Clinical Haematology: Warfarin Management Guideline

This guideline is intended to inform medical and nursing staff employed within the Clinical Haematology department. All anticoagulant management within RCH occurs under the supervision and guidance of a Consultant Haematologist. The guideline may be modified according to individual patient requirements.

Warfarin is the generic name for the most commonly used oral anticoagulant. There are 2 brands of warfarin, although they are distributed by the same company. Brands should not be used interchangeably. Both brands of warfarin colour-code their tablets. The following table describes the available tablet strengths and their corresponding colour. All new patients commencing warfarin should receive Coumadin.

Commencing Warfarin Therapy

1. Most patients require 3-5 days of warfarin before achieving a stable maintenance phase. (ref)
   
   
2. For infants, consideration must be given to formula vs breast fed babies. For babies exclusively breast fed, supplementing feeds with one formula feed/day to provide a constant intake of Vitamin K may be required. For patient receiving infant formula or other enteral feeding formulations containing Vitamin K, at least 1 hour should separate the conclusion of a feed and the administration of warfarin.
   
   
3. Warfarin should be commenced whilst concurrent heparinoid (unfractionated heparin or low molecular weight heparin) therapy is being administered, in order to reduce the risk of thrombosis. Heparinoid therapy can be ceased when the INR is therapeutic for 2 consecutive days.
   
   
4. The following table provides common Target Therapeutic INR Ranges for specific clinical indications. Patients with a primary cardiac indication for warfarin usually have their TTR determined by the referring cardiologist/cardiac surgeon.
   
   Target Therapeutic INR Range

5. If the patient is receiving other medications (eg. antibiotics), or not tolerating oral, nasogastric or parenteral nutrition, the loading dose (see below) may need to be adjusted accordingly.
   
   
6. Warfarin is NOT evenly distributed within each tablet. As such, doses should be given in whole tablet sizes. Many patients will require alternate day doses e.g. alternating 3mg and 4mg daily, instead of 3.5mg daily.

Loading Dose - Day 1

Administer 0.2mg/kg orally as a single nocte dose, up to a maximum 5mg. (For patients with liver dysfunction, severe renal impairment, post-surgical or coagulopathic reduce this to 0.1mg/kg to a maximum of 5mg, or delay initiation). For adult patients commencing warfarin begin with a loading dose of 5mg.

Loading Dose - Day 2-4

Subsequent loading doses are based on individual INR response.
The dose reductions in table below are critical to avoid "over-shooting" the target range.

If the INR is not > 1.5 on Day 4, the patient should be reassessed and the loading dose per kg increased based on the individual clinical need.

For patients commencing warfarin after cardiac surgery, the Cardiac surgeon is responsible for commencing warfarin and providing initial doses. Handover to the Clinical Haematology unit generally occurs on day 3-4, once wires and chest drains have been removed, however the Clinical Haematology team should be updated regularly regarding these patients. Handover on the day of, or day immediately prior to discharge may result in delay of discharge.

7. During inpatient admission, it is the responsibility of the Clinical Haematology Inpatient Registrar, in consultation with the Clinical Haematology Consultant on ward service, to develop the warfarin management plan for each patient. This includes:
   a)     Liaising with the primary medical team (as required)
   b)     Ordering of INR tests and documentation of warfarin prescription
   c)     Entering relevant details onto the Warfarin Database pre-discharge
   d)     Provision of discharge prescription for warfarin (preferably Coumadin) with a range of tablet doses reflective of the patient’s current warfarin requirements.
   e)     Booking follow up appointments for CNC Anticoagulation and Haematologist review
   f)     Booking relevant imaging to be performed post-discharge

 NB: warfarin is teratogenic in early pregnancy and reliable birth control is recommended. All patients of child bearing age should discuss contraception and pregnancy with a Haematologist before commencing warfarin. Warfarin is safe during breast-feeding.

Warfarin Maintenance

Warfarin management is complex and affected by numerous factors. Management should be performed by someone experienced in warfarin dosing. Within the Clinical Haematology department, this includes all Haematology Consultants, the Clinical Nurse Consultants (Anticoagulation) and Haematology Registrars who have been trained and assessed as competent, as per the Clinical Haematology Registrar Manual.

 Outpatient Management

1. Monitor INR within 3 days of discharge, or as directed by the Clinical Haematology department.
2. The ongoing plan for warfarin therapy is always directed in response to an INR result, or a change in the patient’s medication regime, level of wellness or significant dietary changes. 
3. An INR should be measured at least once every 4 weeks. Most children requiring warfarin have an INR checked every 2 weeks, however some patients require more frequent INR monitoring. These patients include:
   a)     Patients  less than 12 months of age
   b)     Patient requiring frequent changes in medications
   c)     Patients in the acute recovery phase post-surgery
   d)     Patients who are non-adherent with their anticoagulation plan.
   e)     Patients who have had a recent interruption of warfarin therapy due to a planned intervention
   
   
4. Duration of warfarin therapy is dependent upon the indication for anticoagulation. This duration is usually determined at the time of warfarin commencement. Duration may sometimes be altered based on results of follow-up imaging.  The intended duration of warfarin therapy should be documented in the Warfarin Database.
   
   
5. Patients commencing warfarin during an inpatient admission should be booked into the Clinical Nurse Consultant’s (Anticoagulation) clinic on a Friday within 2 weeks of discharge The purpose of this appointment is to:
   a)     Ensure outpatient plan for INR monitoring is feasible for the family and the department is receiving INR results in a timely manner
   b)     Provide thorough warfarin education, as per the validated education template
   c)     Identify significant learning needs in the family and/or patient requiring further education or review
   
   
6. Patients requiring ongoing or indefinite warfarin therapy should be reviewed within the Clinical Haematology outpatient department annually by a Haematology Consultant, with additional appointments booked with the CNC Anticoagulation in accordance with expected or identified needs, including
   a)     Developmentally appropriate warfarin education
   b)     Non-adherence with communicated management plan
   c)     Technical or practical challenges associated with INR monitoring

 INR testing

INR monitoring tests are performed a number of different ways in the hospital and in the community.

Within RCH

1. Point-of-care (CoaguChek XS^TM). For inpatients, the Pathology Collection team will perform INR tests as they conduct their ward rounds. Patients require a signed Pathology Collection request form for testing that can be signed by a Registrar. Pathology Collection will page the Inpatient Clinical Haematology Registrar with INR test results performed on inpatients. These results appear on CLARA.
2. Venous. There are a subset of patients in whom Point-of-Care testing is not appropriate. These include patients with a haematocrit > 0.5 and patients with antiphospholipid antibodies, where correlation between CoaguChek XS and venous INR may be poor. In addition, patients with a Point-of-Care INR result > 5.0, a repeat venous INR is needed to confirm the result. Patients require a signed Pathology Collection request form for testing. These results appear on CLARA.

Community

1. Home INR monitoring. Clinical Haematology has a training program for teaching families to perform point-of-care INR tests in the home. Only families that have completed this training can undertake this form of testing. Families are NOT encouraged or supported to purchase their own monitors, borrow another family’s monitor or commence using a gifted monitor until they have completed our training. Families on the Home INR monitoring program are asked to perform INR tests in office hours or Saturday morning. The INR result from every test performed is to be phoned through to the Haematology answering machine (9345 5827). These families do not require a pathology request slip to perform a home INR test. These results do not appear on CLARA.
2. RCH Outpatient Pathology Collection. Patients can attend the Pathology Collection department for outpatient INR monitoring. The majority of these patients can have point-of-care INR testing (for further details see above “Within RCH” testing details). Patients require a signed Pathology Collection request form that can be signed by a Registrar. These INR results are faxed through to the Clinical Haematology department by 4pm each weekday. On Saturday mornings, Pathology Collection fax the results through to the department and additionally page the Registrar working that morning.
3. Venous INR within RCH. For patients who cannot have a point-of-care INR, or who require a venous INR due to a point-of-care result > 5.0, a venous INR can be collected within Pathology Collection. These patients require a Pathology request form that can be signed by a Registrar. INR results are available via CLARA. The Pathology Collection team will record on the faxed spreadsheet of Point-of-care results that a venous INR was collected for a specific patient.
4. Point-of-Care within a Health Service. Several GP clinics, St John of God Pathology (most centres) and Melbourne Pathology (Lower Templestowe ONLY) offer point-of-care INR monitoring for RCH patients. These INR results will not appear in CLARA. Patients require a pathology request form signed by a Consultant Haematologist. The request slip should specifically request:
   a)     Point-of-Care INR
   b)     Doctor to Dose (ie RCH will dose the patient’s warfarin)
   c)     Fax INR result to 9349 1819
   d)     Rule 3 Exemption
   e)     Please contact the on-call Haematology via RCH switchboard (9345 5522) for any INR results > 4.5

1. Venous INR within a Health Service outside of RCH. A referral for INR testing can be made to any of the recognised Pathology providers. The choice of where to send a patient is usually based on proximity to where they live. These INR results will not appear in CLARA. Patients require a pathology request slip signed by a Consultant Haematologist. The request slip should specifically request:
   a)     INR test to be performed
   b)     Doctor to Dose (ie RCH will dose the patient’s warfarin)
   c)     Fax INR result to 9349 1819
   d)     Rule 3 Exemption
   e)     Please contact the on-call Haematology via RCH switchboard (9345 5522) for any INR results > 4.5

Outpatient Warfarin Dosing

1. Patients requiring warfarin should have INR tests performed according to the management plan communicated to them by the Clinical Haematology department. The department does not support self-management of warfarin therapy.
2. For patients with INR results repeatedly falling within their target therapeutic range, the dose of warfarin ordered should not need to be altered. Each time the INR is in range and the dose of warfarin is not adjusted, the interval between testing can be slowly increased, usually in 1 week increments to a maximum of 4 weeks. For patients who have recently commenced warfarin or who have had a recent interruption of warfarin therapy, this interval between testing may initially be smaller – e.g. several days – until a predictable response to the ordered dose of warfarin is identifiable. 
3. The Clinical Haematology department does not use a nomogram to direct ongoing warfarin dosing. Rather all dosing decisions are made on an individual patient basis. This is based on our clinical experience with demonstrated improved outcomes in terms of target therapeutic range achievement and adverse event rates compared to that reported internationally.
4. When an INR result is below the target therapeutic range:
   a)     Review the patient’s entry in the Warfarin Database to determine if they require concomitant LMWH if their INR is below a target threshold. Such patients should already
           have a prescription for LMWH and have been educated in how to administer LMWH in such situations. Recommend the patient commence the prescribed dose of LMWH and                 continue it until their INR returns to the acceptable range.
   b)     Review prior dosing schedule to determine total mg of warfarin administered across the preceding week.
   c)     Note how far below the lower limit of the target range the patient’s INR result is, and consider the patient’s clinical risk for thrombosis is in light of this subtherapeutic result                   and any factors that may have contributed to this low INR result (e.g. Medication changes, illness, dietary change). This information will inform the extent of alternation to the                 recommended dose of warfarin.
   D)     The greater the change to the dose of warfarin recommended, the smaller the interval between INR testing. Examples of acceptable dose changes are in the table below:

^$ Bactrim is known to increase warfarin sensitivity and push the INR higher. Reducing the warfarin dose in conjunction with a short interval until repeat INR measurement is recommended.

^{^} Patient will likely reach TTR within 5 days using the dose they have previously achieved their TTR with. As they have a prosthetic valve, LMWH cover is recommended until the INR is > 2.0

^# The patient has been very stable. This one-off INR >3.0 may be an incidental finding. Reducing the dose of warfarin in response to 1 slightly elevated INR may create a chain of events where settling into the TTR again could be challenging. In the setting of a well child where no other causes of an elevated INR are evident, it is best to make no change but to re-test the INR within 1-2 weeks.

^% Diarrhoea can cause the INR to increase quickly, due to the loss of Vitamin K generating normal flora in the gut. INRs great than 5 should be discussed with a Haematology Consultant. If obtained using point-of-care monitoring, the INR should be repeated using venous blood collection.

Warfarin Education

Every patient referred to Clinical Haematology for warfarin management requires comprehensive parent and/or patient education. This education must be specific to age, gender, underling health condition and developmental stage. Parent and patient education regarding warfarin therapy is a dynamic process that is never finalised. The Haematology Department aims to provide education to the entire family that recognised their past learnings, educational abilities and individualised needs. Families receive ongoing re-assessment of their level of understanding to ensure the delivery of learning opportunities that succeed in producing the desired knowledge outcomes.

Education should be commenced as soon as the patient commences warfarin therapy. If warfarin commences during an acute admission related to an underlying health problem, it is recommended to provide only minimal information during the admission, and continue a thorough education at an outpatients appointment within 2 weeks of discharge from hospital. After the initial (thorough) education session, we recommend the patient have a follow up outpatient appointment with the Anticogulation CNC and a Haematology Consultant in outpatients within 3-6 months. The purspose of this follow up appointment is to consolidate education and ensure the patient is in the system of ongoing outpatient follow up.

Parental/patient understand should also be assessed on a regular basis (at least annually) and knowledge deficits identified. Education targeting these knowledge deficits should be provided promptly.

Documentation stating what educational information has been provided and by whom should be clearly outlined in the patient’s medical record using the Warfarin Education template.

Warfarin Interactions

Medications

It must be assumed that all medications will influence a child’s response to warfarin, even if adults taking warfarin do not experience a change in INR in response to that medication. As a general rule, the impact of any medication change (including dose changes, commencing or ceasing a medication) should take 2-3 days before it impacts upon the INR. Patients and families are educated to discuss any medication changes with the Clinical Haematology team to facilitate identification of this risk factor for INR alteration. Medication changes should be documented in the warfarin database to facilitate future review should the child require that medication again (e.g. antibiotics). For families electing to commence over-the-counter medications (e.g. vitamins, herbal therapies etc) they should be informed of the risk that the medication may impact warfarin and the need to monitor an INR 3 days post commencing the medication. 

Paracetamol based medications are safe to use with warfarin. Non-steroidal anti-inflammatory medications (e.g. Nurofen) should not be used as their anti-platelet activity introduces an additive risk of bleeding in the patient taking warfarin.

Unless expressly advised to do so by a medical doctor, patient taking warfarin should not take aspirin.

Diet

Patients requiring warfarin therapy are advised to have a healthy, varied diet. Consistency is recommended across the course of a week, but is not necessary day-to-day. For most families, a change in diet causing alteration to the INR is usually related to the child not eating due to intercurrent illness, school holidays (snacking eating practices versus portions eaten when at school) or overseas travel and associate changes in the kinds of food eaten. We do not recommend families portion control their child’s consumption of Vitamin K rich foods, such as broccoli, legumes or other leafy vegetables.

Patients requiring a fat-free diet (e.g. due to Chyle Effusion) whilst requiring warfarin will likely have changed warfarin requirements post-introduction of the diet. This reflects Vitamin K being a fat-soluble vitamin. Monitoring of the INR within 3 days of commencing a fat-free diet is recommended.

As previously stated, infant formulas and enteral feed solutions can impact response to warfarin as they are Vitamin K fortified. Any change to the volume of feeds administered or the interval of feeding (e.g. bolus versus continuous feeds) may impact warfarin response. It is recommended that an INR test be performed 3 days post such changes. In addition, ensure there is always at least 1 hours between the administration of any vitamin K containing formula and the administration of warfarin.

Changes in Health Status

Minor respiratory illnesses are unlikely to impact upon response to warfarin, provided the child continues to eat normally and does not require antibiotics. Any viral illness lasting more than 3 days should be reported to the Clinical Haematology team, to consider whether an alteration to the current management plan is required.

Gastroenteritis, and diarrhoea in particular, can cause a significant change in response to warfarin, causing the INR to increase rapidly. Diarrhoea can cause the INR to increase rapidly within 24 hours. Families are advised to call Haematology to inform them that their child has diarrhoea if symptoms persist for more than 24 hours. An INR should be performed within the next 24 hours and warfarin dose reduction is likely necessary.

Deterioration in a patient’s underlying illness may alter their response to warfarin. If families report such deterioration to Clinical haematology, it is wise to arrange for an INR to be performed in order to rule out a change in their management plan being necessary.

Adverse Events

Bleeding

The major adverse event associated with warfarin is bleeding. The reported rate of major bleeding in patients requiring warfarin is less than 1% per patient year. In an audit of bleeding events at RCH, our major bleeding rate was found to be 0.05% per patient year. Families with a child commencing warfarin are educated regarding the use of routine first aid measures for any injury their child sustains. Should the bleeding experienced by a child on warfarin not be controlled using first aid measures, families are advised to go to Emergency for medical assessment.  For patients taking warfarin primary thromboprophylaxis (having never had a blood clot), warfarin is usually withheld until the cause of bleeding is resolved. For patients at high risk of thrombosis in the setting of sub-therapeutic anticoagulation, Haematology Consultant review is required to prioritise the need for ongoing anticoagulation during an episode of bleeding.  

Osteoporosis

Warfarin is a vitamin K antagonist. As osteocalcin is a vitamin K dependent protein, warfarin may also impact upon osteocalcin’s role in supporting bone growth and deposition. Patients are not advised to commence vitamin or mineral supplementation at the time of commencing warfarin. It is recommended patients have the recommended three serves of dairy foods per day and participate in weight-bearing exercise as tolerated. Patients requiring warfarin for more than 12 months should have a bone mineral density scan performed. If this scan result is within acceptable age-related parameters, repeat BMD testing should be performed every second year for as long as warfarin continues. Referral to Endocrinology may be necessary for patients with BMD results more than 2 standard deviations below age-related norms.

Warfarin Reversal

There are 3 options available to reduce a patient’s INR. This may be a desired action if the INR is well above the target therapeutic range or in the presence of bleeding and/or bruising. The appropriate option is dependent upon the urgency of INR reduction/normalisation or the patient’s risk of bleeding and/or bruising.

Withholding of warfarin doses

In the setting of an elevated INR in a child who is not unwell and has no bleeding or bruising, withholding warfarin will allow the INR to slowly drift into the target range. This option is desirable when maintenance of the child’s anticoagulation is desirable, and reversal of treatment is not clinically required.

Vitamin K

Vitamin K reverses the effects of warfarin. The dose to be administered and the indications for concurrent FFP or prothrombin concentrate are clinically driven and should be directed by the Clinical Haematology consultant. In the presence of a high INR results without bleeding, vitamin K can be administered sublingually, subcutaneously or intravenously at a dose range of 0.5 to 2mg, depending on the child’s weight and INR value. NB. The half-life of Vitamin K is shorter than that of warfarin, so the INR may rise again after the administered Vitamin K wears off. Daily INR monitoring is recommended.

Fresh Frozen Plasma or Prothrombin complex concentrate

For patients with either an elevated INR or an INR within their target therapeutic range, but with concomitant bleeding, FFP or Prothrombin concentrate (Prothrombinex) can be administered to immediately reverse warfarin’s effect.

References

1. Monagle P, Chan A, Goldenberg N, Ichord R, Journeycake J, Nowak-Gottl U, Vesely S. Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based clinical practice guidelines. Chest. 2012;141:e737-e801S.

3. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, DeRosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Rowlands S. Developmental haemostasis: Impact for clinical haemostasis laboratories. Thrombosis and Haemostasis. 2006;95:362-72.

4. Monagle P, Newall F. Anticoagulation in Children. Thrombosis Research. 2012;130:124-46.

5. Tran HA, Chunilal, SD, Harper PL, Tran H, Wood EM, Gallus AS. An update of consensus guidelines for warfarin reversal. Medical Journal of Australia. 2013; 198(4): 198-199

6. Recommendations for the development of a dedicated paediatric anticoagulation service. Newall F, Jones S, Bauman M, Bruce A, Massicotte P, Monagle P. Journal of Thrombosis and Haemostasis. 2014. (In press)

7. Quality Of Life Assessment in Children Requiring Oral Anticoagulant Therapy. Jones S. Monagle P, Manias E, Bruce A, Newall F. Thrombosis Research. 2013, 132 (1): 37-43.

8. Development of a Home INR Monitoring Program: Strategic Approach and Evaluation. Journal of Paediatrics and Child Health. Jones S, Newall F. Journal of Paediatrics and Child Health. 2013, 49(9): E357-E360

9. Recommendations for point-of-care home International Normalised Ratio testing in children on vitamin K antagonist therapy. Bauman M, Bruce A, Jones S, Newall F, Massicotte MP, Monagle P. Journal of Thrombosis and Haemostasis. 11:366-368. 2012.

10. Commencement of warfarin therapy in children following the Fontan procedure. Crone E, Hume E, George S, Saliba N, Newall F, Jones S. Thrombosis Research. 131(4): 304-307. 2013 

11. HEADDSSS assessment for adolescents requiring anticoagulation therapy. Jones S, Alhucema P, Mertyn E, Monagle P, Newall F. Archives of Diseases in Childhood. 2012;97:5 430-433.

Prepared by the Clinical Haematology Department. August 2014