Warfarin Therapy

Indications for Warfarin therapy

1. Prophylaxis and treatment of venous thrombosis

2. Prophylaxis and treatment of pulmonary embolism

3. Prophylaxis and treatment of thromboembolic disorders, e.g. stroke

4. Treatment of atrial fibrillation with risk of embolism

5. Adjunct in the prophylaxis of systemic embolism after myocardial infarction
6. Prophylaxis to reduce risk of recurrent myocardial infarction
Contra-indications to Warfarin Therapy
1. Anaphylaxis/hypersensitivity
2. Bleeding see complications. The clinician must assess the patients risk
for bleeding, and weigh this up against the therapeutic benefit of warfarin,
in each individual patient.
3. Heparin-induced thrombocytopenia: Use with caution in patients with
heparin-induced thrombocytopenia and DVT; limb ischemia, necrosis, and
gangrene have occurred when warfarin was started or continued after
heparin was stopped. Warfarin monotherapy is contraindicated in the
initial treatment of active HIT;
4. Infection: antibiotics and fever may alter response to warfarin.
5. Renal impairment: Use with caution in patients with moderate-to-severe
renal impairment.
6. Thyroid disease: Use with caution in patients with thyroid disease.
7. Elderly
The elderly may be more sensitive to anticoagulant therapy.

The elderly are more prone to falls/trauma

The elderly are more prone to polypharmacy, and thus drug
interactions.
The elderly are more prone to dementia and cognitive decline,
which may significantly impair compliance/correct
administration.
8. Alcoholics compliance/monitoring difficulties, serious interaction with
alcohol and warfarin may lead to over-coagulation.

9. Illicit drug users compliance/drug interactions/monitoring difficulties

10. Pyschosis compliance, monitoring difficulties.
Laboratory Monitoring
The laboratory test most commonly used to measure the effects of warfarin is the onestage prothrombin time (PT). The PT is sensitive to reduced activity of factors II, VII, and
X.
In order to promote standardization of the PT for monitoring oral anticoagulant therapy,
the World Health Organization (WHO) developed an international reference
thromboplastin from human brain tissue and recommended that the PT ratio be expressed
as the International Normalized Ratio or INR. The INR is the PT ratio obtained by testing
a given sample using the WHO reference thromboplastin.
Serial monitoring of the INR will detect many patients who are overanticoagulated before
they have had a bleeding episode.
Mechanism of Action
The anticoagulant effect of warfarin is mediated through:
Inhibition of the vitamin K- dependent coagulation factors II, VII, IX, and X .This results
in the synthesis of detectable but inactive forms of these coagulation proteins.
However, warfarin also has pro-coagulant effects:
Warfarin also inhibits the vitamin K-dependent proteins C and S. Activated protein C in
the presence of protein S inhibits activated factor VIII and activated factor V activity.
Reference Ranges for Therapeutic Dosage of Warfarin Therapy
The INR is calculated from the following formula:

INR = [Patient PT Control PT]

As it is a ratio the normal value is 1.0

INR should be increased by 2-3.5 times depending upon indication. An INR >4 does not
generally add additional therapeutic benefit and is associated with increased risk of
bleeding.
INR Ranges (Adults) Based Upon Indication
Indication

Target INR Range

Atrial fibrillation:

2.0-3.0

Mechanical aortic valve:

2.0-3.0

Mechanical mitral valve:

2.5-3.5

Mechanical valve and risk factors

2.5-3.5

Bioprosthetic mitral valve:

2.0-3.0

Bioprosthetic aortic valve:

2.0-3.0 (or aspirin 81 mg/day)

Bioprosthetic valve with atrial fibrillation:

2.0-3.0

Rheumatic mitral valve disease

Venous thromboembolism

2.0-3.0
2.0-3.0

Administration
Oral: Initial dosing must be individualized.
Consider the patients
1. hepatic function
2. cardiac function
3. age
4. nutritional status
5. concurrent therapy
6. risk of bleeding
7. Clinical situation.
Commencing warfarin therapy

Start 5-10 mg daily for 2 days. Adjust dose according to INR

results; usual maintenance dose ranges from 2-10 mg daily.
Maintenance doses of warfarin vary significantly from patient to
patient, ranging from less than 2 mg/day to 10 mg/day, depending
upon the patient's nutritional status, genetic makeup, and the

presence of drug interactions .The goal INR varies with the clinical
state.

Frequent INR determinations are required initially to establish that

therapeutic anticoagulation levels have been achieved.

Once the anticoagulant effect and patient's warfarin dose

requirements have been stabilized for at least one to two weeks, the
INR can be monitored less frequently, at intervals in the range of
every two to four weeks.

The INR should be monitored more frequently to minimize the risk

of complications, if there are factors that may produce an
unpredictable response to warfarin (eg, concomitant drug therapy,
other medical conditions, variable intake of vitamin K)

The initiation of warfarin therapy with initial loading doses in excess of 5

mg/day has several potential complications, including a transient
hypercoagulable state due to a precipitous decline in protein C levels in
first 36 hours. Therefore, it is of utmost importance to overlap heparin
and warfarin therapy for four to five days, in order to have the benefit
of anticoagulation from heparin until the full effect of warfarin has been
achieved.

Factors affecting warfarin levels (INR control)

1. Management setting (outpatient/inpatient setting, follow-up in

anticoagulation clinic, community physicians, self-management).
2. Patient compliance
3. Interaction with other medications that might influence warfarin metabolism.
4. Alterations in dietary intake of vitamin K
5. Genetics - CYP2C9 is the enzyme principally involved in metabolising
warfarin. Several studies have identified the presence of mutations in the
CYP2C9 gene resulting in reduced enzymatic activity, impaired metabolism
of and increased sensitivity to standard warfarin doses. The allelic frequency
occurs in 21% of the white population. They are less common in African
American populations and Asian populations. The presence of the mutation is
closely correlated with increased bleeding complications.
Falsely elevated INRs
6. Presence of heparin in the blood sample.
7. Inadequate filling of collection tubes.
Drug interactions
A large and increasing number of drugs interact with warfarin. Interactions lead to:
1. Over-anticoagulation
2. Under-anticoagulation
3. Increased bleeding independent of changes in the INR.

Mechanisms that can be associated with such unfavourable interactions include:

1.
2.
3.
4.
5.

Altered platelet function (eg, aspirin, clopidogrel)

Gastrointestinal injury (eg, NSAIDs)
Altered vitamin K synthesis in the GI tract (eg, antibiotics)
Interference with vitamin K metabolism (eg, acetaminophen)
Alterations in warfarin metabolism due to cytochrome p450 induction or
inhibition (eg, amiodarone, rifampin)

Medications that interfere with the effect of warfarin

Increased warfarin effect

Decreased warfarin effect

Acetaminophen

Azathioprine

Allopurinol

Antithyroid drugs

Anabolic steroids

Carbamazepine

Aspirin

Dicloxacillin

Amiodarone

Glutethimide

Capecitabine

Griseofulvin

Cephalosporins

Haloperidol

Cimetidine

Nafcillin

Ciprofloxacin

Oral contraceptives

Clofibrate

Phenobarbital

Clopidogrel

Rifampin

Diclofenac

Vitamin K

Disulfiram
Erythromycin
Fluconazole
Fluorouracil (5-FU)
Fluoxetine
Glucagon
Influenza virus vaccine
Metronidazole
Macrolide antibiotics
Omeprazole
Sulfamethoxazole/trimethoprim

Tamoxifen
Thyroid hormone
Tolbutamide

Genetics
Genetic variants may also influence the metabolism of warfarin this explains why the
dosage needed to maintain a therapeutic INR depends on the individual patient. The
genetics involved are usually variants in the cytochrome p450 enzymes in the liver.
Diet
The current recommended dietary allowance for vitamin K is in the range of 65 - 80
micrograms/day. This amount is easily exceeded by the ingestion of one serving of green
leafy vegetables. The effect of increased dietary vitamin K intake can be overcome by a
higher warfarin dose.
Complications of Warfarin therapy
The main complication of warfarin therapy is bleeding, especially intracranial
haemorrhage.

It is one of the top ten medications with the largest number of adverse side-effects
recorded in the United States each year. It is imperative that the patient is counselled
on the possible complications prior to commencement of therapy, and is fully aware
of the requirement for careful monitoring. A medication guide and information booklet
should be provided to each patient.

Clinicians should counsel patients about prevention measures to minimize bleeding and
to report immediately signs and symptoms of bleeding. Patients need to attend their GP or
an outpatient warfarin clinic, for regular monitoring of INR, and dosage adjustments.
The risk of major bleeding episodes in patients treated with warfarin is related to the
degree of anticoagulation as well as the presence in the patient of pre-existing risk factors
for bleeding.
Major risk factors for bleeding
1. Increased age (variously given as >60, >65, >75, or >80 years)
2. Female sex
3. Diabetes mellitus
4. Presence of malignancy
5. Hypertension (ie, systolic >180 or diastolic >100 mmHg)
6. Acute or chronic alcoholism, liver disease
7. Renal impairment
8. Anaemia
9. Poor drug compliance/clinic attendance
10. Prior stroke or intracerebral hemorrhage
11. Presence of bleeding lesions (eg, gastrointestinal blood loss, peptic ulcer
disease)
12. Bleeding disorder (coagulation defects, thrombocytopenia)
13. Concomitant use of aspirin, nonsteroidal antiinflammatory drugs (NSAIDs),
antiplatelet agents, or antibiotics
14. Instability of INR control and INR >3.0
15. Pre-treatment INR >1.2
16. Previous severe hemorrhage during treatment with warfarin with an INR in
the therapeutic range

Recommended management of a supratherapeutic INR

INR

Bleeding
present

>Therapeutic, No
<5.

Recommended action
Lower warfarin dose, or
Omit a dose and resume warfarin at a lower dose when
INR is in therapeutic range, or
No dose reduction needed if INR is minimally
prolonged

>5.0 to 9.0

No

Omit the next 1 to 2 doses of warfarin, monitor INR more

frequently, and resume treatment at a lower dose when
INR is in therapeutic range, or
Omit a dose and administer 1 to 2.5 mg oral vitamin K

>9.0

No

Hold warfarin and administer 5 to 10 mg oral vitamin K.

Monitor INR more frequently and administer more
vitamin K as needed, Resume warfarin at a lower dose
when INR is in therapeutic range

Any

Serious or life- Hold warfarin and administer 10 mg vitamin K by slow

threatening
IV infusion; supplement with prothrombin complex
concentrate, fresh frozen plasma, or recombinant human
factor VIIa, depending on clinical urgency. Monitor and
repeat as needed.

The optimal method for returning the International Normalized Ratio (INR) to the desired
range depends upon its degree of initial elevation and whether or not clinically significant
bleeding is present.
Other complications of warfarin therapy
Skin necrosis Skin necrosis has been reported in some patients within the first few
days of receiving large doses of warfarin. The skin lesions occur on the extremities,
breasts, trunk, and penis.

Skin necrosis appears to be mediated by the rapid reduction of protein C levels on the
first day of therapy, which induces a transient hypercoagulable state.
Pregnancy Warfarin derivatives are generally felt to be contraindicated during at least
the first trimester of pregnancy because of their teratogenic effects. Patients should be
alternatively anticoagulated with heparin during pregnancy.
Cholesterol embolization Embolization of cholesterol crystals (cholesterol
microembolism) is a rare complication of anticoagulation with warfarin. Typically, this
occurs after several weeks of therapy, and presents as a dark, purplish, mottled
discolouration of the plantar and lateral surfaces. This condition has been variously called
"blue toe syndrome.

Warfarin Therapy in the surgical patient

1. For patients at low risk for perioperative bleeding, anticoagulation can be
maintained at or below the low end of the therapeutic range (INR 2.0).
2. For patients with a high risk of bleeding, the INR should be 1.5. Within this
group, patients at low risk for thrombosis can stop warfarin two to five days
preoperatively; patients at high risk for thrombosis can stop warfarin but
should probably be treated with intravenous or subcutaneous heparin when
the INR is subtherapeutic.
3. Warfarin and/or heparin can be restarted postoperatively when there is no
contraindication to anticoagulation.
Giving advice to the patient commencing warfarin

The patient should be advised to call his/her doctor if he/she has any of the following:
1. A fever or developing illness, including vomiting, diarrhoea, or infection
2. Pain, swelling, discomfort or any other unusual symptoms
3. Prolonged bleeding from cuts, nosebleeds
4. Unusual bleeding from gums when brushing teeth
5. Increased menstrual flow or vaginal bleeding
6. Red or dark brown urine
7. Red or tarry-black stools
8. Unusual bruising for unknown reasons
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9. Pregnancy
10. Planning a pregnancy
11. Sustaining a serious fall or trauma

12. Before starting, changing, or discontinuing any medication (including

OTC medications)
13. Severe diarrhoea (alters absorption of vitamin K) to discuss the need to
check INR.
The patient should be advised to
1. Try to keep the same general diet
2. Avoid excessive amounts of alcohol.
3. Carry Medi-Alert ID identifying drug usage.
4. Consult doctor before undergoing dental work or elective
surgery.
5. Strictly adhere to the prescribed dosing schedule. Dosage is
highly individual and may need to be adjusted several times
based on lab test results.
Scenario 1
A 28 year old man presents to Accident and Emergency Department with
palpitations. He had been on a stag weekend in Amsterdam, and felt weak and
noticed his heart was racing, on arrival in Dublin airport. An ECG reveals fast
atrial fibrillation at a rate of 150bpm.
He is commenced on warfarin therapy and an anti-arrhythmic agent. {How would
you commence warfarin?}You are the intern on the team. On discharge from
hospital, what advice do you give him with regard to his warfarin therapy?
1.
2.
3.
4.
5.
6.

Importance of compliance
Regular checking of INR level
Organise who will check INR GP follow-up, warfarin clinic
Outline complications, especially bleeding
Outline that certain medications can change the INR level
Outline importance of contacting physician before commencing any new
medication/OTC preparation/Herbal remedy
7. Outline importance of moderating alcohol intake, increased risk of bleeding with
alcohol intake.
8. Emergency plan if bleeding occurs

The same gentleman calls you on your pager two months later. He got in a fight last
night in the pub, and was hit in the nose. His nose has been bleeding all night, and
he has started to feel light-headed. What do you advise him to do?
1. Do not take warfarin dosage for that day.
2. Present to Accident and Emergency department (get friend/relative to accompany
him)
3. Following treatment and stabilization of INR, reiterate the necessity to decrease
alcohol consumption.
4. Organise follow-up INR test for the following week.
5. Discuss with multi-disciplinary team the appropriateness of warfarin therapy in
patient who is non-compliant with recommendations for usage.
Scenario 2
You are a GP trainee working in Co. Clare. Mrs. Ryan, a 77 year old lady and her
daughter attend your clinic. Mrs. Ryan had a right sided parietal infarct two years
ago, and has been on warfarin therapy ever since. She made an excellent recovery
following her stroke. However, her daughter has now noticed that she is becoming
increasingly forgetful. She has left the oven on while at mass one day, and is
constantly misplacing objects around the house. She is on a lot of medications, and
now occasionally gets confused as to which medication she has to take, and when.
Her daughter is concerned that this will affect her INR levels. How do you manage
the situation?
1. Formal assessment of cognition MMSE, CT Brain, delirium screen to outrule an
acute confusional state, detailed history, occupational therapy assessment.
2. If there is clinical evidence of a dementia process, discuss with Mrs. Smith and
her family the benefit of continuing warfarin medication (in prevention of
recurrent thromboembolic disease), versus the risk of bleeding, if careful
monitoring of medication administration cannot be ensured.
3. Discuss alternatives to discontinuing warfarin therapy Mrs. Smiths
family/relatives/home help supervising medications, and organizing INR checks.
4. Discuss alternatives to anti-coagulation, e.g anti-platelet agents such as
aspirin/clopidogrel, which do not confer the same bleeding risk.
Scenario 3
You are the SHO on the haematology team. The warfarin nurse specialist calls you
about Ms. Gleeson, a 23 year old lady who is on warfarin following being diagnosed
with a deep vein thrombosis two months ago. She has planned a holiday to Spain for
a fortnight, and will not be able to have her INR checked while she is away. What
advice do you give her to ensure her INR level remains within the therapeutic
range?

1. Have INR checked the day before leaving for holiday to ensure level is
therapeutic, and within a week of returning.
2. Avoid increasing alcohol intake while on holidays.
3. Avoid taking any new medications/preparations without consulting a physician.
4. Advise to consult a physician if she experiences any mucosal bleeding
(overcoagulation), chest pain, dyspnoea, leg swelling (Recurrent DVT/PE due to
undercoagulation)
Scenario 4
Mrs. Gleeson is an 82 year old lady who is brought to the Accident and Emergency
Department by ambulance. She was found collapsed on the floor of her kitchen by
her niece, who tells you that she went to her GP four days ago, complaining of
dysuria, frequency, urgency and suprapubic tenderness. Her GP prescribed
trimethoprim/sulphamethoxazole (septrin). She was due to attend the warfarin
clinic yeaterday, but did not go, as she had still felt unwell. She is now unresponsive
with a GCS of 3.
Explain Mrs. Gleesons clinical condition.
1. Fall due to fraility/intercurrent illness causing dehydration,syncope
2. Antibiotic therapy interacting with cytochrome p450 enzymes inhibiting
enzymes, decreasing warfarin metabolism, increasing warfain levels, increasing
INR.
3. Combination of trauma and elevated INR predisposed to intracranial
haemorrhage.
Scenario 5
Mrs. Walsh attends the respiratory clinic, for follow-up, after being diagnosed with
a pulmonary embolism two months previously. She is well, and her INR is
therapeutic. She tells you she and her husband are planning to have a baby. What
advice do you give her?
1. Warfarin is teratogenic (can cause abnormalities in the growth of the fetus).
2. She must discontinue warfarin therapy, prior to attempting conception.
3. She must begin subcutaneous low molecular weight heparin injections prior to
discontinuing warfarin therapy.
4. She must use one of the following regimens:
a. Adjusted-dose LMW heparin therapy throughout the pregnancy in doses
adjusted according to weight.
b. Unfractionated or LMW heparin therapy (as above) until the 13th week,
and change to warfarin until the middle of the third trimester, and then
restart unfractionated or low molecular weight heparin until delivery.

5. Long-term anticoagulation should be resumed postpartum regardless of which

regimen is used. Heparin can be restarted 12 hours post-cesarean delivery and 6
hours post-vaginal birth, if no significant bleeding has occurred. Heparin is either
continued, or replaced with warfarin (stopping the heparin when the INR is
therapeutic).
Scenario 6
Mr. Dawson is a 55 year old gentleman referred to the gastroenterology clinic with a
two month history of change in bowel habit and 6kg weight loss. Your consultant
asks you to organize a colonoscopy +/- biopsy for him. Mr Dawson has a mechanical
aortic valve, and is warfarinised. How will you manage his anti-coagulation prior to,
during, and after the procedure?
1. Warfarin therapy should be discontinued 3 to 5 days before the procedure.
2. Administer intravenous heparin once the INR falls below the therapeutic
level should be individualized.
3. Heparin should be discontinued 4 to 6 hours before the scheduled
procedure and may be resumed 2 to 6 hours after the procedure.
4. Warfarin therapy may generally be resumed the night of the procedure.
5. Heparin infusion and warfarin should overlap for a period of 4 to 5 days or
until the INR has achieved the target therapeutic range for 2 to 3 days.
Scenario 7
A 33 year old man is admitted to hospital, complaining of palpitations. An ECG
reveals atrial fibrillation at a rate of 150bpm. He is commenced on an antiarrhythmic agent for rate control, and warfarin for thromboembolic prophylaxis.
He undergoes elective cardioversion three weeks later and the heart rate is reverted
to sinus rhythm. He wishes to discontinue warfarin therapy at this point. What
advice should you give him?
Patients treated with rhythm control remain at risk for embolization even when in sinus
rhythm for two main reasons: recurrent episodes of AF are common and asymptomatic in
up to 90 percent; and some patients have other reasons for thromboembolic risk such as
complex aortic plaque or left ventricular systolic dysfunction. Most patients with AF,
regardless of whether a rate control or rhythm control strategy is chosen, should be
chronically anticoagulated with warfarin or a comparable agent, with a target INR of 2-3.