NHS DUMFRIES AND GALLOWAY PRIMARY CARE GUIDELINE FOR … · NHS DUMFRIES AND GALLOWAY PRIMARY CARE GUIDELINE FOR THE MANAGEMENT OF PATIENTS ON WARFARIN Author ... The practice record

NHS DUMFRIES AND GALLOWAY

PRIMARY CARE GUIDELINE FOR THE

MANAGEMENT OF PATIENTS ON

WARFARIN

Author Gordon Loughran, Prescribing Support Pharmacist, on behalf of

NHS Dumfries & Galloway’s Patient Safety in Primary Care Group

Publication date July 2013

Review date July 2015

CONTENTS

Page

Introduction 1

Initiating warfarin 2

Contra-indications and special considerations 4

Patient education 5

Indications, target INRs and duration of treatment 6

Starting regimens 7

Maximum INR testing recall periods in maintenance therapy 10

Dose adjustments in maintenance therapy 11

Management of bleeding 13

Interactions with warfarin 15

Appendix 1 – Quick reference guide 24

References 26

1

INTRODUCTION

These guidelines have been developed by NHS Dumfries & Galloway’s

Patient Safety in Primary Care Group in conjunction with Dumfries & Galloway

Royal Infirmary’s Haematology Department. The aim is to ensure a safe,

effective and reliable approach to the management of adult patients in

Primary Care receiving treatment with warfarin. The prescribing information

contained within these guidelines is issued on the understanding that it is

considered to represent the best practice from available evidence and

national guidelines at the time of issue.

The guidelines offer advice to healthcare professionals on issues that must be

considered both prior to starting treatment and on an ongoing basis

throughout treatment. They also offer advice on how to initiate warfarin, the

regularity of INR checks, how to adjust doses, how to manage bleeding whilst

on warfarin, how to take account of interacting drugs and what education

should be provided to patients upon starting treatment and during it.

A quick reference guide containing key information has been prepared and

healthcare professionals may find this useful when needing to quickly access

the information they will most commonly need.

The guideline will be reviewed and updated on an ongoing basis taking into

account any changes in national guidance and evidence base. An

important point to note is that the guideline does not address the use of

newer anticoagulants such as dabigatran, rivaroxaban and apixaban since

its aim, as stated previously, is to ensure the safe, effective and reliable

management of patients on warfarin.

2

Initiating warfarin

The following good practice points are taken from SIGN Guideline 129 –

Antithrombotics: Indications and management:-

• After clinical assessment has demonstrated an indication for oral

anticoagulant treatment, the patient’s medical history, drug history,

and compliance with medication should be assessed

• The indication for oral anticoagulants, the appropriate target

therapeutic range of the INR, and the proposed duration of treatment

should be recorded in the case records, along with other medications

• A baseline blood sample should be obtained prior to starting warfarin

to assess FBC, LFTs, U &Es, APTT/PT and CrCl. This may

showcontraindications or risk factors for bleeding, such as anaemia,

thrombocytopenia, renal failure, or aprolonged prothrombin time due

to liver disease

• Many drugs affect the response to warfarin, most by enhancing, but

some by suppressing the anticoagulant effect. The patient’s drug

regimen should be simplified if appropriate to reduce the possibility of

drug interactions

• Where possible, non-interacting drugs within a class should be selected

and aspirin avoided unless combination therapy is indicated

• In patients with peptic ulcer, H. pylori eradication therapy should be

considered

• Patients should be advised to take their daily dose of warfarin at a fixed

time

• An anticoagulant treatment booklet should be issued to patients

(available from: [email protected]).

Other good practice points:-

• An annual review of the patient’s health should be carried out in

patients on long-term warfarin to determine the ongoing suitability of

prescribing the drug

• Methods should be in place to ensure that the quality of service being

offered to patients on warfarin is safe, effective and consistent.

• INR monitoring should be carried out by trained staff and systems in

place to audit clinical performance

• An appropriate recording and documentation system should be in

place. This must include documentation of cumulative records of INRs

and warfarin doses

• Every INR result and dosage should be entered in the patient’s Yellow

Book. The practice record should serve as the patient’s primary and

permanent record.

3

• A patient recall system should be in place and the following factors

should be considered:-

o Formal arrangements for processing reports to ensure that the

result reaches the appropriate clinician timeously

o INR results not within range or marked as urgent should reach the

appropriate clinician on the day of receipt

o A system is in place for informing patients of results and dose

changes

o Arrangements for weekends and public holiday periods are

clearly set out

o Practice guidelines exist detailing referral pattern to secondary

care when needed

When transferring patients from primary to secondary care the following

should be carried out:-

• Advise the patient to take their Yellow Book to the specialist that are

going to be seeing

• Notify the specialist that the patient is on warfarin and give the details

of the GP responsible for monitoring the patient

• Inform secondary care of the following:-

o Indication for warfarin

o Target INR

o Current dose

o Date when warfarin started

o Recent changes and INR results

o Cocomitant medications

o Comorbid conditions including any recent worsening in any of

these

4

Contra-indications and special considerations

Definitive contra-indications to warfarin are as follows:-

• Haemorrhagic stroke

• Clinically significant bleeding

• History within the previous 72 hours of major surgery with risk of severe

bleeding

• Within 48 hours postpartum

• 1st and 3rd trimesters of pregnancy

• Use with interacting drugs which may lead to significantly increased risk

of bleeding

• Known hypersensitivity to warfarin

The decision to use warfarin is however, very much dependent on patient’s

individual circumstances and is often a balance of risks and benefits. An

individual assessment of these risks and benefits should therefore always be

made prior to commencing treatment and, as a minimum, on an annual

basis thereafter. If doubt exists over the suitability of a patient for warfarin

therapy, specialist advice should be sought. A risk/benefit assessment should

be made each time the patient’s condition or circumstances change.

Situations and conditions in which a risk/benefit assessment should made are

shown below. It should be noted however, that this list is not exhaustive and

clinicians should always exercise their clinical judgement when deciding

whether or not a patients is suitable for warfarin therapy.

Special considerations:-

• Known bleeding tendency

• Thrombocytopenia

• Uncontrolled hypertension

• Uncompensated liver cirrhosis

• Non-compliance with medication and/or with monitoring

• Drug abuse

• Trauma related activities and recurrent falls

• Recent trauma or surgery to central nervous system or eyes

• Contraception and pregnancy

• Purple toes syndrome

• Avoid intra-muscular injections where possible

• Intra-articular injections are contra-indicated in patients receiving

warfarin treatment

5

Patient education

Prior to commencing warfarin, patients should be supplied with an

anticoagulation treatment booklet (Yellow Book) and counselled on the

following points:-

• Reason for anticoagulation

• Strength of different tablets

• The need to take warfarin at the same time every day

• The importance of having regular INR checks

• To always carry their Yellow Book

• Never to double their dose in the event of a missed dose

• The potential for warfarin to interact with many medications

• To discuss with their GP or pharmacist any change in medication

• To not start taking any Over The Counter or herbal/complimentary

medications without speaking to their GP or pharmacist

• The potential for warfarin to be affected by changes in diet and to

inform their GP if they make any major changes to their diet

• The potential for warfarin to be affected by alcohol consumption

and to moderate their intake and avoid binge drinking

• The potential for interaction between warfarin and cranberry juice

and grapefruit juice – see section on “Drug Interactions” on page 15

of this guideline

• The need to seek urgent medical attention if they experience any

unusual or unexplained bleeding or bruising

• To inform their dentist that they are taking warfarin

• Women of childbearing age should be informed of the potential

teratogenicand harmful effects of wafarin on the foetus and

advised accordingly on methods of contraception and to inform

their GP if they become pregnant or are planning to become

pregnant

6

Indications, target INRs and duration of treatment

Table 1

The target INRs and recommended duration of treatments described in the

following table apply to adult males and adult non-pregnant females.

Specialist advice should be sought in women who become pregnant whilst

on warfarin or who are already on long-term warfarin treatment and are

planning to become pregnant. All women of childbearing age who require

to be treated with warfarin should be counselled on the teratogenic and

harmful effects of the drug and, if appropriate, advised to use secure

methods of contraception.

Indications, target INRs and treatment durations

INDICATION TARGET

INR

RECOMMENDED

DURATION

Pulmonary embolism 2.5 Minimum 6 months

Proximal DVT 2.5 Minimum 6 months

Calf vein DVT with temporary risk factors 2.5 6 weeks to 3 months

Calf vein DVT with permanent risk

factors 2.5 Minimum 3 months

Recurrence of VTE when no longer on

warfarin 2.5

Lifelong (Discuss with

Consultant)

Recurrence of VTE while on therapeutic

warfarin treatment 3.5 Lifelong

Inherited thrombophilia with VTE 2.5 Lifelong (Discuss with

Consultant)

Antiphospholipid Syndrome with VTE 2.5 Lifelong

Non-valvular atrial fibrillation 2.5 Lifelong

Atrial fibrillation due to rheumatic or

congenital heart disease 2.5 Lifelong

Cardioversion 2.5 4-5 weeks before and 1

month after

Mural thrombus 2.5 Duration decided by

Cardiologist

Cardiomyopathy 2.5 Lifelong

Aortic bileaflet valve 2.5 Lifelong

Aortic tilting disc valve; Mitral bileaflet

valve; Mitral tilting disc valve 3.0 Lifelong

Caged ball or caged disc aortic or

mitral valve 3.5 Lifelong

7

Starting regimens

Different dosing schedules may be used for the initiation of warfarin. In non-

acute situations, such as non-valvular atrial fibrillation, patients requiring long-

term prophylaxis can be initiated on a less intense slow-start regimen such as

that described in tables 2, 3 and 4 below. This regimen has been shown to be

safe, requires less frequent testing and dosage changes in the initial phase

and achieves therapeutic anticoagulation in the majority of patients within 3

to 4 weeks.

For those patients who require rapid anticoagulation, such as those with

active thromboembolism, a more intense starting regimen must be used. Two

such regimens are described in table 5. The high loading dose regimen (the

one commencing with a 10mg dose) will be appropriate in patients who are

otherwise fit and healthy. The low loading dose regimen (the one

commencing with a 5mg dose) is appropriate in those patients who fall into

one of the following categories:

• Elderly patients >70 years old

• Patients who are debilitated or are malnourished

• Patients who have congestive heart failure

• Patients who have liver disease

• Patients who are taking medicines that increase warfarin sensitivity

• Patients known to have Protein C or Protein S deficiency(discuss with

haematologist)

Table 2

Initiation of warfarin in non-urgent scenarios in Primary Care

This regimen is suitable for patients who do not require urgent anticoagulation. Such

patients include those with chronic or paroxysmal atrial fibrillation, selected patients with

left ventricular thrombus, selected patients with mitral stenosis, selected patients with

pulmonary hypertension and stroke outpatients in sustained atrial fibrillation who have

waited 14 days following the acute event and have had a CT scan that has excluded

intracranial haemorrhage.

Day Action

Prior to

commencing

warfarin

Check baseline coagulation screen, LFTs, U+Es and platelet count

1 Commence warfarin at a dose of 2mg once daily and check INR in

7days

8

INR <3; Continue on 2mg once daily and check re-check INR in 7days

INR >3; Reduce dose to 1mg and seek specialist advice as likely

warfarin sensitive

15 Calculate predicted maintenance dose according to table 3 below

and re-check INR in 7days

22 Adjust dose according to table 3 below and re-check INR in 7days

23 to 42 Continue checking INR at weekly intervals, adjusting dose as

necessary using Table 4

8

Table 3

Predicted Maintenance Dose

Male Female

INR at week 2 Maintenance dose INR at week 2 Maintenance dose

1.0 6mg daily 1.0 – 1.1 5mg daily

1.1 – 1.2 5mg daily 1.2 – 1.3 4mg daily

1.3 – 1.5 4mg daily 1.4 – 1.9 3mg daily

1.5 – 2.1 3mg daily 2.0 – 3.0 2mg daily

2.2 – 3.0 2mg daily >3.0 1mg daily

>3.0 1mg daily

If INR >4.0. omit warfarin for 2 days and reduce daily dose by 1mg

Table 4

Dose Adjustment

INR Result Adjustment

1.5 – 3.5 Continue on same dose

<1.4 for 2 consecutive weeks Increase daily dose by 1mg

3.6 – 4.0 Decrease daily dose by 1mg

>4.0 Stop warfarin for 2 days then restart at daily dose

1mg less than before

See next page for Table 5 – Rapid initiation of warfarin

9

Table 5

This regimen should be used for those patients who require urgent

anticoagulation

Rapid initation of warfarin

Day INR Warfarin Regimen

High Loading dose Low loading dose

1 <1.4 10mg 5mg

2

<1.8

1.8 to 2.0

>2.0

10mg

1mg

Omit

5mg

1mg

Omit

3

≤1.4

1.5 to 1.9

2.0 to 2.2

2.3 to 2.5

2.6 to 2.9

3.0 to 3.3

3.5 to 3.5

3.6 to 5.0

5.1 to 8.0

>8.0

10mg

10mg

5mg

4mg

3mg

2mg

1mg

Omit

Omit one dose; check INR

next day; if high risk of

bleeding give 1-2mg oral

Vitamin K

Stop warfarin; Give 2.5mg

oral Vitamin K; discuss with

Haematologist on-call

10mg

5mg

3mg

3mg

1mg

Omit

Omit

Omit

Omit one dose; check INR next

day; if high risk of bleeding give

1-2mg oral Vitamin K

Stop warfarin; Give 2.5mg oral

Vitamin K; discuss with


4

<1.4

1.4 to 1.5

1.6 to 1.7

1.8 to 1.9

2.0 to 2.3

2.4 to 2.7

2.8 to 3.0

3.1 to 3.5

3.6 to 4.0

4.1 to 5.0

5.1 to 8.0

>8.0

10mg

8mg

7mg

6mg

5mg

4mg

4mg

3mg

3mg


next day


next day; if high risk of

bleeding give 1-2mg oral

Vitamin K

Stop warfarin; Give 2.5mg

oral Vitamin K; discuss with


10mg

6mg

5mg

4mg

3mg

3mg

2mg

1mg

Omit


day


day; if high risk of bleeding give

1-2mg oral Vitamin K

Stop warfarin; Give 2.5mg oral

Vitamin K; discuss with


Day 5

onwards

Titrate dose as per INR. Refer to Tables 6 and 7 once stable for INR intervals

and dosage adjustments

10

Maximum INR testing recall periods in maintenance therapy

Table 6 below describes the recommended INR testing recall periods for use

in NHS Dumfries and Galloway. However, relevant patient information and

dosing/INR history must also be considered when determining the timing of

the next appointment, for example where there has been difficulty in

achieving an initial therapeutic INR, a repeat INR earlier than the

recommended 2 weeks is appropriate.

It should also be noted that this schedule does not apply to individuals with

prosthetic heart valves where the maximum INR check interval is 6 weeks.

These individuals may also require more frequent monitoring in the first few

weeks following discharge from hospital.

Table 6

INR monitoring schedule in stable patients

Scenario Next INR check

One INR therapeutic 2 weeks

Two INRs therapeutic at two weekly

monitoring

4 weeks

Two INRs therapeutic at four weekly

monitoring

8 weeks

Two INRs therapeutic at 8 weekly

monitoring

12 weeks

11

Dose adjustments in maintenance therapy

Table 7 on the next page details when warfarin dosage adjustments should

be made, how these adjustments should be made and what additional

monitoring, if any, is required. The following important points should always be

borne in mind however:-

• Dose adjustments are not required for minor INR fluctuations where the

result is within +/- 0.5 of the target INR

• Dose adjustments should never be made in isolation – the patient’s

dosing history and other relevant patient factors need to be

considered at all times

• Fluctuations of INR of more than 0.5 from the patient’s target should

always be investigated and corrected where possible. Potential causes

such as a previous change in warfarin dose, poor patient compliance,

concomitant medications, change in diet, change in alcohol intake,

initiation of an interacting drug and intercurrent illness, should always

be considered.

12

Table 7

Dose adjustments where INR is more than 0.5 units above or below the target INR

Practices with computerised dosing software should utilise that to amend doses in patients

who have an INR that is more than 0.5 units above or below the target INR. All other

practices should refer to this table.

INR TARGET INR = 2.5 NEXT INR

CHECK INR TARGET INR = 3.5

NEXT INR

CHECK

1.0 – 1.4

Increase daily dose

by 1mg; repeat INR in

1 week

1 week 1.0 – 1.4

Increase daily dose


1 week

1 week

1.5 – 1.9

Increase daily dose

by 0.5mg*; repeat INR

in 1 week

1 week 1.5 – 1.9

Increase daily dose


1 week

1 week

2.0 – 3.0

SAME DOSE As per

Table 6 2.0 – 2.9

Increase daily dose

by 0.5mg*; repeat INR

in 1 week

1 week

3.1 – 3.9

Decrease weekly

dose by 10% then

divide by 7 for new

daily dose

1 week 3.0 – 4.0

SAME DOSE

As per

table 6

4.0 – 5.0

Omit one dose then

reduce weekly dose

by 10%-20% and

divide by 7 for new

daily dose

4-5 days 4.1 – 5.0

Decrease weekly

dose by 10% and

divide by 7 for new

daily dose

1 week

5.1 – 8.0

STOP WARFARIN

Check INR daily

Restart warfarin when

INR<5.0; reduce

weekly dose by 20%

and divide by 7 for

new daily dose

5 days

after

restarting

warfarin

5.1 – 8.0

STOP WARFARIN

Check INR daily


INR<5.0; reduce

weekly dose by 20%

and divide by 7 for

new daily dose

5 days

after

restarting

warfarin

>8.0 (not

bleeding)

STOP WARFARIN

Give 2.5mg oral

Vitamin K and check

INR daily


INR<5.0; reduce

weekly dose by 20%

and divide by 7 for

new daily dose

Daily

until INR

<5.0

3-5 days

after

restarting

>8.0 (not

bleeding)

STOP WARFARIN

Give 2.5mg oral

Vitamin K and check

INR daily


INR<5.0; reduce

weekly dose by 20%

and divide by 7 for

new daily dose

Daily

until INR

<5.0

3-5 days

after

restarting

*The use of 0.5mg tablets is not recommended. In situations where an adjustment to the daily

dose of 0.5mg is made, the dose should be rounded downwards and upwards to the nearest

whole numbers and given on alternate days, e.g patient on 3mg daily requires an increase in

the daily dose of 0.5mg; the new dosing regimen would be 3mg/4mg on alternate days

starting with the 4mg on the 1st day.

DRUG INTERACTIONS: When commencing a medication that has the potential to interact with

warfarin, particularly antibiotics, the INR should be checked 2 to 3 days after the patient starts

taking the new medicine. A list of medicines that can interact with warfarin can be found on

page 15 of this guideline.

13

Management of bleeding

All patients receiving treatment with warfarin should be continuously assessed

for signs and symptoms of bleeding. Risk factors for bleeding include:-

• Previous history of bleeding

• Recent surgery

• Hypertension

• Cerebrovascular disease or stroke

• Serious heart disease or recent MI

• Renal insufficiency

• Liver disease

• Other pre-existing bleeding disorder e.g. thrombocytopenia

• Age >65 years

• Severe anaemia

• Diabetes

• Concomitant medications that potentiate bleeding

Major bleeding always requires immediate hospital admission and includes

the following scenarios:-

• GI bleeding

• Intracranial bleeding

• Intra-articular bleeding

• Intraspinal bleeding

• Intra-ocular bleeding

• Retroperitoneal bleeding

Non-major bleeding may be managed in Primary Care if it is judged to be

safe to do so and includes the following scenarios:-

• Haemoptysis

• Purpura

• Unexplained or excessive haematomas

• Epistaxis

• Haematuria

14

Non-major bleeding should be managed as follows:-

• Check INR

• If INR >5, omit warfarin and continue to check INR daily until it is <5

• Once INR is <5, restart warfarin at a weekly dose 20% lower than

previous weekly maintenance dose

• Where reversal of warfarin is judged to be necessary, Vitamin K should

be administered by slow intravenous injection at a dose of 2mg

• Admission to hospital for assessment and observation should be

considered where judged appropriate

• When bleeding occurs whilst INR is in the therapeutic range, further

investigations to identify the cause of the bleed should be carried out

15

Interactions with warfarin

Warfarin interacts with many drugs and, often, these interactions can be

unpredictable as patients may be taking more than one interacting drug.

The most desirable course of action when considering prescribing a drug that

is likely to interact with warfarin is, wherever possible, to instead choose one

that won’t interact. Where no alternatives exist, caution must be exercised.

When commencing a medication that has interacting potential,the INR

should be checked 2 to 3 days after the patient starts taking the new

medicine. For specific advice on individual drugs, table 8 that follows can be

used as a reference however it is important to note that this list is not

exhaustive and nor is it intended to be. It provides details of some of the more

commonly encountered and significant interactions with warfarin but where

any doubt exists, the latest edition of the BNF (www.bnf.org)or the relevant

manufacturer’s Summary of Product Characteristics (SPC) (can be found at

www.medicines.org.uk) should be checked.

One particular point to noteis with regards antibiotics - if a patient is unwell

enough to require one, then it may be prudent to increase the frequency of

INRmonitoringas above, even if no specific drug interaction is expected.

Care must also be taken when using herbal/complimentary medicines

concomitantly with warfarin since many of these have the potential to

interact with it. In the absence of data, it must be assumed that the

herbal/complimentary medicine in question can interact with warfarin.

Furthermore, patients must be asked at the start of treatment and at each

review thereafter, whether they are taking any herbal/complimentary

medicines. This is especially important during any investigation of unexplained

bleeding or abnormal INR. The following table contains information on some

of the more commonly used herbal/complimentary medicines.

16

Table 8 – Selected drug interactions

Interacting Drug Problem Comments

Alcohol Increases effect

of warfarin

Fluctuations in prothrombin time in

heavy drinkers or patients with liver

disease

Allopurinol Increases effect

of warfarin

Evidence poor and no established

pharmacokinetic interaction. Some

case reports of increased effect of

warfarin. Monitor INR more closely.

Amiodarone Increases effect

of warfarin

Onset of this interaction may be slow

and may persist after amiodarone has

been stopped

Amitriptyline Unpredicatable –

can increase or

reduce effect of

warfarin

Monitor INR closely. INR may be

difficult to control in patients taking

tricyclic antidepressants

Anabolic steroids

(e.g. danazol,

stanozolol)

Increases effect

of warfarin

Interaction develops rapidly, possibly

within 2 or 3 days

Aspirin Increases effect

of warfarin

Avoid aspirin as an analgesic – use

paracetamol as safer alternative. Low

dose aspirin 75mg daily appears not to

interact to any clinically relevant

extent but may increase the risk of

bleeding due to antiplatelet effect

Azapropazone Increases effect

of warfarin

Significant risk of bleeding. Concurrent

use NOT recommended

Azathioprine Reduces effect

of warfarin

Warfarin dose may need to be

increased when azathioprine started

and reduced if azathioprine is stopped

Barbiturates (e.g.

Phenobarbital)

Reduces effect

of warfarin

May require 30-60% increase in

warfarin dose. The reduction in

anticoagulant effect begins within a

week, reaching a maximum after

about 3 weeks and may still be

evident up to 6 weeks after stopping

the barbiturate

Bezafibrate Increases effect

of warfarin

Bleeding is likely if warfarin dose is not

reduced appropriately (between 33-

50% and then adjusted as per INR)

Boldo or

Fenugreek

Increases effect

of warfarin

Just one case report of raised INR. No

other evidence.

17


Carbamazepine Reduces effect

of warfarin

Increase INR monitoring when

introducing carbamazepine to

patients already on warfarin.

Requirement to increase warfarin dose

is likely.Oxcarbazepine does not

appear to interact to the same extent.

Cefaclor Increases effect

of warfarin

Refer to NHS Dumfries & Galloway

Antibiotic Guidance for Primary Care

for appropriate alternatives for the

specific indication.

Celecoxib Increases effect

of warfarin

Large case controlled study from UK

General Practice Research Database

points to an increased risk of bleeding

when celecoxib used with warfarin

similar to that seen with the non-

selective NSAIDs

Chamomile Potential

increase in effect

of warfarin

One case report of raised INR with

bleeding complications. No

pharmacokinetic interaction

established. Not possible to reliably

draw a link between chamomile use

and any effect on warfarin.

Cimetidine Increases effect

of warfarin

Unpredictable but common

interaction. Use ranitidine instead.

Ciprofloxacin Increases effect

of warfarin

Unpredictable and potentially serious

interaction. Increased INR monitoring

required. Use a different antibiotic if

possible – refer to NHS Dumfries &

Galloway Antibiotic Guidance in

Primary Care.

Ciprofibrate Increases effect

of warfarin

Bleeding likely if warfarin dose is not



Clarithromycin Increases effect

of warfarin

Increases in INR have been reported.

Across all macrolides, studies suggest

interactions are occasional but

unpredictable. Those that metabolise

warfarin slowly (the elderly and those

on low doses) appear to be most at

risk. Increased INR monitoring is

recommended.

Clopidogrel Mild bleeding

even though INRs

remain stable

and in range

Increased risk of bleeding due to

antiplatelet effect. Manufacturer

advises avoid concomitant use.

18


Colestyramine Reduces effect

of warfarin

Separating the dosages as much as

possible may minimise the effects of

this interaction

Co-enzyme Q10 Uncertain effect Some evidence suggests no

interaction whilst other evidence

suggest a reduced effect and other

evidence still, suggest increased

bleeding with concomitant use.

Advise to avoid use of Co-enzyme

Q10 if possible. Increase INR

monitoring where it is used.

Combined oral

contraceptives

Unpredictable

effect on INR –

can either

increase or

reduce effect of

warfarin

Generally avoided in thromboembolic

disorders. Where they require to be

used however, the potential to alter

the effect of warfarin should be taken

into account when monitoring INR

Co-proxamol Increases effect

of warfarin

Uncommon and unpredictable. Use

paracetamol if possible.

Corticosteroids Variable

response

depending on

dose of

corticosteroid

Low to moderate doses can increase

or decrease effect of warfarin. High

doses have been reported to increase

the effect of warfarin. Monitor INR.

Cranberry juice Increases effect

of warfarin

Studies now indicate that moderate

doses of cranberry juice are unlikely to

have an important impact on INR

control however, previous CSM/MHRA

to avoid unless health benefits of

cranberry juice are judged to

outweigh the benefits are still in place

Cytotoxics Increased effect

of warfarin with

some cytotoxics

Refer patients on concurrent cytotoxic

agents for Specialist advice

Diclofenac Uncertain effect

on warfarin

Cases of raised INRs have been

reported but the causes of these are

unexplained. Like all NSAIDs,

diclofenac is best avoided if possible

due to increased risk of GI bleeding.

Diflusinal Increases effect

of warfarin

Unpredictable – monitor INR and for

signs of bleeding

Dipyridamole Mild bleeding

even though INRs

remain stable

and in range

Increased risk of bleeding due to

antiplatelet effect

19


Disulfiram Increases effect

of warfarin

Most individuals will demonstrate this

interaction. Take care when

introducing disulfiram in a patient

already on warfarin and vice versa.

Dose adjustments may be required

when withdrawing disulfiram from

patients also taking warfarin and a

smaller loading dose is advised when

commencing warfarin in patients

already on disulfiram

Erythromycin Increases effect

of warfarin

Increases in INR have been reported.

Across all macrolides, studies suggest

interactions are occasional but

unpredictable. Those that metabolise

warfarin slowly (the elderly and those

on low doses) appear to be most at

risk. Increased INR monitoring is

recommended.

Fenofibrate Increases effect

of warfarin




Fish oils Potential

increased risk of

bleeding due

antiplatelet

effect

One large study suggests no increase

in bleeding episodes in patients on

warfarin. Manufacturers of Omacor do

however state that patients should be

monitored and warfarin dose adjusted

accordingly. However, given that if

any interaction exists then it is likely to

be pharmacodynamic, INR monitoring

would not pick this up. Advise patients

to be aware of signs and symptoms of

bleeding and to seek medical

attention should any problematic

bleeding occur

Fluconazole Increases effect

of warfarin

Increase frequency of INR monitoring.

Reductions in warfarin dose of around

20% can be required when used with

fluconazole 50mg. Dose adjustments

may also be necessary with

concomitant use of a fluconazole

150mg stat dose – increased INR

monitoring required.

20


Flutamide Increases effect

of warfarin

Monitor and reduce warfarin dose as

necessary

Garlic Possible

antiplatelet

effects

One small study showed no effect on

INR or bleeding risk. One case report

of increased INR. In view of this and

potential antiplatelet effects, it may

be prudent to consider an increase in

severity of any bleeding that occurs

Gemfibrozil Increases effect

of warfarin




Ginger Uncertain effect

on warfarin

One study suggests no effect on effect

of warfarin while another suggests an

increased incidence of bleeding.

There are also 2 case reports of raised

INRs and it is listed as a herb with

antiplatelet activities. Best avoided if

possible. Increase INR monitoring if

patient decides to use.

Gingko biloba Isolated reports

of bleeding on

ginko alone and

one of over

anticoagulation

Advise patients to monitor for early

signs of bruising & Bleeding to seek

medical attention if bleeding

problems occur

Ginseng Uncertain but if it

does anything,

then it’s most

likely a reduction

in the effect of

warfarin

Confusing picture. Studies suggest

reduced effect of warfarin BUT lab

studies show ginseng contains

antiplatelet components so increased

risk of bleeding also cannot be ruled

out although a very small study

suggests it’s probably unlikely.

Grapefruit juice Increases effect

of warfarin

May cause a modest rise in INR.

Further studies needed. Current

evidence suggests routine INR testing

should be sufficient to detect any

interaction

Glucagon Large doses

(≥50mg over 2

days) increase

the effect of

warfarin

Reduce dose of warfarin and monitor

INR closely. Smaller doses (total of

30mg) are reported not to interact

Glucosamine Reports of

increases in INR

Recommended not to take

glucosamine

21


Glucosamine

/chondroitin

Increased risk of

bleeding

Chondroitin contains heparinoid

components and therefore has some

anticoagulant effect. Should be

avoided in patients taking warfarin

Griseofulvin Reduces effect

of warfarin

Unpredictable interaction (effects

some but not all patients). Monitor INR

Indometacin Gastric irritation

and reduced

platelet

aggregation

Avoid NSAIDS in patients taking

warfarin if possible. If concurrent use is

essential then monitor INR closely.

Influenza

vaccine

Usually safe and

uneventful but

small numbers of

bleeding

episodes

reported

Evidence shows that influenza

vaccination in warfarin patients is

normally safe and uneventful. Advise

patient to report any unexplained

bleeding.

Itraconazole Case report of

increased effect

of warfarin

Increase INR monitoring and reduce

dose if necessary. Advise patients to

report any unexplained bruising or

bleeding.

Ketoconazole Case reports of

increased effect

of warfarin

Increase INR monitoring and reduce

dose if necessary. Advise patients to

report any unexplained bruising or

bleeding.

Ketorolac Serious risk of GI

bleeding

Oral ketorolac is contra-indicated in

patients taking warfarin

Metronidazole Increases effect

of warfarin

Well established and clinically

important interaction. If concurrent

use cannot be avoided then increase

frequency of INR monitoring and

adjust warfarin dose accordingly.

Miconazole Increases effect

of warfarin

Avoid. Potentially serious interaction.

Use Nystatin instead.

NSAIDs Gastric irritation

and reduced

platelet

aggregation

Avoid NSAIDs where possible. If

concomitant use cannot be avoided,

monitor INR and for signs of bleeding.

Omeprazole Increases effect

of warfarin

A small change in INR may be seen.

Occasionally, clinically significant

interactions occur. Use lansoprazole as

an alternative.

22


Orlistat Potentially

increased effects

of warfarin

Orlistat may alter the absorption of fat

soluble vitamins such as Vitamin K. This

may lead to increased warfarin effects

due to lower quantities of dietary

Vitamin K being available to

antagonise it. Additionally, the

adoption of a lower fat diet may

compound this effect.

Paracetamol Potentially

increased effects

of warfarin

The effect of paracetamol use on the

effects of warfarin uncertain. Some

studies suggest an increased effect of

warfarin which has led to suggestions

of increased INR monitoring

requirements in regular paracetamol

users. Overall however, it is not possible

with the current evidence base, to

either firmly advise increased INR

monitoring nor to dismiss it.

Penicillins Unpredictable –

both increased

and reduced

effects on

warfarin have

been observed

Very uncommon and unpredictable

effect on warfarin. Broad picture is of

no clinically relevant interaction and

no clear mechanism of interaction has

been established however case

reports of increased and reduced

effect of warfarin do exist. Increased

monitoring of INR is recommended.

Phenytoin Can either

increase or

reduce the

effect of warfarin

Unpredictable interaction - Monitor

INR and adjust dose of warfarin

Rifampicin

/rifabutin

Marked

reduction in

effect of warfarin

Monitor INR closely. Reduction in

anticoagulant effect is seen within 5 to

7 days. Warfarin dose should be

adjusted accordingly.

SSRIs SSRIs are

associated with

increased risk of

bleeding when

used alone

Fluvoxamine is the only SSRI for which

a pharmacokinetic interaction with

warfarin has been established. All SSRIs

are associated with an increased risk

of bleeding and this should be borne

in mind when co-prescribing with

warfarin

23


Statins Increased effect

of warfarin with

some statins

Rosuvastatin and fluvastatin increase

the effects of warfarin and increased

INR monitoring when starting or

stopping or changing the dose of both

these statins is recommended.

Simvastatin and atorvastatin appear

to have little effect on the

anticoagulant effects of warfarin

however the manufacturers of both

recommend increased INR monitoring

when starting/stopping/changing the

dose of both these statins. Pravastatin

appears to have no effect.

St John’s Wort Moderate

reduction in

effect of warfarin

Best avoided if possible. If already on

the combination then stop St John’s

Wort and adjust dose of warfarin

accordingly. If starting St John’s Wort

whilst already taking warfarin then

monitor INR accordingly and adjust

dose of warfarin as necessary.

Sulindac Gastric irritation

and reduced

platelet

aggregation

Avoid NSAIDs in patients taking

warfarin if possible. If concurrent use is

essential then INR should be monitored

closely.

Tamoxifen Marked increase

in effect of

warfarin

Monitor INR and reduce dose warfarin

as necessary. Dose may need to be

reduced by as much as 50%.

Thyroid

hormones

Increases the

effect of warfarin

Monitor INR and adjust warfarin dose

as necessary. Warfarin dose may need

to be altered as thyroid hormone

doses are altered

Tramadol Uncertain effect

on effect of

warfarin

Isolated cases of interaction with

warfarin reported but incidence seems

to be low. In view of uncertainty,

choosing an alternative analgesic,

such as codeine, or increasing INR

monitoring following addition of

tramadol may be prudent

Vitamin K Effect of warfarin

is reduced or

abolished

altogether

Vitamin K may be present in enteral

feeds, health foods, food

supplements, some green vegetables

and green tea. If patients are

“warfarin resistant” then consider this

interaction as a possible cause.

24

Appendix 1 – Quick reference guide

Table 1 – Initiation of warfarin in non-urgent scenarios in Primary Care This regimen is suitable for patients who do not require urgent anticoagulation. Such patients include those with chronic or paroxysmal atrial

fibrillation, selected patients with left ventricular thrombus, selected patients with mitral stenosis, selected patients with pulmonary

hypertension and stroke outpatients in sustained atrial fibrillation who have waited 14 days following the acute event and have had a CT

scan that has excluded intracranial haemorrhage.

Day Action

Prior to commencing warfarin Check baseline coagulation screen, LFTs, U+Es and platelet count

1 Commence warfarin at a dose of 2mg once daily and check INR in 7days

8 INR <3; Continue on 2mg once daily and check re-check INR in 7days

INR >3; Reduce dose to 1mg and seek specialist advice as likely warfarin sensitive

15 Calculate predicted maintenance dose according to table 2 below and re-check INR in 7days

22 Adjust dose according to table 3 below and re-check INR in 7days

23 to 42 Continue checking INR at weekly intervals, adjusting dose as necessary using Table 3

Table 4 – Rapid initation of warfarin

This regimen should be used for those patients who require urgent anticoagulation

Day INR Warfarin Regimen

High Loading dose Low loading dose

1 <1.4 10mg 5mg

2

<1.8

1.8 to 2.0

>2.0

10mg

1mg

Omit

5mg

1mg

Omit

3

≤1.4

1.5 to 1.9

2.0 to 2.2

2.3 to 2.5

2.6 to 2.9

3.0 to 3.3

3.5 to 3.5

3.6 to 5.0

5.1 to 8.0

>8.0

10mg

10mg

5mg

4mg

3mg

2mg

1mg

Omit

Omit one dose; check INR next day; if high risk of

bleeding give 1-2mg oral Vitamin K

Stop warfarin; Give 2.5mg oral Vitamin K; discuss with


10mg

5mg

3mg

3mg

1mg

Omit

Omit

Omit





4

<1.4

1.4 to 1.5

1.6 to 1.7

1.8 to 1.9

2.0 to 2.3

2.4 to 2.7

2.8 to 3.0

3.1 to 3.5

3.6 to 4.0

4.1 to 5.0

5.1 to 8.0

>8.0

10mg

8mg

7mg

6mg

5mg

4mg

4mg

3mg

3mg

Omit one dose; check INR next day





10mg

6mg

5mg

4mg

3mg

3mg

2mg

1mg

Omit

Omit one dose; check INR next day





Day 5

onwards

Titrate dose as per INR. Refer to Tables 6 and 7 once stable for INR intervals and dosage adjustments

Table 2 – Predicted Maintenance Dose Male Female

INR at week 2 Maintenance

dose

INR at week 2 Maintenance

dose

1.0 6mg daily 1.0 – 1.1 5mg daily

1.1 – 1.2 5mg daily 1.2 – 1.3 4mg daily

1.3 – 1.5 4mg daily 1.4 – 1.9 3mg daily

1.5 – 2.1 3mg daily 2.0 – 3.0 2mg daily

2.2 – 3.0 2mg daily >3.0 1mg daily

>3.0 1mg daily

If INR >4.0. omit warfarin for 2 days and reduce daily dose by 1mg

Table 3 – Dose Adjustment

INR Result Adjustment

1.5 – 3.5 Continue on same dose

<1.4 for 2 consecutive

weeks Increase daily dose by 1mg

3.6 – 4.0 Decrease daily dose by 1mg

>4.0

Stop warfarin for 2 days then

restart at daily dose 1mg less

than before

25

Table 5 – Indications, target INRs and treatment durations INDICATION TARGET INR RECOMMENDED DURATION

Pulmonary embolism 2.5 Minimum 6 months

Proximal DVT 2.5 Minimum 6 months

Calf vein DVT with temporary risk factors 2.5 6 weeks to 3 months

Calf vein DVT with permanent risk factors 2.5 Minimum 3 months

Recurrence of VTE when no longer on warfarin 2.5 Lifelong (Discuss with Consultant)

Recurrence of VTE while on therapeutic warfarin treatment 3.5 Lifelong

Inherited thrombophilia with VTE 2.5 Lifelong (Discuss with Consultant)

Antiphospholipid Syndrome with VTE 2.5 Lifelong

Non-valvular atrial fibrillation 2.5 Lifelong

Atrial fibrillation due to rheumatic or congenital heart disease 2.5 Lifelong

Cardioversion 2.5 4-5 weeks before and 1 month after

Mural thrombus 2.5 Duration decided by Cardiologist

Cardiomyopathy 2.5 Lifelong

Aortic bileaflet valve 2.5 Lifelong

Aortic tilting disc valve; Mitral bileaflet valve; Mitral tilting disc valve 3.0 Lifelong

Caged ball or caged disc aortic or mitral valve 3.5 Lifelong

Table 6 – INR monitoring schedule in stable patients Scenario Next INR check

One INR therapeutic 2 weeks

Two INRs therapeutic at two weekly monitoring 4 weeks

Two INRs therapeutic at four weekly monitoring 8 weeks

Two INRs therapeutic at 8 weekly monitoring 12 weeks

This schedule does not apply to individuals with prosthetic heart valves where the maximum INR check interval is 6 weeks. These

individuals may also require more frequent monitoring in the first few weeks following discharge from hospital.

Table 7 – Dose adjustments where INR is more than 0.5 units above or below the target INR Practices with computerised dosing software should utilise that to amend doses in patients who have an INR that is more than 0.5 units

above or below the target INR. All other practices should refer to this table.

INR TARGET INR = 2.5 NEXT INR

CHECK INR TARGET INR = 3.5

NEXT INR

CHECK

1.0 – 1.4 Increase daily dose by 1mg; repeat INR in

1 week 1 week 1.0 – 1.4

Increase daily dose by 1mg; repeat INR

in 1 week 1 week

1.5 – 1.9 Increase daily dose by 0.5mg*; repeat INR

in 1 week 1 week 1.5 – 1.9

Increase daily dose by 1mg; repeat INR

in 1 week 1 week

2.0 – 3.0 SAME DOSE As per

Table 6 2.0 – 2.9

Increase daily dose by 0.5mg*; repeat

INR in 1 week 1 week

3.1 – 3.9 Decrease weekly dose by 10% then divide

by 7 for new daily dose 1 week 3.0 – 4.0

SAME DOSE As per

table 6

4.0 – 5.0

Omit one dose then reduce weekly dose

by 10%-20% and divide by 7 for new daily

dose

4-5 days 4.1 – 5.0

Decrease weekly dose by 10% and

divide by 7 for new daily dose 1 week

5.1 – 8.0

STOP WARFARIN

Check INR daily

Restart warfarin when INR<5.0; reduce

weekly dose by 20% and divide by 7 for

new daily dose

5 days

after

restarting

warfarin

5.1 – 8.0

STOP WARFARIN

Check INR daily



new daily dose

5 days

after

restarting

warfarin

>8.0 (not

bleeding)

STOP WARFARIN

Give 2.5mg oral Vitamin K and check INR

daily



new daily dose

Daily until

INR <5.0

3-5 days

after

restarting

>8.0 (not

bleeding)

STOP WARFARIN

Give 2.5mg oral Vitamin K and check

INR daily



new daily dose

Daily until

INR <5.0

3-5 days

after

restarting *The use of 0.5mg tablets is not recommended. In situations where an adjustment to the daily dose of 0.5mg is made, the dose should be

rounded downwards and upwards to the nearest whole numbers and given on alternate days, e.g patient on 3mg daily requires an

increase in the daily dose of 0.5mg; the new dosing regimen would be 3mg/4mg on alternate days starting with the 4mg on the 1st day.

DRUG INTERACTIONS: When commencing a medication that has the potential to interact with warfarin, particularly antibiotics, the INR

should be checked 2 to 3 days after the patient starts taking the new medicine. A list of medicines that can interact with warfarin can be

found in the full version of this guideline.

Table 8 – Management of non-major bleeding Check INR; if >5, omit warfarin and continue to check INR daily until<5; restart at a weekly dose 20% lower than previous maintenance

dose. Where reversal of warfarin is judged to be necessary, Vitamin K at a dose of 2mg should be administered by slow IV injection.

Admission to hospital for assessment and observation should also be considered where judged appropriate. When bleeding occurs whilst

the INR is in the therapeutic range, further investigations for the cause of the bleed should be carried out.

26

References

Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al.Guidelines on oral

anticoagulation with warfarin – fourthedition. Br J Haematol 2011;154(3):311-

24

The British NationalFormulary no. 65. London: British Medical Association

and Royal Pharmaceutical Society of Great Britain; 2012.

Scottish Intercollegiate Guidelines Network (SIGN).Antithrombotics:

Indications and management. Edinburgh: SIGN; 2006. (SIGN publication no.

129). [cited 2nd July 2013] Available

fromhttp://www.sign.ac.uk/pdf/SIGN129.pdf

Oates A, Jackson PR, Austin CA, Channer KS.A new regimen for starting

warfarin therapy in out patients. Br J ClinPharmacol 1998; 46: 157-161

Kim YK, Nieuwlaat R, Connolly SJ, Schulman S, Meijer K, Raju N, Kaatz S and

Eikelboom JW. Effect of a simple two-step warfarin dosing algorithm on

anticoagulant control as measured by time in therapeutic range: a pilot

study. J ThrombHaemost2010; 8: 101-106

Baxter K (ed), Stockley’s Drug Interactions 10. [online] London:

Pharmaceutical Press <http://www.medicinescomplete.com/> (Accessed on

2nd July 2013).

Documents

NHS DUMFRIES AND GALLOWAY PRIMARY CARE GUIDELINE FOR … · NHS DUMFRIES AND GALLOWAY PRIMARY CARE GUIDELINE FOR THE MANAGEMENT OF PATIENTS ON WARFARIN Author ... The practice record