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Armadale Health Service
RENAL NURSE PRACTITIONER CLINICAL PROTOCOL
TITLE:
WARFARIN THERAPY IN HAEMODIALYSIS PATIENTS
This Clinical Protocol is devised for an exclusive use by the Renal Nurse Practitioner,
Armadale Health Service.
Compiled by:
Casey Light
Renal Nurse Practitioner
Dr. Hemant Kulkarni
Renal Physician
Clinical Protocol Development Review Panel
Chris Bone
Director of Nursing
Acting Executive Director, Armadale Bentley Group
Eleri Griffiths
Acting Director of Nursing
Chairperson Nursing Practice Committee
Dr. Reg Andrews
Deputy Director Clinical Services
Dr. Antonia Bagshawe
Director Medical Specialties
Professor Stephen Lim
Principal Pharmacist
Chairperson Drugs and Therapeutics Committee
Frank Mancini
Managing Scientist Pathology
Melita Sandiford
Clinical Nurse Specialist
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TABLE OF CONTENTS
CONTENTS
Table of Contents
Purpose of this protocol
Expected outcomes
Scope of this protocol
Background
Indications for warfarin use
Contraindications for warfarin use
Major adverse effects of warfarin
Other adverse effects of warfarin
Pharmacology
Pharmacodynamics and dosing considerations
Anticoagulant activity
Antithrombotic effect
In-vitro monitoring of warfarin effect
International Normalised Ratio (INR)
Monitoring and dosing adjustment
Frequency of INR monitoring
Dose adjustment-maintenance therapy
Interrupting warfarin therapy for surgery
Patient education
Clinical performance and evaluation
Drug Formulary
Warfarin
Marevan
Coumadin
Clexane
Vitamin K
Glossary
References
Authorisation
TABLES:
Table 1 Warfarin drug interactions
Table 2 Usual INR ranges in adults
Table 3 Warfarin Therapy Guide: Maintenance dosage adjustments
Table 4 Management of elevated INR in adult patients with or
without bleeding
FLOW CHARTS
Peri-operative management of warfarin therapy in haemodialysis patients
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PURPOSE OF THIS PROTOCOL
Provide clinical practice guidelines for the Renal Nurse Practitioner (RNP) for:
- Management of Warfarin therapy in haemodialysis patients, including
initiating dose changes as per the protocol in various clinical settings
- Reducing dependence on Primary Care Physicians for day to day monitoring
of warfarin therapy for dialysis patients
- Initiate timely therapy changes in unstable clinical situations, where
community clinic would have limited input
- Act as liaison person between the dialysis unit and clinicians, during an
inpatient or outpatient stay.
EXPECTED OUTCOMES
To manage warfarin therapy in haemodialysis patients
- in conjunction with routine hemodialysis, without need to visit community
clinics (avoiding multiple blood tests)
- Maintain safe anticoagulation with initiating appropriate changes during at
risk periods (eg surgery, interventions)
- Reduce bleeding complications by maintaining therapeutic INR
SCOPE OF THIS PROTOCOL
This protocol covers haemodialysis patients at the Armadale Dialysis Unit under the
care of the RNP and Renal Physician.
BACKGROUND
Warfarin is the most frequently used oral anticoagulant to control and prevent
thromboembolic disorders since its use in 1950s (Horton, 1999). Common indications
for warfarin therapy include atrial fibrillation (AF), pulmonary embolus (PE),
prosthetic valve replacements, embolic stroke, and venous thromboembolism (Hortin,
1999; Gallus et al, 2000; Campbell et al, 2001). Warfarin is used with limited / no
evidence to prevent dysfunction of tunnelled cuffed dialysis catheters (TCCs)
dysfunction or arterio-venous dialysis access. (Willm, L. & Vercaigne, L. 2008)
Warfarin therapy management is complicated in the HD population. Platelet
dysfunction, anticoagulation for the extracorporeal dialysis circuit and increasing comorbid conditions increases risk for bleeding complications than the general
population especially gastrointestinal bleeding (Wasse, H., Gillen, D. & Ball, A. et al,
2003) There is limited high level data about efficacy of warfarin therapy in a
particular condition in the settings of dialysis, and the decision to initiate therapy
remains with the treating Physician. Physician must clarify the therapeutic target of
INR for an individual patient considering the indication and risk factors.
Monitoring of INR on warfarin therapy is mandatory. Low and full-intensity
anticoagulation use in HD patients is associated with a significant bleeding risk,
which has to be balanced against any potential benefit of therapy. Bleeding must be
monitored carefully in this population, especially in patients using antiplatelet
medications for concurrent conditions. The available evidence indicates that rates of
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major bleeding episodes in HD patients exposed to full-intensity anticoagulation with
warfarin ranged from 0.1 to 0.54 events/patient-yr of exposure. (Elliot, M.,
Zimmerman, D. & Holden, M. 2007)
Involvement of patients and their family is important and should be implemented
wherever possible with standard management programs. The RNP will manage the
Warfarin dosing as per protocol whilst INR is collected prior to dialysis sessions,
avoiding the need for patients to attend GPs or community anticoagulation clinics.
It is essential that the RNP have knowledge of the limitations of warfarin therapy,
elevated risks in dialysis population, drug pharmacology, and adverse effects to
ensure effective monitoring. This protocol provides guidelines for RNP to be able to
deliver therapeutic anticoagulation for the indicated purpose as well as perioperative
management when the therapy is interrupted
INDICATIONS FOR WARFARIN USE
Established indications for warfarin therapy in non-dialysis related situations are:
A) Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary)
B) Prophylaxis and treatment of embolic complications arising from atrial fibrillation
or cardiac valve replacement;
C) Adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after
myocardial infarction
Indications for warfarin therapy in haemodialysis settings are limited, and are not
supported by high level evidence:
a) Reduce incidence of catheter related central venous thrombosis
b) Reduce incidence of thrombosis in arteriovenous fistula ( AVF) or arteriovenous
graft (AVG)
CONTRAINDICATIONS FOR WARFARIN USE:
•
•
•
•
•
•
•
Elevated Risk of bleeding: Active or occult bleeding, risk for falls
Hypersensitivity to warfarin or any component of the formulation;
Haemorrhagic tendencies (eg, patients bleeding from the gastrointestinal (GI),
respiratory, or genitourinary (GU) tract; aneurysm; cerebrovascular haemorrhage;
following spinal puncture and other diagnostic or therapeutic procedures with
potential for significant bleeding; history of bleeding diathesis);
Recent or potential surgery; major regional lumbar block anaesthesia or surgery
resulting in large, open surfaces; blood dyscrasias;
Severe uncontrolled or malignant hypertension; pericarditis or pericardial
effusion; subacute bacterial endocarditis;
history of warfarin-induced necrosis;
Unreliable, noncompliant patient; alcoholism; unsupervised senile or psychotic
patient; eclampsia/pre-eclampsia, threatened abortion, pregnancy
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MAJOR ADVERSE EFFECTS OF WARFARIN THERAPY:
Major adverse effects of warfarin in the dialysis patient include:
a) Bleeding (major and minor): Can virtually happen at any site
• Risk factor for major bleed include:
a) genetic variations in the proteins CYP2C9 and VKORC1
b) High intensity anticoagulation (INR >4), age (≥65 years), variable INRs,
history of GI bleeding, hypertension, cerebrovascular disease, serious heart
disease, malignancy, trauma, vasculitis, indwelling catheters, menstruating
and postpartum women, drug-drug interactions, long duration of therapy.
b) Warfarin induced skin necrosis (can be confused with calciphylaxis)
c) Promotion of medical arterial calcification (proven in animal studies),
osteoporosis
OTHER ADVERSE EFFECTS OF WARFARIN THERAPY:
Angina, chest pain, oedema, haemorrhagic shock, hypotension,
pallor, syncope, vasculitis
Central nervous system: Coma, dizziness, fatigue, fever, headache, lethargy, malaise,
pain, stroke
Dermatologic:
Alopecia, bullous eruptions, dermatitis, rash, pruritus, urticaria
Gastrointestinal:
Abdominal cramps, abdominal pain, anorexia, diarrhoea,
flatulence, gastrointestinal bleeding, mouth ulcers, nausea, taste
disturbance, vomiting
Genitourinary:
Hematuria, priapism
Haematological:
Agranulocytosis, anaemia, leukopenia, retroperitoneal
hematoma,
Unrecognised bleeding sites (eg, colon cancer) may be
uncovered by anticoagulation
Hepatic:
Cholestatic jaundice, hepatic injury, hepatitis, transaminases
increased
Neuromuscular & skeletal: Joint pain, muscle pain, osteoporosis (potential association
with long-term use), paralysis, paraesthesia, weakness
Respiratory:
Dyspnoea, tracheobronchial calcification
Miscellaneous:
Anaphylactic reaction, cold intolerance,
hypersensitivity/allergic reactions, skin necrosis, gangrene,
"purple toes" syndrome
Cardiovascular:
Special Concerns:
Concerns related to adverse effects:
• Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including
anaphylaxis; use with caution in patients with anaphylactic disorders.
• Bleeding: [U.S. Boxed Warning]: Patient must be instructed to report
bleeding, accidents, or falls as well as any new or discontinued medications,
herbal or alternative products used, or significant changes in smoking or
dietary habits. Unrecognized bleeding sites (eg, colon cancer) may be
uncovered by anticoagulation.
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•
•
Skin necrosis/gangrene: Necrosis or gangrene of the skin and other tissue can
occur (rarely, <0.1%) due to paradoxical local thrombosis; onset is usually
within the first few days of therapy and is frequently localized to the limbs,
breast, or penis. The risk of this effect is increased in patients with protein C
or S deficiency.
"Purple toe" syndrome, due to cholesterol microembolization, has been rarely
described with coumarin-type anticoagulants. Typically, this occurs after
several weeks of therapy, and may present as a dark, purplish, mottled
discoloration of the plantar and lateral surfaces. Other manifestations of
cholesterol microembolisation may include rash; livedo reticularis; gangrene;
abrupt and intense pain in lower extremities; abdominal, flank, or back pain;
hematuria, renal insufficiency; hypertension; cerebral ischemia; spinal cord
infarction; or other symptoms of vascular compromise.
Disease-related concerns:
• Dietary insufficiency: Use with caution in patients with prolonged dietary
insufficiencies (vitamin K deficiency).
• Heparin-induced thrombocytopenia (HIT): 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; warfarin initially inhibits the synthesis of protein C, potentially
accelerating the underlying active thrombotic process.
• Hepatic impairment: Reduced liver function, regardless of etiology, may
impair synthesis of coagulation factors leading to increased warfarin
sensitivity.
• Infection: Use with caution in patients with acute infection or active TB or any
disruption of normal GI flora; antibiotics and fever may alter response to
warfarin.
• Renal impairment: Use with caution.
• Thyroid disease: Use with caution.
Special populations:
• Elderly: The elderly may be more sensitive to anticoagulant therapy.
• Ovulating women: May be at risk of developing ovarian hemorrhage at the
time of ovulation.
• Patients with genomic variants in CYP2C9 and/or VKORC1: Presence of the
CYP2C9*2 or *3 allele and/or polymorphism of the vitamin K oxidoreductase
(VKORC1) gene may increase the risk of bleeding. The *2 allele is reported to
occur with a frequency of 4% to 11% in African-Americans and Caucasians,
respectively, while the *3 allele frequencies are 2% to 7% respectively. Other
variant 2C9 alleles (eg, *5, *6, *9, and *11) are also associated with reduced
metabolic activity and thus may increase risk of bleeding, but are much less
common. Lower doses may be required in these patients; genetic testing may
help determine appropriate dosing.
• Paediatrics: Safety and efficacy have not been established in children; monitor
closely.
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PHARMACOLOGY
Warfarin is a racemic mixture of R-& S-enantiomers. The S-enantiomer exhibits 2-5
times more anticoagulant activity than the R-enantiomer in humans, but generally has
a more raid clearance.
Warfarin is an antagonist of vitamin K, an essential element in the synthesis of
clotting factors II, VII, IX and X, as well as the endogenous anticoagulant proteins C
and S. These factors and proteins are biologically inactive without the carboxylation
of certain glutamic acid residues. This carboxylation process requires a reduced
vitamin K as a cofactor. Vitamin K antagonism or deficiency reduces the rate at
which the clotting factors and proteins are produced, thereby creating a state of
anticoagulation (Majerus, P., Broze G., Miletich J. &, Tollefsen, D. 1996).
Onset of action: Anticoagulation: Oral: 24-72 hours
Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours
Duration:
2-5 days
Absorption: Oral: Rapidly and completely absorbed from the GI tract
Distribution: 0.14 L/kg
Protein binding: 99% bound to protein, specifically albumin.
Metabolism: Hepatic, primarily via CYP2C9; minor pathways include CYP2C8,
2C18, 2C19, 1A2, and 3A4
Genomic variants: Approximately 37% reduced clearance of S-warfarin in patients
heterozygous for 2C9 (*1/*2 or *1/*3), and ~70% reduced in patients
homozygous for reduced function alleles (*2/*2, *2/*3, or *3/*3)
Half-life elimination: 20-60 hours; Mean: 40 hours; highly variable among individuals
It has a half-life of approximately 40 hours, factor VII are inhibited
more rapidly (half-life of 5 hr), whereas factors IX, II, and X have halflives of 24 to 48 hr. When the shorter acting coagulation factors are
inhibited, the international normalized ratio (INR) is abnormal but the
patient needs an additional 4 to 5 days to become fully anticoagulated
because of the slower effect of warfarin on other coagulation factors.
Time to peak, plasma: Oral: ~4 hours
Excretion:
Urine (92%, primarily as metabolites)
Drug interactions:
Drug interactions of varying severity have been identified with warfarin therapy. The
interacting drugs either inhibit or induce warfarin metabolism. Table 1 lists the
interactive effects on warfarin. Close INR monitoring is required during the initiation
or discontinuation of these drugs (Hortin, 1999)
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Table 1
Drug interactions
INCREASED
effect of warfarin
Anti-platelet agents
Analgesics
Abciximab(ReoPro),
Paracetamol(large doses
Aspirin, Dipyridamole,
ie. 4-7 g/week)
NSAIDs
Tramadol
Clopidogrel, Tirofiban
COX-2 inhibitors
Anticonvulsants
Celecoxib, Rofecoxib
Phenytoin
Antibiotics
Cephalosporins,
Macrolides,
Quinolones
tetracycline
Metronidazole,
sulphonamides, quinolones
vancomycin
Cotrimoxazole
Antifungals
Itraconazole, Fluconazole
miconazole
Antiarrhythmics
Amiodarone, Mexiletine,
Verapamil, Quinidine
Herbal medicines
Dong quai, garlic, papaya.,
St Johns Wort, Ginkgo,
ginger and garlic ( large
amount), Guarana.
Selective serotonin
reuptake inhibitors
Fluoxetine
Tricyclic antidepressants
DECREASED
effect of warfarin
Ascorbic acid ( large
doses)
Vitamin K
Anticonvulsants
Carbamazepine
Phenytoin (rare)
Antibiotics
dicloxacilin
Rifampicin
Rifabutin
Sedatives
Barbiturates
Raloxifene
Tamoxifen
Quinine
and Quinidine
Miscellaneous
Anabolic steroids
Chloral hydrate
Cimetidine
Clofibrate
Disulfiram
Heparins
Omeprazole
Simvastatin
Tamoxifen
Thyroxine
Fish Oil
Herbal medicines
Ginseng,
Slippery elm bark,
Vitamin-K containing
herbs (eg, alfalfa, green
tea)
Co-enzyme Q10
Miscellaneous
Barbiturates
Carbamazepine
Chlordiazepoxide
Azathioprine
Cyclosporine
Etretinate
Trazodone
Glucosamine
Source: Initiation and Maintenance of Warfarin Therapy, Guidelines & Protocols,
BC Health Services. http://health.gov.bc/gpac/pdf/warfarin-therapy
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PHARMACODYNAMICS AND DOSING CONSIDERATIONS
Anticoagulant activity:
The anticoagulant activity of warfarin depends on the clearance of functional clotting
factors from the systemic circulation after administration of the dose. The clearance of
these clotting factors is determined by their half-lives.
The earliest changes in the INR are typically noted 24 to 36 hours after a dose of
warfarin is administered.
These changes are due to the clearance of functional factor VII, which is the vitamin
K dependent clotting factor with the shortest half-life (six hours). However, the early
changes in the INR are deceptive because they do not actually affect the body's
physiologic ability to halt clot expansion or form new thrombosis. (Hirsh, J., Dalen,
J., Deykin, D., Poller, L. & Bussey, H. 1995).
Antithrombotic effect
The antithrombotic effect of warfarin, or the inability to expand or form clots, is not
present until approximately the fifth day of therapy. This effect depends on the
clearance of functional factor II (prothrombin), which has a half-life of approximately
50 hours in patients with normal hepatic function.
NOTE:
The antithrombotic effect depends on the prothrombin clearance (which may take up
to five days), loading doses of warfarin are of limited value. Because warfarin has a
long half-life (40 hours), increases in the INR may not be noted for 24 to 36 hours
after administration of the first dose, and maximum anticoagulant effect may not be
achieved for 72 to 96 hours. (Hirsh, J., Dalen, J., Deykin, D., Poller, L. & Bussey, H.
1995).
In-Vitro monitoring of Warfarin effect:
Prothrombin time (PT): Time taken by plasma to clot after addition of tissue factor (or
thromboplastin). Prolongation of PT depends on reductions in three of the vitamin K
dependent clotting factors (II, VII and IX).
Changes in the PT in the first few days are primarily due to reductions in clotting
factors with the shortest half-lives; factor VII (6 hours) and factor IX (24 hours)
International Normalised Ratio (INR)
The early changes in PT vary based on the responsiveness of the particular
thromboplastin that a laboratory uses to perform the test. The International Sensitivity
Index (ISI) is used to measure and compare the variability in thromboplastin
responsiveness. World Health Organization Expert Committee on Biologic
Standardization in 1982 developed the International Normalised Ratio (INR) to
correlate for the various laboratory standards ( Hortin, 1999).
When starting or stopping a drug, particularly antibiotics, the INR must be checked 12 days after the change in therapy.
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MONITORING AND DOSING ADJUSTMENT
Table 2 : Usual INR Ranges in Adults
Indications
Prevention of TCC/ AVF/AVG clotting
INR range
Targeted INR
2.0 -3.0
2.5
(Obialo et al, Scan J Neph 2003)
Medical conditions
Acute myocardial infarction (high risk)
Atrial fibrillation
St Jude Medical bileaflet mechanical aortic valve
Carbomedics bileaflet/Medtronic Hall tilting disk
mechanical aortic valve (NSR, Nl LA size)
Bioprosthetic mitral/ aortic valve
Bioprosthetic mitral or aortic valve with AF
Rheumatic mitral valve disease and NSR
(left atrial diameter >5.5 cm)
Venous thromboembolism
Lupus inhibitor (no other risk factors)
Bileaflet or tilting disk mechanical mitral valve
Caged ball or caged disk mechanical valve
Mechanical prosthetic valve with systemic embolism
despite adequate anticoagulation
Mechanical valve and risk factors (atrial fibrillation,
MI, left atrial enlargement, low EF, endocardial
damage)
Lupus inhibitor and recurrent thromboembolism
2.0-3.0**
2.5
2.0-3.0
2.5
2.5-3.5
3.0
**
High-risk includes a large anterior MI, significant heart failure, intracardiac
thrombus, thromboembolism
( Hortin, 1999; Callus et al, 2000,)
Frequency of INR monitoring
During the induction phase, INR should be monitored every 1-3 days until the INR is
in the patient’s target range for two consecutive values.
Once stable, INR may be performed less frequently (every 1-4 weeks), depending on
the stability of the results.
Dosage adjustment – maintenance therapy
As long as the INR results remain within the patient’s target range, dosage adjustment
is not required for minor fluctuations.
When fluctuation of INR beyond target range occurs, the patient’s history and INR
trend should be assessed and investigated as needed.
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TABLE 3
WARFARIN THERAPY GUIDE:
MAINTAINENCE DOSE ADJUSTMENTS
INR Target: lower limit (LL) – Upper limit (UL)
Dosage Adjustment
INR
INR declining trend to (LL – 0.4)
See trend, minimal change
INR at (LL-0.5)
Increase dose by 0.5-1.0 mg
INR (LL - >0.5 and <1.0)
Increase dose by 1.0 mg –2.0 mg
INR (LL - >1.0)
Increase dose by 25-50% or more
Within target range (LL –UL)
NO CHANGE
INR (UL + <0.5)
See trend, minimal change
INR (UL + >0.5 & <1.0)
Reduce Warfarin by 0.5 – 1.0 mg
INR (UL + >1.0)
Reduce dose by 1.0 – 2.0 mg
INR > 4.0 but < 5.0
Reduce dose significantly 50% -75%
INR above 5.0
Contact Doctors, and refer to Warfarin
reversal guidelines for Fremantle
Hospital
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Warfarin reversal guidelines for Fremantle Hospital
TABLE 4:
Management of elevated INR in adult patients
with or without bleeding
INR 5.0-9.0
(No/minor bleed)
(As directed by the
consultant)
Stop warfarin, Inform Doctors
If high bleeding risk give vitamin K 1-2 mg oral OR 0.51 mg IV
Remeasure INR in 12 hours
Monitor patient
Restart warfarin at a reduced dose when INR in normal
therapeutic range
INR >9
(no/ minor bleed)
(Outside the scope of NP)
Low risk
Inform Doctors
Stop warfarin
Give vitamin K 2.5-5 mg oral OR
1 mg IV
Remeasure INR 6-12 hours
Restart warfarin at a reduced dose
when INR is in normal therapeutic
range
High risk:
Call Physician
Stop warfarin
Give Vitamin K 1 mg IV
Consider clotting factor replacement
with prothrombinex VF 25 IU/kg
and FFP 1 unit
Remeasure INR in 6-12 hours
Monitor patient
Restart warfarin at a reduced dose
when INR is in normal therapeutic
range
Major bleeding
(at any INR)
Call Physician
(Outside the scope of NP)
Stop warfarin
Seek Physician advice and transfer to tertiary hospital
Give 5-10 mg IV Vitamin K PLUS prothrombinex VF 25
IU/kg and one unit FFP
( or if prothrombinex unavailable – FFP 10-25 ml/kg)
Monitor patient and INR frequently until in normal
therapeutic range, and bleeding ceased.
Reassess warfarin therapy with supervising team.
Source: Fremantle Hospital & Health Service Transfusion Medicine, Fremantle
Haematology Manual (Revised 15th August 2008)
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INTERUPTING WAFARIN THERAPY FOR SURGERY
Anticoagulation with warfarin needs reversal prior to any invasive procedures to
reduce the risk of post procedure bleeding. Warfarin therapy should be ceased early
enough to reverse the therapeutic effect (5 -7 days prior to planned procedure).
Reversal in emergency situations must be carried out by the Medical Team.
Patients with high risk of thrombosis or thromboembolic complications (e.g. recurrent
PE, coronary artery stents, prosthetic heart valves, prothrombotic states with systemic
complications) must receive alternative anticoagulation with low molecular weight
heparin (LMWH) during the reversal period, until full therapeutic anticoagulation is
established after surgery. Immediate peri-procedure anticoagulation must be guided
by the Medical Team, taking into consideration the nature of procedure, and risks of
bleeding v/s thrombosis.
Common indications for Warfarin Therapy interruption in this HD setting:
Non renal related:
Dental extractions
Renal related:
Insertion / rewiring / removal of central venous catheter
Creation / revision of AVF / AVG
Insertion of peritoneal dialysis (PD) tube
Parathyroidectomy
Common Guidelines for management of dialysis patient:
• Perform dialysis procedure a day prior to the planned procedure
• Plan anticoagulation in conjunction with surgeon and anaesthetist
• Remember antiplatelet agents: Aspirin and Clopidogrel may also need to be
stopped a week prior to procedure
• Use Heparin-Free Dialysis immediately following invasive procedure or in
presence of active bleeding or uremic serositis
• Watch for internal and external bleeding following procedure. Inform any
significant bleeding event to the Physician.
Recommencing Warfarin Therapy after the surgical procedure:
• Discuss with Surgeon regarding initiation of warfarin therapy
• Ensure bleeding free period of at least 1-2 weeks with surgeries involving
visceral organs, or 48 hours for superficial surgeries (skin, dental extractions)
• Restart Warfarin at 2 mg above the past therapeutic maintenance dose (MD +
2 mg) and monitor INR on each dialysis.
• Readjust Warfarin dose as per INR guidelines, monitor for a rapid rise in
INR.
• NB: Table 3 does not apply to initiating post-operative anticoagulation
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This flow chart provides guidance for the RNP in this unit
Peri-operative management of Warfarin therapy in Haemodialysis population.
Surgical details:
•
Details of Surgical Procedure
•
Date of the Surgical Procedure
•
Location/Hospital of procedure
•
Dialysis Planning before and after procedure
Pre-surgical dialysis planning:
•
On the day of surgery or prior to the day of surgery
•
Location of dialysis – if surgery outside AHS
•
•
•
Withhold Warfarin a week prior and replace it with heparin
anticoagulation as below.
Use LMWH (eg Clexane1mg/kg) on dialysis in all patients
until the day before surgery
High Risk Patients need LMWH injections until day prior to
surgery even on NON-Dialysis days
ON THE DAY OF SURGERY:
•
Measure INR, Hb, EUC
•
Heparin Free dialysis – if necessary
•
Liaise with Surgeon / Anaesthetist for intra and post
operative anticoagulation
POST –OP ANTICOAGULATION
•
Heparin Free dialysis – if necessary
•
Liaise with Surgeon / Anaesthetist for post operative
anticoagulation
•
If a decision to restart Warfarin is made, continue use of
LMWH for dialysis and monitor INR until targeted INR is
achieved
•
Observe and report internal or external bleeding
* High Risk Patient Group (recurrent PE, coronary artery stents, prosthetic heart
valves, prothrombotic states with systemic complications)
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PATIENT EDUCATION:
Patients commencing warfarin therapy are given the handbook “Living with
Warfarin- Information for patients” developed by the WA Medication Safety Group
(WAMSG), a subcommittee of the WA Therapeutics Advisory Group (WATAG).
This handbook provides vital information to assist the patients to take warfarin
correctly and safely.
The RNP’s role is to educate the hemodialysis patients on warfarin about its
indication, need for dose changes, monitoring the risks and complications of therapy.
Patients will also need to be aware of the need for change in doses according to the
change in circumstances.
CLINICAL PERFORMANCE AND EVALUATION
The purpose of this clinical protocol (CP) is to guide the RNP to deliver a safe warfarin
treatment in dialysis population. Performance audit and evaluation should be carried out to
assess the validity of the protocol and safety of the patient.
This clinical protocol must be audited after six months of its implementation and then at least
every twelve months by the Nurse Practitioner.
The modifications in the protocol based on the audit must be approved by the Nursing
Practice Committee to ensure current best practise.
Assessment parameters considered are:
INR MEASURENTS
Jan
No. of patients on warfarin
No. of INR measurements
% measurements outside INR target
No. of dose adjustment in adherence to CP
No. of dose-interruption related to clinical
needs
ADVERSE EVENTS
Bleeding
Clotting
Others
Total
STABLE PATIENTS
No. of patients
No. of dose adjustment in adherence to CP
No. dose changes per patient
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Feb Mar Apr May
June
DRUG FORMULARY—WARFARIN (MAREVAN)
Drug generic name
Warfarin Sodium
Product name: MAREVAN
Manufacturer: Boots Healthcare Australia Pty. Ltd.
Poison schedule
S4
Therapeutic class
Vitamin K dependent factor anticoagulant
Preparation &
Dosage
Tablets
1 mg ( brown, scored, marked M1)
3 mg ( blue, scored, marked M3)
5 mg ( pink, scored, marked M5)
Routes
Orally
Administration
frequency
5-10 mg daily for 2 days
Maintenance 1-10 mg daily adjusted according to target INR
Duration of order
Varies with indication
Titrate to recommended INR targets
Target INR 2-3 for most indications
Action
Inhibits the synthesis of Vitamin K- dependent clotting factors II, VII, IX
and X and the antithrombotic factors protein C and S.
Indication for use
Prevent and treatment of:
venous thromboembolism (DVT, PE)
thromboembolic complications of atrial fibrillation
thromboembolism in patient with prosthetic heart valves
Prevention of dialysis catheter thrombosis
Side effects
Common
Bleeding, headache, dizziness, shortness of breath, difficult breathing
or swallowing, unexplained swelling, weakness.
“Purple toes syndrome”; Purple patches on feet and toes which
wax and wane, legs may also be painful.
Uncommon
Allergic reactions, hepatitis, jaundice, elevated liver enzymes, fever,
rash, tiredness, nausea and vomiting, diarrhoea, itching, hair loss,
cold intolerance
Contraindications
Bleeding disorders, previous GI bleeding, haemorrhagic retinopathy,
intracerebral aneurysm or haemorrhage, severe hypertension, bacterial
endocarditis, alcoholism, unsupervised dementia, frequent falls.
Interactions
Warfarin is known to interact with approximately 250 different drugs. A
detail list is attached (Table1, page 6). Often it is possible to substitute an
alternative non-interacting drug
Storage
Store below 25 degrees
Keep out of reach of children.
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Dialysability
Not dialysed during haemodialysis
Renal consideration
Manufacturer recommendations: No dosage adjustment is necessary for
patients with renal impairment
Source: Warfarin product information pamphlet, AMH (2006), MIMS (Online),
Cervelli, M. (2007)
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DRUG FORMULARY—WARFARIN (COUMADIN)
Drug generic name
Warfarin Sodium
Product name: COUMADIN
Manufacturer: Sigma.
Poison schedule
S4
Therapeutic class
2(k) Anticoagulants, antithrombotics-cardiovascular system
Preparation & Dosage
Tablets
1 mg ( light tan, scored, marked 1)
2 mg ( lavender, scored, marked 2)
5 mg ( green, scored, marked 5)
Routes
Orally
Administration frequency
5-10 mg daily for 2 days
Maintenance 1-10 mg daily adjusted according to target INR
Duration of order
Patient individualisation
Varies with indication
Titrate to recommended INR targets
Target INR 2-3 for most indications
Action
Inhibits C1 subunit of the vitamin K epoxide reductase (VKORC1)
enzyme complex
Indication for use
Prophylaxis and treatment of PE, venous thrombosis and its
extension
Thromboembolic complications associated with AF
Coronary occlusion adjunctive treatment
Prevention of dialysis catheter thrombosis
PRECAUTIONS
NOT bioequivalent to Marevan
Adverse reactions
Haemorrhage; skin , tissue necrosis; systemic cholesterol
microemblolism complications including “purple toe” syndrome; GI
upset; fever; skin reactions; hepatic effects; priapism;
tracheobronchial calcification (rare).
Contraindications
Bleeding disorders, previous GI bleeding, haemorrhagic retinopathy,
intracerebral aneurysm or haemorrhage, severe hypertension,
bacterial endocarditis, alcoholism, unsupervised dementia, frequent
falls.
Interactions
Warfarin is known to interact with approximately 250 different
drugs. A detail list is attached (Table 1 page 6). Often it is possible
to substitute an alternative non-interacting drug
Storage
Store below 25 degrees
Keep out of reach of children.
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Dialysability
Not dialysed during haemodialysis
Renal consideration
Renal clearance is considered to be a minor determinant of
anticoagulant response to warfarin. No dosage adjustment is
necessary for patients with renal impairment
Impaired hepatic function
Hepatic dysfunction can potentiate the response to warfarin through
impaired synthesis of clotting factors and decreased metabolism of
warfarin.
Source: Warfarin product information pamphlet, AMH (2006), MIMS (Online),
Cervelli, M. (2007)
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DRUG FORMULARY--CLEXANE
Drug generic name
Enoxaparin Sodium
Product name: CLEXANE
Manufacturer : Aventis Pharma Pty Limited
Poison schedule
S4
Therapeutic class
Low Molecular Weight Heparin, anti Xa and thrombin anticoagulant
Preparation & Dosage
Injection (Syringe)
20 mg, 0.2 ml (2,000 IU anti-Xa)
40 mg, 0.4 ml (4,000 IU anti-Xa)
60 mg, 0.6 ml (6,000 IU anti-Xa)
80 mg, 0.8 ml (8,000 IU anti-Xa)
100 mg, 1.0ml (10,000 IU anti-Xa)
Routes
Sub cutaneous injections
Haemodialysis- inject into arterial line at start of dialysis
Administration frequency
Specific to indication of use
Duration of order
Varies with indication
Peri-operative use during warfarin withholding period
Action
Inhibition of thrombin generation
Inhibition of coagulation factor Xa
Indication for use
Prevention of venous thromboembolism in surgical patients
Prevention of venous thromboembolism in medical patients
bedridden due to acute illness
Treatment of venous thrombosis
Treatment of unstable angina and non-Q-wave myocardial infarction
Prevention of extracorporeal thrombosis during haemodialysis
Adverse effects
Common
Bleeding
Uncommon
Thrombocytopenia, Allergic reactions, rash, tiredness,
itching, hair loss
Contraindications
Bleeding disorders, previous GI bleeding, haemorrhagic retinopathy,
intracerebral aneurysm or haemorrhage, severe hypertension,
bacterial endocarditis, alcoholism, unsupervised dementia, frequent
falls.
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Interactions
Agents which affect haemostasis should be discontinued prior to
enoxaparin sodium therapy unless strictly indicated
These agents include medications such as anticoagulants
thrombolytic
NSAIDs ,aspirin preparations, ticlopidine, dextran 40, clopidogrel
antiplatelet agents .
Storage
Store below 25 degrees. Shelf life: 2 years
Keep out of reach of children.
Dialysability
Not dialysed during haemodialysis
Renal consideration
Increase risk of bleeding in patients with severe renal impairment
(CrCl <30 ml/min) due to significant increase exposure of
enoxaparin , dosage adjustment is recommended for therapeutic and
prophylactic dosage ranges
No dose adjustment is recommended for patients with CrCl 30-80
ml/min, careful clinical monitoring is advised
Source: Clexane product information pamphlet, AMH (2006), MIMS (Online),
Cervelli, M. (2007)
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DRUG FORMULARY—Vitamin K
Drug generic name
Phytomenadione
Product name: VITAMIN K1
Manufacturer : Roche Products Pty Ltd
Poison schedule
Unscheduled
Therapeutic class
Section 21 Haemostatic agents
Preparation & Dosage
Tablets
10 mg (White, sugar coated) 100’s
Ampoules ( Micelle solution ) 10 mg/ml 5’s
Routes
Oral or intramuscular
Administration frequency
Specific to indication of use
Duration of order
Specific to indication of use
Action
Promotes the formation of coagulation factors II ( prothrombin),
VII, IX, and X in the liver
Promotes the formation of coagulation inhibitors protein C and
Protein S within the body
Indication for use
Haemorrhage or threatened haemorrhage as a result of severe
hypoprothrombinaemia ( i.e. Deficiency of coagulation factors II,
VII, IX, & X) due to , for instance, to overdose of anticoagulant of
the discoumarol type or their combination with pheylbutazone, or to
other forms of hypovitaminosis K ( eg, obstructive jaundice, hepatic
and intestinal disorders or prolonged administration of antibiotics,
sulfonamides or salicylates)
Adverse reactions
Rare
Severe anaphylactoid reactions
Very rare
Injections site reactions, venous irritation phlebitis, facial
flushing, sweating, unusual taste.
Contraindications
Should not be used for patient with pronounced allergic diathesis
Should not be administrated intramuscularly as this route of
administrating exhibits depot characteristics which may cause
difficulties in the reinstitution of anticoagulation therapy.
Intramuscular administration of medications to anticoagulated
patients causes a risk of haematoma formation.
Interactions
Vitamin K antagonises the effect of coumarin type anticoagulant
Co administration of anticonvulsant can impact the action of
Vitamin K
Should not be mixed with infusion solutions
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Storage
Tablets
Store below 30 degrees C
Shelf life 5 years
Keep out of reach of children
Ampoules
Store below 25 degrees C
Shelf life 2 years
Protect from Lighthouse
Keep out of reach of children
Dialysability
Unlikely to be dialysed
Renal consideration
Normal dose in patients with renal impairment
Source: Clexane product information pamphlet, AMH (2006), MIMS (Online),
Cervelli, M. (2007)
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GLOSSARY
AF
AHS
AVF
AVG
CKD
CP
DVT
EF
GI
GU
HD
HIT
INR
ISI
LMWH
MI
PD
PE
PT
RNP
TCC
Atrial Fibrillation
Armadale Health Service
Arteriovenous fistula
Arteriovenous graft
Chronic Kidney Disease
Clinical protocol
Deep Vein Thrombosis
Ejection fraction
Gastrointestinal
Genitouretal
Hemodialysis
Heparin induced thrombocytopenia
International Normalised Ratio
International Sensitivity Index
Low Molecular Weight Heparin
Myocardial infarction
Peritoneal dialysis
Pulmonary Embolus
Prothrombin Time
Renal Nurse Practitioner
Tunnel cuffed catheter
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REFERENCE
AMH. (2006). Australian medicines handbook. Adelaide: AMH Pty Ltd.
Bennett, W.(2006). Should dialysis patients ever receive warfarin and for what
reasons? Clinical Journal American society of Nephrology, 1:1357-1359.
retrieved August 27th 2008, from
http://cjasn.asnjournals.org/cgi/content/full/1/6/1357
Campbell, P., Roberts, G., Park, D., Eaton, V., Coghlan, D. and Gallus, A. (2001). Managing
warfarin therapy in the community. Australia Prescriber, 24(4), 86-89.
Cervelli, M. (2007). The Renal Drug Reference Guide. Adelaide, South Australia.
Elliot, M., Zimmerman, D. & Holden, M. (2007). Warfarin Anticoagulation in
Hemodialysis Patients: A Systematic Review of Bleeding Rates. American Journal of
Kidney Disease, 50 (3),
Gallus, A., Baker, R., Chong, B., Ockelford, D. and Street, A. (2000). Consensus guidelines
for warfarin therapy: Recommendations from the Australasian Society of Thrombosis
and Haemostasis. Medical Journal of Australia, 172, 600-605. Retrieved: August
27th, 2007 from: http://www.mja.com.au
Hirsh, J., Dalen, J., Deykin, D., Poller, L. and Bussey, H (1995). Oral anticoagulants:
mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest
108(4 Suppl):231S-46S.
Horton, J. & Bushwick, B. (1999). Warfarin therapy: Evolving strategies in anticoagulation.
Clinical Pharmacology, 59 (3). Retrieved: August 26th, 2007 from
http://www.aafp.org/afp/990201ap/635.html
Majerus, P., Broze, G., Miletich, J. and Tollefsen, D. (1996).Anticoagulant thrombolytic, and
antiplatelet drugs. In: Hardman JG, Limbird LE, eds. Goodman and Gilman's The
pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1347-51.
MIMS On-line, MIMS Australia Pty Ltd, 1996-2006. Retrieved: August 18th, 2007,
from www.mims.com.au
Obialo, C., Conner, A. & Lebon, L. (2003). Maintaining patency of tunnelled hemodialysis
catheters – efficacy of aspirin compared to warfarin. Scandinavian Journal of
Urol Nephrology 37, 172-176
Wasse, H., Gillen, D., Ball, A., et al (2003): Risk factors for upper gastrointestinal bleeding
among end-stage renal disease patients. Kidney International 64:1455-1461
Willms, L. & Vercaighe, L.M. (2008) Does warfarin safely prevent clotting of
hemodialysis catherers? Seminar in Dialysis, Vol 21 (1) pg
Zellweger, M., Bouchard,J., Raymond-carrier, S., Laforest-Renald, A., Querin, S. and
Madore, F. (2005). Systemic anticoagulation and prevention of hemodialysis
catheter malfunction. ASAIO Journal, Jul-Aug; 51 (4):360-5. Retrieved
August 28th, 2007 from
http://www.ncbi.nim.nih.gov.smahslibresources.health.wa.gov.au
- 25 -
COMPILED BY:
Casey Light, Renal Nurse Practitioner, Armadale Health Service
Dr. Hemant Kulkarni, Renal Physician, Armadale Health Service
AUTHORISED BY:
Eleri Griffiths
Acting Director of Nursing
Chairperson Nursing Practice Committee
………………………………………….(Signature)…………………………(Date)
Dr.Reg Andrews
Deputy Director Clinical Services
………………………………………….(Signature) …………………………(Date)
DATE FIRST ISSUED:
DATE LAST REVIEWED:
DATE THIS REVIEW:
March 2010
N/A
N/A
FILE TITLE:
Nurse Practitioner Clinical Protocol:
Warfarin Therapy in Haemodialysis Patients
NEXT REVIEW:
2013
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