Tristan Groves
Lead Pharmacist Anticoagulation
Cardiff and Vale University Health Board
May 2013
Plan
 Why we have to be so vigilant with Warfarin.
 The primary and secondary care interface
 Information required for safe monitoring of patients

Communication problems
 Care pathway
 When do things go wrong?
 Improving the safety of Warfarin prescribing.



Knowing the indication.
Starting Warfarin.
How to deal with Low and High results
 The future of oral anticoagulation.
The benefit of guidelines without
knowledge?
Why do we have to be so careful
with Warfarin?
Warfarin and its challenging
therapeutic
window
Therapeutic
20
range
Stroke
Odds ratio
15
Intracranial bleed
10
5
1
0
1
2
3
4
5
6
International normalized ratio (INR)
7
8
The Impact of Warfarin
on ICH
 Warfarin increases the risk of ICH 2- to 5-fold and nearly
doubles the mortality associated with ICH1,2
 50% of patients with Warfarin-associated ICH die within
30 days1

OR 4.6; 95% CI, 1.0 to 21.8 for 3-month mortality2
1. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92;
2. Flibotte JJ, et al. Neurology. 2004;63(6):1059-1064.
6
Why time in therapeutic range
(TTR) matters
Warfarin group
Cumulative survival
1.0
71–100%
61–70%
51–60%
41–50%
31–40%
<30%
Non Warfarin
0.9
0.8
0.7
0.6
0
500
1000
1500
Survival to stroke (days)
Morgan CL et al. Thrombosis Research 2009;124:37–41
2000
What is an interface?
 interface
n.) A boundary across which two independent systems
meet and act on or Communicate with each
other
Communication between primary
and secondary care
What do we need to know from
each other in order to safely
monitor a Warfarin patient?
 Doses patient has taken
 Recent INR results ? How many
 New medication started or existing medication
stopped?
 Changes in patient’s condition-i.e. new diseases
 Worsening of existing diseases i.e.. reduced cognitive
function.
 Diet changes?- i.e.. on dietetic supplements?
What does the NPSA say
Patient safety alert 18
“In many cases, the healthcare professional who issues
repeat prescriptions for anticoagulants, for example
the general practitioner, is not the same practitioner
who monitors and adjusts the dosage of the therapy,
for example the anticoagulant clinic practitioner. It is
for the prescriber supplying the repeat prescription to
ensure that it is safe to do so. Repeat prescriptions of
anticoagulants should only be issued if the prescriber
has checked that the patient is regularly attending the
anticoagulant clinic, that the INR test result is within
safe limits”
What does the NPSA say
Patient safety alert 18 (2007)
“Many medicines interact with oral anticoagulant therapy. Often,
the healthcare professional prescribing other medicines, for
example the general practitioner, might not be the same person
monitoring and adjusting the dosage of the therapy, who could
be the anticoagulant clinic practitioner. If possible, medicines
should be selected that do not produce clinically significant
interactions. If this is not possible, the prescriber who initiates or
discontinues a prescription for an interacting medicine is
responsible for ensuring that the patient is informed that an
interacting medicine has been commenced or discontinued.
They should also tell the patient to arrange an INR test within
four to seven days of the start or discontinuation of the
interacting medicine. The patient should be instructed to
provide details of the change in therapy when the blood sample
is taken”.
The Warfarin care pathway
 Developed to try to ensure the patient is safely initiated on
Warfarin and that a patient’s care is safely transferred from
secondary care to primary care
 No patient on Warfarin is to be discharged from a Hospital
within the Health Board, without having a completed
Warfarin care pathway. (section 2 to be completed for all
patients and section 1 and 2 for newly started patients).
 This combined with the Warfarin treatment chart and the
DAL provides the information required for the safe transfer
of care.
The Adult IN-patient Warfarin
chart and Care Pathway
Warfarin chart
All Wales Warfarin Treatment Chart AWA001.pdf
Care pathway
CV Warfarin Care Pathway.pdf
The Warfarin care pathway
 All patients must have a confirmed appointment
made with a monitoring clinic prior to discharge
 Great variability in primary care as to when patients are
“stable” enough to be seen
What actually happens
 Discharge Audits at UHW, Cardiff
2001 2002 2008
INR in range on discharge
41%
43% 67%
Appointment made for INR check 71%
79% 74%
Completed yellow book
59%
53% 65%
Indication specified
87%
82% no info
Recent INR/dosing information
49%
58% 52%
When things go wrong
Raised INR audit 2010
 Dual site both UHW and LLandough
 All inpatients with an INR ≥5.0 were identified by the
coagulation labs.
 Data collection period June09-Jan 2010
 All patients where possible had a root cause analysis
form completed by the ward Pharmacist normally
within 72 hours of elevated result.
 LLandough
95
 UHW
96
 Coagulation labs across UHW and LLandough complete an
average of approximately 4000 inpatient INR tests monthly.
When things go wrong
% of total result occuring on day of admission
40
35
% of results
30
25
20
% of total
15
10
5
0
Llan
UHW
site
An example
 94 yr old gentleman admitted due to heamaturia.
Patient on Warfarin for AF (range 2.0-3.0) admitted
with INR>22 !!!! (vitamin K administered)
 Had been started on Trimethoprim 8 days earlier . Gp
had done INR one day after starting course (INR was
4.3) but dose not changed (according to relative).
 Patients book was available on admission but no doses
were recorded in the book and dates not fully
completed.
 Due to patients age range decreased on discharge (1.52.5)
Another example
 61 yr old woman on Warfarin for VTE. Admitted to
surgical admissions for cholecystitis. Found on
admission to have INR>22. (vitamin K administered)
 Liver function tests on admission:
Alk phos 1147 (30-115)
ALT 535 (5-40)
Bil 65 (1-22)
 Patient normally on co-agucheck system at GP. Has
results on print out. Pt un able to confirm doses taken
and no way of confirming doses of Warfarin over
weekend with GP.
Poor practice happens on both
sides
 84 yr old patient on Warfarin for AF (range 2.0-3.0).
 Discharged from rehab ward with INR 3.6. ? Any
follow up appointment made with a monitoring clinic?
 Pt having diarrhoea on discharge!
 Five days later patient admitted to hospital following
an INR of 12.1 at GP clinic.
 Raise INR though to be due to Diarrhoea and poor
understanding of the treatment by the patient (?poor
compliance)- these issues should have been addressed
before discharge.
Improving the safety of
prescribing
 Things to consider when treating a patient:
 Are you sure of the indication?
 How to start Warfarin treatment.
 Frequency of dose changes. (avoiding over
tinkering).
 How to deal with low and high results
Knowing the indication
 Will affect the Desired INR range
 i.e..... “heart valve”
 Aortic Bioprosthtic valve- may only need Aspirin
 Medtronic Valve (aortic) INR range 2.0-3.0
 Starr Edwards Valve (mitral) INR range 3.5-4.5
 Will affect how we start Anticoagulation/
frequency of monitoring
 Will affect duration of treatment
 Will affect how we deal with Low and high results
 Will affect how we deal with procedures (i.e....
dental surgery)
Starting patients on
Warfarin
 Patient specific and disease specific loading regimen
should be utilized.
 Concomitant use of Heparin/LMWH
 Need for intensive monitoring when first starting ?
Always appropriate
 All patients must have baseline INR result and Full
blood count.
Starting patients on Warfarin
 Examples of Loading Regimens
 10mg,10mg,5mg –INR Day 3
 10mg,5mg,5mg- INR Day 3
 10mg,3mg,3mg -INR Day 3
 5mg Daily – Monitor INR Day 4
 3mg Daily – Monitor INR Day 7
 2mg Daily – Monitor INR Day 14
Initiating Warfarin for AF
 In general the short term risk of a stroke is low and as a result patients
with AF can be anticoagulated on an outpatient basis with Warfarin
alone (1).
 A slow-low dose loading regimen is suitable for patients with AF and
achieves therapeutic anticoagulation in the majority of patients within
3 – 4 weeks (2).
 A baseline INR should Always be taken. If the INR is <1.4 the patient
can be commenced on a low dose of Warfarin e.g. 3mg per day, for 7
days before a repeat INR measurement is required (3)
1.
Singer et al. Antithrombotic therapy in atrial fibrillation. Antithrombotic and thrombolytic therapy:
ACCP evidence based clinical practice guidelines (8th edition). Chest 2008; 133: 546-592.
2.
Baglin et al. British Committee for Standards in Haematology Guidelines on oral anticoagulation
(Warfarin). British Journal of Haematology 2005; 132: 277-285.
3.
Janes et al. Safe introduction of Warfarin for thrombotic prophylaxis in atrial fibrillation requiring only
a weekly INR. Clinical and Laboratory Haematology 2004; 26: 43-47.
Our AF protocol
 3mg Warfarinisation Protocol.doc
Frequently changing the dose
 The earliest changes in the International Normalized Ratio
(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 Kdependent 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 thromboses.
How to deal with low and high
results
 Treatment options depend on:
 Clinical condition of patient
 Actual INR- How low is low, How High is High
 Condition being treated
 How long has patient been on Warfarin
 Identifiable cause of abnormal result
Advice given to GPs
 From service level agreement.
Warfarin therapy: maximum recall periods during maintenance therapy*
*(not initiation)
One INR high: recall in 7-14 days (stop treatment for 1-3 days) (maximum 1 week
in prosthetic
valve patients)
One INR low: recall in 7-14 days
One INR therapeutic: recall in 4 weeks
Two INRs therapeutic: recall in 6 weeks (maximum for prosthetic valve patients)
Three INRs therapeutic: recall in 8 weeks, apart from prosthetic valve patients
Four INRs therapeutic: recall in 10 weeks, apart from prosthetic valve patients
Five INRs therapeutic: recall in 12 weeks, apart from prosthetic valve patients
NB Patients seen after discharge from hospital with prosthetic valves may need
more frequent INRs in the
first few weeks.
(Based on data from Ryan et al (1989) British Medical Journal 299, 1207-1209)
Guidelines for the management of excessive
oral anticoagulation
Treatment depends on the INR, and whether there is major,
minor or no bleeding. Also depends on indication for
anticoagulation (e.g. heart valve )
The following recommendations are adapted from those of the British Society for
Hematology and are on the back of the all Wales Adult In-patient Warfarin Treatment
chart
 INR in therapeutic range - patient bleeding.
• Investigate source of bleeding. Consider risk/benefit of stopping Warfarin
 INR < 6.0 but > 0.7 above target INR - no bleeding
• Reduce the dose following the ‘Maintenance Dosing’ table above
 INR > 6 - no bleeding or minor bleeding from mucosae (nose, oropharynx,
urinary tract, rectum, anus)
• Stop Warfarin and restart when INR < 5.0
• Assess patient for their risk of bleeding: recent surgery/trauma, extensive bruising, minor mucosal bleeding
If at high risk of bleeding give Vitamin K 2mg orally:Use 0.2 ml Konakion® MM paediatric
(phytomenadione 2mg in 0.2ml). Draw up using oral dispenser provided, then drop onto the tongue
• Recheck INR after 24 hours, repeat dose of Vitamin K if INR is still too high
 Major bleeding: Life or limb threatening bleeding, including intracranial
haemorrhage
• Stop Warfarin.
• Give 10mg vitamin K IV (1ml phytomenadione 10 mg/ml - Konakion MM®.) Give as an IV bolus over 3-5
minutes
undiluted or diluted with 10-20ml with glucose 5% to aid slow administration
• Give prothrombin complex concentrate (PCC - Factor II, VII, IX, and X concentrate) - dose to be advised by
haematologist.
• Repeat INR within 1 hour of giving of PCC - consider further dose if INR remains >1.5 and patient still
bleeding
• Consider risk/benefit of recommencing Warfarin
So what is the future?
 The new oral agents
 How do they work
 Advantages and disadvantages
 Where are we in terms of prescribing these agents?
Characteristic of an ideal
anticoagulant
 Oral administration
 Effective reduction in thromboembolic events
 Predictable dose response / kinetics
 Low bleeding rate
 No routine monitoring
 Wide therapeutic window
 No dose adjustments
 Little interaction food / drugs
The new agents
 Oral Direct thrombin inhibitors
 Dabigatran (Pradaxa®)
 Oral Factor Xa inhibitors
 Rivaroxaban (Xarelto®)
 Apixaban (Eliquis®)
 Edoxaban
 Betrixaban
Rivaroxaban,
Apixaban
Dabigitran
How a clot forms (simplified!)
Rivaroxaban,
Apixaban
Dabigitran
What are they licensed for?
 Dabigatran (Pradaxa®)
 110mg dose BD
 Primary prevention of venous thromboembolic events in adult patients
who have undergone elective total hip replacement surgery or total
knee replacement surgery.
 Nonvalvular AF (see below).
 150mg dose BD
 Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial
fibrillation with one or more of the following risk factors:
 • Previous stroke, transient ischemic attack, or systemic embolism (SEE)
 • Left ventricular ejection fraction < 40 %
 • Symptomatic heart failure, New York Heart Association (NYHA) Class 2
 • Age ≥75 years
 • Age 65 years associated with one of the following: diabetes mellitus,
coronary artery disease, or hypertension
What are they licensed for?
 Rivaroxaban (Xarelto®)
 10mg dose OD -Prevention of venous thromboembolism
(VTE) in adult patients undergoing elective hip or knee
replacement surgery.
 20mg dose OD-Prevention of stroke and systemic
embolism in adult patients with non-valvular atrial
fibrillation with one or more risk factors, such as congestive
heart failure, hypertension, age ≥75 years, diabetes
mellitus, prior stroke or transient ischemic attack.
 Treatment of deep vein thrombosis (DVT) and PE, and
prevention of recurrent DVT and PE following an acute
DVT in adults. (following loading of 15mg BD)
What are they licensed for?
 Apixaban (Eliquis®)
 2.5mg dose BD-Prevention of venous thromboembolic
events (VTE) in adult patients who have undergone
elective hip or knee replacement surgery.
 5.0mg BD- Prevention of stroke and systemic
embolism in adult patients with non-valvular atrial
fibrillation (NVAF), with one or more risk factors, such
as prior stroke or transient ischemic attack (TIA); age≥
75 years; hypertension; diabetes mellitus; symptomatic
heart failure (NYHA Class ≥ II).
What the patient sees and
hears
“Blood clot-busting pills that slash the risk of strokes”
“£2.50 a day pill to beat strokes: A million Britons could benefit
from drug available for use within weeks”
“Ask your doctor -How can I avoid all these blood tests?”
“Lets change everybody on Warfarin to the new Drugs
“Blood-thinning drug 'better than Warfarin‘”
!”
A note of caution.
 Patient’s Indication- (current licences for the new agents







are for VTE prevention post hip/knee surgery/ AF/ New
DVT, depending on agent). Lack of evidence of efficacy
in Heart valve or patients with recurrent thrombosis etc.
Patients with Renal or Liver impairment
COST ?
Recurrent clot on new agent – what do we do?
How to reverse the new agents? (Betrixaban- antidote)
Lack of clinical experience ? Bridging therapy
How to assess compliance?- monitoring?
Future drug interactions/ post marketing side effects
(Ximelagatran)/ bleeding rates seen in other countries.
Nice guidance
 This tends to be quite non specific:
 E.g.
“The decision about whether to start treatment with
dabigatran etexilate should be made after an informed
discussion between the clinician and the person about
the risks and benefits of dabigatran etexilate compared
with Warfarin. For people who are taking Warfarin, the
potential risks and benefits of switching to dabigatran
etexilate should be considered in light of their level of
international normalised ratio (INR) control”
Scottish guidelines
 The statement advises that:
on balance of risks and benefits, Warfarin remains
the anticoagulant of clinical choice for moderate or
high risk atrial fibrillation patients(CHA2DS2-VASc
≥ 2) with good INR control, and clinicians should
consider prescribing dabigatran or rivaroxaban in
patients with:  poor INR control despite evidence that they are
complying, or
 -allergy to or intolerable side effects from coumarin
anticoagulants.
Any Questions?