By: Hadeel Al-Kofide MS.c

Warfarin interactions:

Drug-drug interactions

Herb-drug interaction

Bridge therapy:

Bridge therapy during invasive procedures

Bridge therapy during dental procedures

Patient education

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

Presents to AC clinic

INR 18.5 (repeated and verified)

Hgb/Hct: 7.5/22

Guiac: +

When he was asked why he took it:

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?

1. Warfarin + NSAIDs

2. Warfarin + Sulfa drugs

3. Warfarin + Macrolides

4. Warfarin + Quinolones

5. Warfarin + Phenytoin

6. ACE inhibitors + Potassium supplements

7. ACE inhibitors + Spironolactone

8. Digoxin + Amiodarone

9. Digoxin + Verapamil

10.Theophylline + Quinolones

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 INRASA &

clopidogrel

INR = International Normalized Ratio

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

NSAIDs = Non-Steroidal Anti-Inflammatory Drugs

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

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

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

DrugRisk on

hemorrhage (INR)

Mechanism

EstrogenVitamin K ↓ Increase synthesis

of clotting factors

Cholestyramine ↓ Reduce absorption of warfarin

Thyroid Hormones ↑ Increase catabolism

of clotting factors

Separate dose 2-6 hrs

DrugRisk on

hemorrhage (INR)

Mechanism

NafcillinBarbiturates

RifampinPhenytoin

↓Induction of

warfarin metabolism

MacrolidesCo-trimoxazole,Metronidazole,

Fluoroquinolones↑

Inhibition of vitamin K synthesis by intestinal flora,

inhibition of hepatic warfarin

metabolism, or both

DrugRisk on

hemorrhage (INR)

Mechanism

Fluconazole, miconazoleAmiodarone

↑Inhibition of

warfarin metabolism

Acetylsalicylic acid, Clopidogrel,

TiclopidineNSAID

↑ Interference with primary hemostasis

UFHLMH ↑

Additive anticoagulant

response

DrugRisk on

hemorrhage (INR)

Mechanism

Chinese wolfberry, Cranberry

juice, grapefruit juice

↑Inhibition of

warfarin metabolism

GarlicGingerGinkgo

↑ Inhibition of plateletaggregation

St. John’s wort ↓Induction of

warfarin metabolism

DrugRisk on

hemorrhage (INR)

Mechanism

Green tea ↓ Contain vitamin K

Ginseng ↓ Unknown

Patients taking warfarin are susceptible to numerous drug interactions

Can we avoid them??

Close monitoring of INR

Adjust warfarin dose according to INR

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

1. Management of anticoagulation around invasive procedures

2. Management of anticoagulation around dental procedures

GI = Gastro-Intestinal

Thrombosis Risk

CrCl Bridge Therapy

High

> 30

Pre-Procedure Post-Procedure

Day 5 Day 3 Day 1 12-24 hr12-48

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 enoxapari

n

Resume enoxapari

n

Resume

warfarin

AF = Atrial Fibrillation; DVT = Deep Vein ThrombosisPE = Pulmonary Embolism

Thrombosis Risk

CrCl Bridge Therapy

High

≤ 30

Pre-Procedure Post-Procedure

Day 3 Day 2 Day 1 12-24 hr12-48

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/kgMD 15 U/kg

If INR >1.5 give vitamin K 1

mg IVStop UFH 6 hrs pre-procedure

Resume UFH

Resume

warfarin

UFH = Un-Fractionated HeparinIV = IntraVenous

Thrombosis Risk

CrCl Bridge Therapy

Low

All

Pre-Procedure Post-Procedure

Day 4 Day 2 Day 1 12-24 hr12-48

hr

Cardiome-gally with no history of thrombosis

DVT/PE > 3 mo

Last dose

warfarin

Vitamin K 2.5 mg PO

----- -----

Resume

warfarin

Bleeding Risk

Procedure Recommendations

Low1. Surgical scalling2. Simple restoration3. Local anesthetic

injection

1. Do not interrupt warfarin treatment

2. Use local measures to prevent or control bleeding

Bleeding Risk

Procedure Recommendations

Moderate

1. Subgingival scalling

2. Restoration with subgingival preparations

3. Standard root canal therapy

4. Simple extraction5. Regional injection

of local anesthetics

1. Interruption of warfarin treatment is not necessary

2. Use local measures to prevent or control bleeding

Bleeding Risk

Procedure Recommendations

High

1. Extensive surgery2. Apicoectomy (root

removal)3. Alveolar surgery

(bone removal)4. Multiple

extractions

1. Need to reduce INR or even return to normal hemostasis

2. Follow bridge therapy guideline for invasive procedures based on risk of thromboembolism

Group Discussion