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Sukhum

ANTICOAGULATION CLINIC GUIDELINE

Contents

Chapter 1

• Warfarin characteristic.
• Average Warfarin daily dose.
• Factors effect the Warfarin daily dose.
• Warfarin tablets
• Generic Warfarin (Update soon)
• Treatment Monitoring, standard and Point of Care

Chapter 2

• Initiation dose.
  • Inpatient.
  • Outpatient.
  • Ethnic Difference for Pacific-Asian or Chinese-Asian
  • Table. Warfarin Initiation
• Maintenance dose.
  • Weekly dose.
  • Daily schedule.
  • Dose adjustment
• Warfarin dose schedule table.

Chapter 3

• Target INR.
• Target INR for Atrial Fibrillation-Atrial Flutter
• Target INR for Venous Thrombosis (DVT and PE)
• Target INR for Various Conditions
• Target INR for Heart Valve Prostheses

Chapter 4

• Managing high INR.
• Vitamin K.

Chapter 5

• Managing anticoagulation during surgeries.
• Heparin bridging therapy
• Anticoagulation in pregnancy

Chapter 6

Drugs interact with warfarin (Updating)

Chapter 7

References and anticoagulation web sites. (Updating)

Chapter 8

Patient education.

 

Introduction

This guidelines was prepared for outpatient Warfarin (Coumadin) management, related to cardiology work such as atrial fibrillation and prosthetic heart valve. Other conditions are briefly included.

This guidelines was first prepared in 2001, for Central Minnesota Heart Center Anticoagulation Clinic. There was an 2004 updated. In 2007 this guidelines has inserted ethnic difference information in few appropriate areas, to be the guidelines for Bangkok Hospital Anticoagulation Clinic program. It follows the major anticoagulation guidelines, i.e. 6th and 7th ACCP Consensus Conference on Antithrombotic Therapy (Chest 2001and 2004), ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation. and ACC/AHA 2006 practice Guidelines for the Management of Patients with Valvular Heart Disease. Some other databases are also listed in the bibliography section. Database on ethnic difference is limited at the present time.

It is expected that physicians may choose different approaches in certain patients for various reasons, however uniform practice will make the anticoagulation clinic run more efficiently.

Dub Sukhum
2007

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Chapter 1

Warfarin

1. Long half-life of 20 - 60 hours. The mean half-life is approximately 40 hours. The duration of effect is 2 - 5 days. The maximum effect of a dose occurs up to 48 hours after administration, and the effect last for the next 5 days. Steady State requires 5-7 days.
2. Blocking hepatic biosynthesis of the Vitamin K dependent anticoagulation factors. These include Factor II (42-72), Factor VII (4-6), Factor IX (21-30), Factor X (27-48), Protein C (8), and Protein S (30).
   • (In parenthesis represents half-life in hours).
3. Indication (Target INR section).
4. Contraindication.
• Warfarin allergy.
• Active severe bleeding or intracranial bleeding within 6 weeks.
• Pregnancy.
• Others:
  • Active PUD.
  • Known coagulation defects.
  • Thrombocytopenia (platelet<50,000).
  • Non compliant or unreliable patients.
  • History of recurrent falls or traumatically prone patients.
  • Occupational risk for bleeding.
  • Excessive alcohol intake.
5. Adverse effects.
   • Bleeding.
   • Skin necrosis. Usually occurs from 3-8 days of therapy.
   • Purple toe syndrome. Usually occurs in the first 3-10 weeks.
   • Allergy.
   • Less serious adverse effects, i.e.. alopecia, GI discomfort.

Average Daily Dose

There are differences among various ethnic

About 4-5 mg/day or 28-35 mg/week for caucasian for target INR of 2.5 (2.0-3.0)

About 3-4 mg/day or 21-28 mg/week for Pacific-Asian (exclude caucasian in this region). This dose will be less if target INR is recommended at <2.0.

Factors Effecting the Daily Dose

1. Age ( For caucasian)
   • <35 yr ----- 8.1 mg/day.
   • 35-49 yr --- 6.4 mg/day.
   • 50-59 yr --- 5.1 mg/day.
   • 60-69 yr --- 4.2 mg/day.
   • >70 yr ----- 3.6 mg/day.
2. Genetic. Hereditary warfarin sensitive and resistance.
3. Medicine noncompliance.
4. Drugs interaction, including herbal medicine.
5. Concurrent illness, fever, diarrhea, post op major surgery (i.e.. heart valve replacement), malignancy, lupus anticoagulants.
6. Impaired liver function, CHF with liver congestion.
7. Food effect, vitamin K intake, alcohol.
8. Hyperthyroidism, renal disease.
9. During heparin and direct thrombin inhibitors treatment.

Tablet Size

Warfarin tablets ( Click here to view warfarin tablets)

• Coumadin, a brand name of Warfarin, has several size tablets with number on the tablet and with different color tablet.
• 5 mg is a good choice for caucasian population. The average daily dose is close to 5 mg. For different daily dose, it is easy to make 0.0, 2.5, 5.0, 7.5 or 10 mg .... with this size tablet.
• For Chinese-Asian or Pacific-Asian (exclude caucasian in this region) population warfarin dosing should be based on average daily dose of 3 - 4 mg per day and using 3 of 4 mg size tablet is more suitable.
• 2 mg if weekly dose is <15 mg.

  Generic. When use generic warfarin, only one generic brand should be prescribed for each patient and it should be indicated that brand in the prescription.

Treatment monitoring

Standard

Traditionally patients come into the clinic (or the hospital) to have venous blood drawn for routine laboratory INR determination.

Point of Care

Finger tip capillary blood can be used with small, light weight and portable instruments. The clinical trials result have compared favorably with traditional INR determination.

Use in anticoagulation clinic.

• Need good quality control for point of care INR measurement.
• Faster INR result. Patients are more willing to wait for the result before they go home.
• Direct patient contact for instruction before the patients leave the clinic is more efficient than phone call for the result later.

Home use or Patient Self Test (PST)

• Need good quality control for point of care INR measurement.
• Patient selection is essential.
  • Patients must have long term indication for anticoagulation therapy..
  • Patients must be willing and able to perform self-management.
  • Patients must be willing to record results accurately and attend clinics regularly for quality assurance.
  • Patients must demonstrate competence in using the instrument and interpreting the results.
  • Patients must not have shown previous noncompliance in terms of clinic attendance or medication management.
• Can increase INR testing frequency and decrease complications associated with oral anticoagulation therapy.

Point of Care Instruments

Instrument	Company	Sample Type
CoaguChek	Roche Diagnostics Corp. Indianapolis, IN http://www.coaguchek.com/landing/	Capillary or venous whole blood
Harmony INR Monitoring System	LifeScan Inc., Milpitas, CA www.lifescan.com	Capillary or venous whole blood
INRatio Prothrombin Time Monitoring System	Hemosense, Inc. Milpitas, CA www.hemosense.com	Capillary or venous whole blood
ProTime Microcoagulation System	International Technidyne Corp. Edison, NJ www.itcmed.com	Capillary or venous whole blood

• These instruments are FDA approved for home use.
• These instruments are small, light weight, and portable devices.

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Initiation

• Warfarin Initiation Table for average daily dose of 5 mg and 3 mg
• Section below will cover the patient with average daily dose of 5 mg.

Inpatient

Day 1

(If there is an active or acute thromboembolic condition, warfarin should be started along with heparin, unless there is a contraindication or patient cannot take medicine orally. Following warfarin initiation, heparin should be continued until INR reaches therapeutic level for 2 days).

5 mg (2.5-7.5). This dose is a good choice since it is known that average daily dose is close to 5 mg. Rapid increase INR (anticoagulant) will not achieve fast full antithrombotic effect since factor II half-life is up to 72 hours. Using higher dose than necessary may lead to bleeding complication due to rapidly and severely reduce factor VII. It may deplete protein C too quick, and theoretically can cause hypercoagulable state. The 5 mg size tablet is recommended for both inpatient and outpatient use, making inpatient to outpatient transition more convenient. It is the most commonly used size tablet by the majority of anticoagulation clinics today. If the dose should be changed, it can be given 0.0, 2.5, 5.0, 7.5, 10.0,---- with this size tablet.

The higher dose warfarin initiation have also been tested successfully by using normogram. It may be considered in patient who may need shorter period of time to reach therapeutic INR. It should be done in patient not in the list of "Lower dose" below. INR have to be done frequently enough to prevent over anticoagulation and bleeding complication

Lower dose (2.5 mg).

• >80 yr.
• Concurrent illness.
• On interaction drug.
• S/P major surgery, i.e.. heart valve surgery.
• Chronic malnourished.
• Impaired liver function, liver congestion.
  
  

Higher dose (7.5-10.0 mg).

• Young healthy subject.
• In the first two days.

Day 2

A. If INR <1.5, continue the same dose.
B. If INR >1.5, give lower dose (2.5 mg or none)

Day 3

For #A. of Day 2

• If INR <1.5, suggests a higher than average maintenance dose of 5 mg/day or 35 mg/week will be needed. Give higher dose than 5 mg. i.e.7.5 mg for now.
• If INR 1.5-2.0, suggests an average maintenance dose close to 5 mg/day or close to 35 mg/week will be needed, and continue 5 mg for now.
• If INR >2.0, suggests a lower than average maintenance dose of 5 mg/day or 35 mg/week will be needed. Give less than 5 mg, i.e.2.5 mg or none for now.

For #B. of Day 2

• If INR 1.5-2.0, suggests daily dose will be close to or less than 5 mg/day or close to 35 mg/week or less. May give 5 mg or less for now.
• If INR >2.0, suggests daily dose will be lower than 5 mg/day or less than 35 mg/week. May give 2.5 mg or none for now.

Day 4

If there is no need for heparin therapy, the patient may have been discharged by now, and warfarin initiation is continued as an outpatient.

1. INR 2 times a week until INR is in target range twice in a row, then INR 1 time weekly until INR is in target range twice in a row, then INR 1 time in 2 week until INR is in target range twice in a row, then enter the patient in to maintenance schedule (usually INR every 4 weeks).
2. Patients during an acute illness, or post operative of major surgeries may be more sensitive to warfarin than when they become more stable.

Out patient (See also "Day 4" above)

1. Obtain baseline INR
2. Start with 5 mg daily. See more detail for dose variation in "Inpatient guideline"
3. Check INR 2 times a week, or more often if necessary, during the first week or so. Adjust warfarin dose and timing for INR check as outline in "Inpatient" guidelines.
   

Ethnic Difference for Chinese-Asian or Pacific-Asian (exclude caucasian in this region)

1. Average daily dose of Warfarin for Pacific-Asian (exclude caucasian in this region) or Chinese-Asian is about 3 mg. Weekly dose is about 21-28 mg, or lower if "target INR" for various diagnoses are about 0.4-0.5 lower than those of Caucasian-American-European level.
2. "Target INR" for or Pacific-Asian (exclude caucasian in this region) or Chinese-Asian should be lower than those of Caucasian-American-European. The suggest level for nonvalvular atrial fibrillation is 1.6-2.6, to achieve less combine thromboembolic and major bleeding events. (Need more database for confirmation)
3. Difference in polymorphism of CYP 2C9 and VKORC1which will influence Warfarin dosage

Table. Warfarin Initiation (for patient with average daily dose of 5 mg and target INR >2.0)

DAY	INR	DOSE
		INPATIENT (Usually with daily INR)	OUTPATIENT
1	Normal	5.0 mg ( 2.5 or 7.5-10.0 mg in patients listed in the text )	5.0 mg ( 2.5 or 7.5-10.0 mg in patients listed in the text )
2	< 1.5 > 1.5	5.0 mg 0.0 - 2.5 mg	5.0 mg 0.0 - 2.5 mg
	.	.	[If INR is not measured 5.0 mg]
3	< 1.5 1.5 - 1.9 2.0 - 3.0 > 3.0	5.0 - 10 mg 2.5 - 5.0 mg 0.0 - 2.5 mg 0.0 mg	5.0 - 10 mg 2.5 - 5.0 mg 0.0 - 2.5 mg 0.0 mg
	.	.	INR should be measured today. If INR is not measured, may use the same dose as day 2, and should not > 5 mg
4	<1.5 1.5 - 1.9 2.0 - 3.0 > 3.0	10.0 mg 5.0 - 7.5 mg 0.0 - 5.0 mg 0.0 mg	10.0 mg 5.0 - 7.5 mg 0.0 - 5.0 mg 0.0 mg
	.	.	INR measurement should be done, if INR on day 3 is <1.5 or >3.0
5	< 1.5 1.5 - 1.9 2.0 - 3.0 > 3.0	10.0 - mg 7.5 - 10.0 mg 0.0 - 5.0 mg 0.0 mg	10.0 - mg 7.5 - 10.0 mg 0.0 - 5.0 mg 0.0 mg
	.	.	INR measurement should be done, if INR on day 4 is <1.5 or >3.0
6	< 1.5 1.5 - 1.9 2.0 - 3.0 > 3.0	7.5 - 12.5 mg 5.0 - 10.0 mg 0.0 - 7.5 mg 0.0 mg	7.5 - 12.5 mg 5.0 - 10.0 mg 0.0 - 7.5 mg 0.0 mg
	.	.	INR measurement should be done, if INR on day 5 is <1.5 or >3.0
Note: Frequent INR measurement help prevent over anticoagulation and help reaching target INR sooner.

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Table. Warfarin Initiation (for patient with average daily dose of 3 mg and target INR >1.6)

DAY	INR	DOSE
		INPATIENT (Usually with daily INR)	OUTPATIENT
1	Normal	3.0 mg ( 1.5 or 3.0-6.0 mg in patients listed in the text )	3.0 mg ( 1.5 or 3.0-6.0 mg in patients listed in the text )
2	< 1.3 > 1.3	3.0 mg 0.0 - 1.5 mg	3.0 mg 0.0 - 1.5 mg
	.	.	[If INR is not measured 3.0 mg (1.5-4.5)]
3	< 1.3 1.3 - 1.6 1.6 - 2.6 > 2.6	3.0 - 6 mg 1.5 - 3.0 mg 0.0 - 1.5 mg 0.0 mg	3.0 - 6 mg 1.5 - 3.0 mg 0.0 - 1.5 mg 0.0 mg
	.	.	INR should be measured today. If INR is not measured, may use the same dose as day 2, and should not > 3.0 mg
4	<1.3 1.3 - 1.6 1.6 - 2.6 > 2.6	4.5 - 6.0 mg 3.0 - 4.5 mg 1.5 - 3.0 mg 0.0 mg	4.5 - 6.0 mg 3.0 - 4.5 mg 0.0 - 3.0 mg 0.0 mg
	.	.	INR measurement should be done, if INR on day 3 is <1.3 or >2.6
5	< 1.3 1.3 - 1.6 1.6 - 2.6 > 2.6	6.0 - 7.5 mg 3.0 - 4.5 mg 1.5 - 3.0 mg 0.0 mg	6.0 - 7.5 mg 3.0 - 4.5 mg 1.5 - 3.0 mg 0.0 mg
	.	.	INR measurement should be done, if INR on day 4 is <1.3 or >2.6
6	< 1.3 1.3 - 1.6 1.6 - 2.6 > 2.6	6.0 - 7.5 mg 4.5 - 6.0 mg 1.5 - 3.0 mg 0.0 mg	6.0 - 7.5 mg 4.5 - 6.0 mg 1.5 - 3.0 mg 0.0 mg
	.	.	INR measurement should be done, if INR on day 5 is <1.3 or >2.6
Note: Frequent INR measurement help prevent over anticoagulation and help reaching target INR sooner.

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Maintenance Dosing

(For patient with average daily dose of 5 mg)

Back ground

1. Because warfarin has a long half-life and there is a range for INR (i.e. 2.0-3.0) to work with, there is no need to keep an equal daily dose. In fact it is impossible to do that, since the patient will have to use several tablet size to fit to the different daily dose requirement during the long term follow up. This will create confusion.
2. Using specific days of the week for different daily dose is less confusing.
3. There is no significant INR swing as long as the daily dose difference is not large (i.e. <2.5 mg, when use 5 mg size tablet).
4. Using weekly dose adjustment appears more convenient and it is just as accurate.
5. Applying the above principle along with one size tablet (i.e. 5 mg), a table of weekly-daily dose schedule can be constructed for working convenience (see Warfarin dose schedule table for 5 mg tablet and 3 mg tablet)
6. Note that weekly dose difference can be arranged as low as 2.5 mg per week, equivalent to only 0.4 mg per day difference.

Example

Weekly Dose (mg)/ Daily Dose (mg)

• 35 -------------- 5.0 daily
• 37.5 ----------- 7.5 Mon, 5 ROW
• 40 -------------- 7.5 Mon, Fri, 5 ROW
• 42.5 ----------- 7.5 Mon, Wed, Fri, 5 ROW
• 45 -------------- 5.0 Mon, Wed, Fri, 7.5 ROW
• 47.5 ------------ 5.0 Mon, Fri, 7.5 ROW
• -------------------------
  (ROW = Rest Of the Week)

Weekly Dose	Mon	Tue	Wed	Thu	Fri	Sat	Sun
35	5	5	5	5	5	5	5
37.5	7.5	5	5	5	5	5	5
40	7.5	5	5	5	7.5	5	5
42.5	7.5	5	7.5	5	7.5	5	5
45	5.0	7.5	5.0	7.5	5.0	7.5	7.5
47.5	5.0	7.5	7.5	7.5	5.0	7.5	7.5

Note: Patient should take warfarin in PM (i.e.5-7 PM), and have INR test in AM, for consistency of the INR result. This also allows time to contact the patient before the patient takes warfarin that day.

Table 1. Warfarin Dose Schedule for 5 mg Tablet (2 mg when eekly dose is < 15 mg)

WEEKLY DOSE	DAILY SCHEDULE DOSE				TABLET SIZE	.	WEEKLY DOSE	DAILY SCHEDULE DOSE				TABLET SIZE
2.0	MF	1.0	0.0	ROW	2		52.5	.	7.5	.	Daily	5
3.0	MWF	1.0	0.0	ROW	2		55.0	M	10.0	7.5	ROW	5
4.0	MWF	0.0	1.0	ROW	2		57.5	MF	10.0	7.5	ROW	5
5.0	MF	0.0	1.0	ROW	2		60.0	MWF	10.0	7.5	ROW	5
6.0	M	0.0	1.0	ROW	2		62.5	MWF	7.5	10.0	ROW	5
7.0	.	1.0	.	Daily	2		65.0	MF	7.5	10.0	ROW	5
8.0	M	2.0	1.0	ROW	2		67.5	M	7.5	10.0	ROW	5
9.0	MF	2.0	1.0	ROW	2		70.0	.	10.0	.	Daily	5
10.0	MWF	2.0	1.0	ROW	2		72.5	M	12.5	10.0	ROW	5
11.0	MWF	1.0	2.0	ROW	2		75.0	MF	12.5	10.0	ROW	5
12.0	MF	1.0	2.0	ROW	2		77.5	MWF	12.5	10.0	ROW	5
13.0	M	1.0	2.0	ROW	2		80.0	MWF	10.0	12.5	ROW	5
14.0	.	2.0	.	Daily	2		82.5	MF	10.0	12.5	ROW	5
.	.	.	.	.	.		85.0	M	10.0	12.5	ROW	5
10.0	MWF	0.0	2.5	ROW	5		87.5	.	12.5	.	Daily	5
12.5	MF	0.0	2.5	ROW	5		90.0	M	15.0	12.5	ROW	5
15.0	M	0.0	2.5	ROW	5		92.5	MF	15.0	12.5	ROW	5
17.5	.	2.5	.	Daily	5		95.0	MWF	15.0	12.5	ROW	5
20.0	M	5.0	2.5	ROW	5		97.5	MWF	12.5	15.0	ROW	5
22.5	MF	5.0	2.5	ROW	5		100.0	MF	12.5	15.0	ROW	5
25.0	MWF	5.0	2.5	ROW	5		102.5	M	12.5	15.0	ROW	5
27.5	MWF	2.5	5.0	ROW	5		105.0	.	15.0	.	Daily	5
30.0	MF	2.5	5.0	ROW	5		107.5	M	17.5	15.0	ROW	5
32.5	M	2.5	5.0	ROW	5		110.0	MF	17.5	15.0	ROW	5
35.0	.	5.0	.	Daily	5		112.5	MWF	17.5	15.0	ROW	5
37.5	M	7.5	5.0	ROW	5		115.0	MWF	15.0	17.5	ROW	5
40.0	MF	7.5	5.0	ROW	5		117.5	MF	15.0	17.5	ROW	5
42.5	MWF	7.5	5.0	ROW	5		120.0	M	15.0	17.7	ROW	5
45.0	MWF	5.0	7.5	ROW	5		.	.	.	.	.	.
47.5	MF	5.0	7.5	ROW	5		.	.	.	.	.	.
50.0	M	5.0	7.5	ROW	5		.	.	.	.	.	.

• All doses are in mg.
• M,W,and F - Monday, Wednesday and Friday
• ROW - Rest Of the Week

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Table 1. Warfarin Dose Schedule for 3 mg Tablet (2 mg when weekly dose is < 18 mg)

WEEKLY DOSE	DAILY SCHEDULE DOSE				TABLET SIZE	.	WEEKLY DOSE	DAILY SCHEDULE DOSE				TABLET SIZE
2	MF	1.0	0.0	ROW	2		31.5	.	.	4.5	Daily	3
3	MWF	1.0	0.0	ROW	2		33	M	6.0	4.5	ROW	3
4	MWF	0.0	1.0	ROW	2		34.5	MF	6.0	4.5	ROW	3
5	MF	0.0	1.0	ROW	2		36	MWF	6.0	4.5	ROW	3
6	M	0.0	1.0	ROW	2		37.5	MWF	4.5	6.0	ROW	3
7	.	.	1.0	Daily	2		39	MF	4.5	6.0	ROW	3
8	M	2.0	1.0	ROW	2		40.5	M	4.5	6.0	ROW	3
9	MF	2.0	1.0	ROW	2		42	...	.	6.0	Daily	3
10	MWF	2.0	1.0	ROW	2		43.5	M	7.5	6.0	ROW	3
11	MWF	1.0	2.0	ROW	2		45	MF	7.5	6.0	ROW	3
12	MF	1.0	2.0	ROW	2		46.5	MWF	7.5	6.0	ROW	3
13	M	1.0	2.0	ROW	2		48	MWF	6.0	7.5	ROW	3
14	.	.