By: Hadeel Al-Kofide MS.c Anticoagulation Focusing on Warfarin Drug Interactions Bridge Therapy & Patient Education By: Hadeel Al-Kofide MS.c

Topics we will cover.. Warfarin interactions: Drug-drug interactions Herb-drug interaction Bridge therapy: Bridge therapy during invasive procedures Bridge therapy during dental procedures Patient education

Warfarin Interactions

A Real Case CJ is a 48 y.o. male, s/p cadaveric renal transplant, developed embolic CVA On chronic anticoagulation for 4 years Presented to the primary care clinic with painful, discolored, cracking of great toe Treated with itraconazole 100 mg po qd

14 Days Later.... Presents to AC clinic INR 18.5 (repeated and verified) Hgb/Hct: 7.5/22 Guiac: +

Why??!! When he was asked why he took it: Neither my doctor nor the pharmacist that filled the prescription thought it would be a problem

The Final Outcome Three day admission 4 units PRBC’s transfused Cost to the health care system of $5000-7000 Cost in lost productivity, work time, etc.?????? Could this have been avoided?

List of Top Ten Drug Interactions in Long-Term Care Warfarin + NSAIDs Sulfa drugs Macrolides Quinolones Phenytoin ACE inhibitors + Potassium supplements Spironolactone Digoxin + Amiodarone Verapamil Theophylline +

Why Drugs Interact with Warfain Pharmacokinetic interactions Alteration in: Absorption Protein binding Hepatic metabolism Pharmacodynamic interactions Affect tendency for bleeding or clotting through: Antiplatelet effects Increases or decreases in vitamin K catabolism

Drug Interaction Mechanisms Interference with platelet function: Platelet aggregation is a crucial first step in primary hemostasis Drugs that impair platelet function increase the risk of hemorrhage in patients on warfarin They do so without elevating the INR ASA & clopidogrel INR = International Normalized Ratio

Drug Interaction Mechanisms NSAIDs Injury to gastrointestinal mucosa: NSAIDs cause dose- & duration-dependent gastrointestinal erosions The risk of hemorrhage is high by the concomitant use of warfarin, even in patients whose INR lies within the desired range NSAIDs = Non-Steroidal Anti-Inflammatory Drugs

Drug Interaction Mechanisms Reduced synthesis of vitamin K by intestinal flora Vitamin K is partly dependent on the synthesis of vitamin K2 by intestinal microflora Many antibiotics alter the balance of gut flora, thereby enhancing the effect of warfarin Some antibiotics also inhibit the hepatic metabolism of warfarin. These antibiotics include co-trimoxazole, metronidazole, macrolides & fluoroquinolones

Drug Interaction Mechanisms Interference with warfarin metabolism: Warfarin is metabolized through cytochrome P450 Drugs that inhibit this enzyme (e.g., amiodarone, co- trimoxazole, metronidazole and fluvoxamine) potentiate the effect of warfarin Other drugs that induce CYP 2C9 activity (e.g., rifampin) will do the converse

Drug Interaction Mechanisms Interruption of the vitamin K cycle: The most important drug in this category is acetaminophen One of acetaminophen metabolites inhibits vitamin K- dependent carboxylase, a key enzyme in the vitamin K cycle Some patients may have rapid & dramatic rise in the INR

Risk on hemorrhage (INR) Drug Interactions Drug Risk on hemorrhage (INR) Mechanism Estrogen Vitamin K ↓ Increase synthesis of clotting factors Cholestyramine Reduce absorption of warfarin Thyroid Hormones ↑ Increase catabolism of clotting factors Separate dose 2-6 hrs

Risk on hemorrhage (INR) Metronidazole, Fluoroquinolones Drug Interactions Drug Risk on hemorrhage (INR) Mechanism Nafcillin Barbiturates Rifampin Phenytoin ↓ Induction of warfarin metabolism Macrolides Co-trimoxazole, Metronidazole, Fluoroquinolones ↑ Inhibition of vitamin K synthesis by intestinal flora, inhibition of hepatic warfarin metabolism, or both

Drug Interactions ↑ Drug Risk on hemorrhage (INR) Mechanism Fluconazole, miconazole Amiodarone ↑ Inhibition of warfarin metabolism Acetylsalicylic acid, Clopidogrel, Ticlopidine NSAID Interference with primary hemostasis UFH LMH Additive anticoagulant response

Herbal Interactions ↑ ↓ Drug Risk on hemorrhage (INR) Mechanism Chinese wolfberry, Cranberry juice, grapefruit juice ↑ Inhibition of warfarin metabolism Garlic Ginger Ginkgo Inhibition of platelet aggregation St. John’s wort ↓ Induction of warfarin metabolism

Risk on hemorrhage (INR) Herbal Interactions Drug Risk on hemorrhage (INR) Mechanism Green tea ↓ Contain vitamin K Ginseng Unknown

Management of Drug Interactions Patients taking warfarin are susceptible to numerous drug interactions Can we avoid them?? Close monitoring of INR Adjust warfarin dose according to INR

Bridge Therapy

Risk of thromboembolism Bridge Therapy Temporary use of intravenous UFH or LMWH for a patient on long-term anticoagulation who is about to undergo a surgical procedure is called bridge therapy Risk of thromboembolism Risk of bleeding The introduction of bridge therapy with LMWH has led to significant lowering of perioperative health care costs

Bridge Therapy Management of anticoagulation around invasive procedures Management of anticoagulation around dental procedures

Types of Invasive Procedures High Risk of Bleeding Cardiac surgery Neurosurgery, Most cancer surgery Bilateral knee replacement Kidney biopsy Low Risk of Bleeding Coronary angiography GI endoscopy Colonoscopy Bronchoscopy Biopsy (thyroid, breast, lymph node, pancreas) GI = Gastro-Intestinal

Bridge Therapy During Invasive Procedures Thrombosis Risk CrCl Bridge Therapy High > 30 Pre-Procedure Post-Procedure Day 5 Day 3 Day 1 12-24 hr 12-48 hr AF Stroke history Mechanical valve DVT/PE < 3 mo Last dose warfarin Enoxaparin 1 mg/kg q 12 hr Vitamin K 2.5 mg PO Last dose enoxaparin Resume enoxaparin Resume warfarin AF = Atrial Fibrillation; DVT = Deep Vein Thrombosis PE = Pulmonary Embolism

Bridge Therapy During Invasive Procedures Thrombosis Risk CrCl Bridge Therapy High ≤ 30 Pre-Procedure Post-Procedure Day 3 Day 2 Day 1 12-24 hr 12-48 hr AF Stroke history Mechanical valve DVT/PE < 3 mo Last dose warfarin Vitamin K 2.5 mg PO Admit; IV UFH LD 70 U/kg MD 15 U/kg If INR >1.5 give vitamin K 1 mg IV Stop UFH 6 hrs pre-procedure Resume UFH Resume warfarin UFH = Un-Fractionated Heparin IV = IntraVenous

Bridge Therapy During Invasive Procedures Thrombosis Risk CrCl Bridge Therapy Low All Pre-Procedure Post-Procedure Day 4 Day 2 Day 1 12-24 hr 12-48 hr Cardiome- gally with no history of thrombosis DVT/PE > 3 mo Last dose warfarin Vitamin K 2.5 mg PO ----- Resume warfarin

Bridge Therapy During Dental Procedures Bleeding Risk Procedure Recommendations Low Surgical scalling Simple restoration Local anesthetic injection Do not interrupt warfarin treatment Use local measures to prevent or control bleeding

Bridge Therapy During Dental Procedures Bleeding Risk Procedure Recommendations Moderate Subgingival scalling Restoration with subgingival preparations Standard root canal therapy Simple extraction Regional injection of local anesthetics Interruption of warfarin treatment is not necessary Use local measures to prevent or control bleeding

Bridge Therapy During Dental Procedures Bleeding Risk Procedure Recommendations High Extensive surgery Apicoectomy (root removal) Alveolar surgery (bone removal) Multiple extractions Need to reduce INR or even return to normal hemostasis Follow bridge therapy guideline for invasive procedures based on risk of thromboembolism

Patient Education

What to tell your patients? Group Discussion