Hemorrhage (see Retroperitoneal Hemorrhage, [[Retroperitoneal Hemorrhage]])
- Spinal Epidural Hematoma (see Spinal Epidural Hematoma, [[Spinal Epidural Hematoma]])
- Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage, [[Subarachnoid Hemorrhage]])
- Subdural Hematoma (SDH) (see Subdural Hematoma, [[Subdural Hematoma]])
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]