Title of Guideline (must include the word “Guideline”
(not protocol, policy, procedure etc)
Contact Name and Job Title (author)
Treatment of heparin induced
thrombocytopenia (HIT) in Adults
Julian Holmes (Haemostasis and
Thrombosis Pharmacist)
Directorate & Speciality
Date of submission
Date on which guideline must be reviewed (this should
be one to three years)
Explicit definition of patient group to which it applies
(e.g. inclusion and exclusion criteria, diagnosis)
Diagnostics and Clinical Support
September 2015
September 2018
Adult patients with acute HIT requiring
anticoagulation
Future management of HIT patients post
acute phase
Abstract
Key Words
Statement of the evidence base of the guideline – has
the guideline been peer reviewed by colleagues?
Evidence base: (1-5)
1a
meta analysis of randomised controlled trials
1b
at least one randomised controlled trial
2a
at least one well-designed controlled study
without randomisation
2b
at least one other type of well-designed
quasi-experimental study
3
well –designed non-experimental descriptive
studies (ie comparative / correlation and case
studies)
4
expert committee reports or opinions and / or
clinical experiences of respected authorities
5
recommended best practise based on the
clinical experience of the guideline developer
Consultation Process
Target audience
This guideline has been registered with the trust.
However, clinical guidelines are guidelines only.
The interpretation and application of clinical
guidelines will remain the responsibility of the
individual clinician. If in doubt contact a senior
colleague or expert. Caution is advised when
using guidelines after the review date.
Argatroban, fondaparinux, warfarin, HIT
1a, 1b, 1c, 2c,
Based on BCSH guidelines on the
diagnosis and management of HIT 2nd
edition Oct 2012
SPC for argatroban and fondaparinux
Haemostasis and Thrombosis Service
Drugs and Therapeutics Committee
Renal (Dr Roe and Dr Bebb)
All wards and clinical areas
Page 1 of 16
Thrombosis (HIT)
Introduction
Heparin Induced Thrombocytopaenia (HIT) is an antibody-mediated reaction that
can occur in patients receiving unfractionated heparin or rarely, low molecular weight
heparins. It typically presents 5-10 days after the start of heparin treatment but can
occur sooner if patients have had recent exposure to heparin. HIT involves the
development of antibodies that bind to heparin- platelet factor 4 (PF4) complexes.
This then causes platelet activation and also platelet binding to the endothelium in
blood vessel walls causing thrombin release and thrombosis. The platelet count falls
(often to <50 x 109L and/or a fall >50% from previous count) but there is a
paradoxical increased risk of potentially life-threatening thrombus formation. These
events can occur more rapidly if a patient is re-challenged with heparin after a
previous episode of HIT.
Any patients with a suspected diagnosis of HIT MUST be discussed with a
haematology consultant/registrar before any laboratory tests are ordered or
treatment started. Please complete the 4T score (below) before contacting the
Haematology team
Investigation and Diagnosis of HIT
HIT is predominantly a clinical diagnosis. The ‘4T score’ has been validated as a pretest probability score for the clinical likelihood of HIT. It should be calculated based
on the reduction in platelet count, timing of thrombocytopenia, presence of
thrombosis and whether there is any other cause for thrombocytopenia present.
(BCSH guideline on diagnosis and management of HIT 2nd Edition 2012).
Table1: Calculation of 4T score
Event
Thrombocytopenia
Timing of platelet
count fall or other
sequelae
Thrombosis or other
sequelae (e.g. skin
lesions)
OTher cause for
thrombocytopenia
not evident
Score =2
50% fall or
platelet nadir
20-100 x 109L
Clear onset between
day 5-10 of
treatment or <1 day
if previous heparin
exposure within last
100 days
New thrombosis,
skin necrosis or post
heparin bolus acute
systemic reaction
No other cause for
platelet count fall is
evident
Score =1
30-50% fall or
platelet nadir
10-19 x 109L
Onset of
thrombocytopenia
after 10 days
Score = 0
Fall <30% or platelet
nadir
<10 x 109L
Platelet count fall too
early (without recent
heparin exposure)
Progressive or
recurrent
thrombosis,
erythematous skin
lesions or suspected
thrombosis not yet
proven
Possible other cause
is evident
None
Definite other cause
is present
Page 2 of 16
The result of the 4T score should be used to guide treatment as below whilst
confirmatory testing is performed.
Table 2: Action based on 4T score
Score
6-8
Likelihood of HIT
High
Action
Inform haematology. If appropriate treat as
detailed below
4-5
Intermediate
Discuss with haematologist
0-3
Low
Consider alternative diagnoses. May continue
heparin but review diagnosis frequently
The diagnosis is confirmed by a positive laboratory test result. An initial screening
test is performed and this is available 24 hours a day on both sites. This is followed
by a confirmatory ELISA which requires samples to be sent to the QMC
Haemostasis and Thrombosis reference laboratory and is usually processed within
working hours. All investigative tests should be discussed with a Haematologist
before sending samples to the laboratory. Please refer to HIT report sheet
(Appendix 1) and pre-test probability score sheet (Appendix 2).
Treatment of HIT
ALL HEPARIN MUST BE STOPPED (including flushes and heparin coated
catheters). Platelets should NOT be routinely given as this may cause
thromboembolism. In the event of life threatening bleeding, platelets are very rarely
used but this must be discussed and approved by a Haematologist
On stopping heparin the platelet count will usually recover but there is still a risk of
thromboembolism for several days and even weeks afterwards. If the platelet count
does not improve, the diagnosis should be reviewed and the patient discussed again
with a Haematologist.
Treatment for patients requiring anticoagulation involves the use of an anticoagulant
that does not induce the production of HIT antibodies.
Choice of anticoagulant
If the patient’s calculated creatinine clearance (Cockcroft-Gault – see appendix 3) is
>30ml/min fondaparinux should be used. Fondaparinux is contraindicated in
patients with a creatinine clearance <30ml/min. In this clinical situation, argatroban
should be used.
Fondaparinux
Fondaparinux is a synthetic inhibitor of factor Xa that is unlikely to induce HIT
antibodies. It is unlicensed* for this indication but has the advantage of once daily
subcutaneous dosing rather than a continual infusion.
(* Trust’s unlicensed medicines policy should be followed)
Page 3 of 16
Patient weight (kg) and
creatinine
clearance>30ml/min
<50kg
Fondaparinux dose (mg)
once daily s/c
50-100kg
7.5mg
>100kg
10mg (reduced to 7.5mg on
day 2 if creatinine clearance
is 30-50ml/min)
5mg
Fondaparinux at a treatment dose is contraindicated if the creatinine clearance is
<30ml/min. Creatinine clearance can be calculated using the link:
http://nuhnet/diagnostics_clinical_support/antibiotics/Pages/Calc.aspx
Argatroban
Argatroban is a direct thrombin inhibitor that reversibly binds to thrombin and inhibits
the action of both free and clot associated thrombin. It does not interact with heparin
induced antibodies. This should be used if the patient has renal impairment
(creatinine clearance <30ml/min) or if the patient has had a previous episode of HIT
and undergoing dialysis. (Creatinine clearance can be calculated using the link:
http://nuhnet/diagnostics_clinical_support/antibiotics/Pages/Calc.aspx)
Argatroban dosing





Argatroban is available as 250mg in 2.5ml concentrate for IV infusion; this is
diluted with 250ml sodium chloride 0.9% or glucose 5% to give a final
concentration of 1mg/ml. Mix thoroughly after dilution by repeated inversion of the
solution container for one minute.
o Do not expose diluted solutions to direct sunlight. (but no need to
additionally cover)
o Do not use after 24 hours.
The initial infusion is 2microgram/kg/minute.
o There is a reduced infusion rate for patients with moderate hepatic
impairment (Child-Pugh class B), after cardiac surgery and critically ill
patients of 0.5microgram/kg/minute.
o Argatroban is contraindicated in patients with severely impaired hepatic
function, uncontrolled bleeding and hypersensitivity to argatroban or any of
the excipients (ethanol and sorbitol).
Preferably administer via a central venous access device to avoid potential
venous irritation as the preparation has a low pH. If a central venous access
device is unavailable a risk benefit analysis should be made on an individual
patient basis. If given peripherally, the insertion site should be monitored closely
for phlebitis using a recognised infusion phlebitis scoring tool.
Maximum recommended dose is 10microgram/kg/min and maximum treatment
length 14 days (there is limited clinical experience of administration for longer
periods).
Half life is 52 minutes and time to steady state 1-3 hours
Page 4 of 16



Avoid concomitant use of thrombolytics or antiplatelets – if antiplatelets are
required discuss with cardiology or haematology
Measure baseline aPTT prior to commencing the infusion and adjust as below
See appendix 4 for dosing during haemodialysis.
Body
Initial Infusion rate of
weight
Argatroban 1mg/mL
(kg)
(mL/hr)
(round to
nearest
10kg)
2microgram/kg/min
0.5microgram/kg/min
50
6
1.5
60
7
1.8
70
8
2.1
80
10
2.4
90
11
2.7
100
12
3.0
110
13
3.3
120
14
3.6
130
16
3.9
140
17
4.2
Argatroban Dose modifications
Monitoring is via aPTT - measure baseline aPTT and then repeat 2 hours after the
start of the infusion and adjust the infusion rate according to the table below.
The target aPTT is 1.5-3 times the initial baseline value (but not exceeding
100seconds).
Standard dosing schedule
Critically ill/hepatically impaired
Initial infusion rate 2microgram/kg/min
patients
Initial infusion rate
0.5microgram/kg/min
aPTT (s)
Infusion rate change Next aPTT
Infusion rate change
Next aPTT
<1.5 times
baseline
1.5-3.0 times
baseline (not
exceeding
100seconds)
Increase by
0.5microgram/kg/min
No change
>3.0 times
baseline or
>100seconds
Stop infusion until
aPTT is 1.5-3.0 times
baseline; resume at
half the previous
infusion rate
2 hours
2 hours;
after 2
consecutive
aPTT’s
within target
range check
at least
once per
day
2 hours
Increase by
0.1microgram/kg/min
No change
Stop infusion until
aPTT is 1.5-3.0 times
baseline; resume at
half the previous
infusion rate
4 hours
4 hours;
after 2
consecutive
aPTT’s
within target
range check
at least
once per
day
4 hours
Page 5 of 16
Subsequent treatment of acute HIT
The HIT diagnosis MUST be documented in the patient’s medical notes and put on
NOTIS as an alert The patient must be informed of the diagnosis and counselled
about the risk of recurrence if re-exposed to heparin, avoidance of heparin in the
future and alerting medical staff that they have previously had HIT.
For patients with confirmed acute HIT, once the platelet count has been within
the normal range for 2 consecutive days, oral anticoagulation with warfarin should
be commenced. This should be started with a reduced loading dose (e.g.6mg, 6mg,
3mg): See Warfarin Loading Doses in Adults Guideline available from the Trust’s
Clinical Guidelines Page on the intranet
:http://nuhnet/nuh_documents/Guidelines/Cancer%20and%20Associated%20Special
ties/Clinical%20Haematology/2379.pdf
Patients being treated with fondaparinux
HIT positive patients should continue to receive fondaparinux injection as detailed
above along with oral anticoagulation, unless the patient is bleeding. Fondaparinux
should be continued until two consecutive INR’s above 2 have been attained and
can then be stopped.
Patient being treated with argatroban
If the patient has received argatroban, once oral anticoagulation is indicated, they
should commence warfarin. This should be started with a reduced loading dose and
initially given concomitantly with argatroban. See Warfarin Loading Doses in Adults
Guideline available from the Trust’s Clinical Guidelines Page on the intranet (link).
Concomitant use of warfarin and argatroban produces a combined effect on the INR
test so when INR>4 discontinue argatroban as this correlates with an INR of 2-3 with
warfarin alone.
Patients with acute venous thrombosis
If the patient had a VTE as a result of HIT warfarin should be given for the
appropriate duration (depending on the VTE location). If the patient has HIT but no
VTE warfarin should be given for at least 1 month.
Subsequent anticoagulation in patients with a history of HIT
In patients with a previous history of HIT there exists a risk of recurrence with reexposure to heparins. There is some evidence for re-using heparin (after >100 days
post HIT) but alternative anticoagulants with little or no risk of causing HIT should
ideally be used.
Any further re-exposure to heparin should ALWAYS be discussed with a
Haematologist prior to commencing treatment. This includes low molecular
weight heparin thromboprophylaxis.
Page 6 of 16
Subsequent VTE in patients with previous HIT
If patients require anticoagulation for subsequent VTE they should receive treatment
doses of fondaparinux (or argatroban) and warfarin. Advice can be sought from the
Haematology team if required,
Thromboprophylaxis
Patients who have had a previous episode of HIT and subsequently require
thromboprophylaxis (e.g. in immobile medical and surgical patients) should receive
prophylactic doses of fondaparinux 2.5mg s/c daily. This dose should be reduced to
1.5mg s/c once daily in patients with a creatinine clearance of 20-30ml/min.
Fondaparinux at a prophylactic dose is contra-indicated in patients with a creatinine
clearance of <20ml/min.
Pregnancy
HIT in pregnancy should be discussed with Haematology.
Patients with previous HIT in pregnancy should be referred to the obstetric
haematology clinic in any subsequent pregnancies; this service is available on both
NCH and QMC sites.
Haemodialysis patients
Appendix 4 gives the argatroban dosing for anticoagulation during haemodialysis for
patients with acute or previous HIT.
PCI patients
Appendix 5 gives the argatroban dosing for patients with HIT undergoing PCI
Summary of acute HIT treatment
Appendix 6 summarises the treatment of acute HIT.
Anticoagulation in patients with a history of HIT
Appendix 7 outlines anticoagulation in patients with a history of HIT
References
Argatroban (Exembol) – Mitsubishi Pharma Europe Summary of Product
Characteristics [updated 28.6.12] on Electronic Medicines Compendium: (accessed
on [1.10.14]) via www.medicines.org.uk/ Drugdex® System. Thomson Micromedex,
Greenwood Village, Colorado accessed via http://www.micromedexsolutions.com/
[July 2014]
Fondparinux (Arixtra) – Aspen trading. Summary of Product Characteristics [
updated 23.9.14] on Electronic Medicines Compendium: (accessed on [1.10.14]) via
www.medicines.org.uk/ Guidelines on the diagnosis and management of Heparin
induced thrombocytopenia: second edition 2012 (BCSH
Page 7 of 16
Appendix 1: HIT report sheet
HEPARIN INDUCED THROMBOCYTOPENIA (HIT) Questionnaire
ALL HIT requests MUST be discussed with a member of the Haematology
medical team before the request will be accepted
IT IS ESSENTIAL THAT THE FOLLOWING INFORMATION IS FAXED BACK TO
0115 970 9189 OR SENT WITH THE SAMPLE BEFORE TESTING FOR HIT WILL
BE UNDERTAKEN
Haematology doctor contacted regarding this
request…………………………………………
Pre test probability score
Patient Name
DOB
Hospital No
Ward
0 1 2 3 4 5 6 7 8 (please circle)
…………………………………………
…………………………………………
…………………………………………
…………………………………………
Previous THREE platelet counts
Date ………….
Count ………. x109/l
Date ………….
Count ………. x109/l
Date ………….
Count ………. x109/l
Current (or recent) heparin administered
Type
…………………………..
Date started
…………………………..
Date stopped
…………………………..
Previous heparin administered in last 100 days (document all exposure)
Type
…………………………..
Date started
…………………………..
Date stopped
…………………………..
Type
Date started
Date stopped
…………………………..
…………………………..
…………………………..
Does the patient have a THROMBOTIC event?
If YES, please specify
Yes / No
………………………………………..
NOTE: SAMPLE REQUIRED FOR HIT SCREENING IS 1 PLAIN CLOTTED
(SERUM) SAMPLE. SSTR GEL TUBES CANNOT BE USED
Page 8 of 16
Appendix 2: HIT pre-test probability scoresheet
Diagnosis of HIT
This is by using the pre-test probability score (four T’s – see below), based on
clinical suspicion, a reduction in the platelet count, unexplained thromboembolic
problems and positive laboratory test results.
Circle and score all that apply to patient:
Event
Thrombocytopenia
Timing of platelet
count fall or other
sequelae
Thrombosis or
other sequelae
(e.g. skin lesions)
OTher cause for
thrombocytopenia
not evident
Score =2
50% fall or platelet
nadir 20-100 x
109L
Clear onset
between day 5-10
or <1 day if
previous heparin
exposure within
last 100 days
New thrombosis,
skin necrosis or
post heparin bolus
acute systemic
reaction
No other cause for
platelet count fall is
evident
Score
6-8
Likelihood of HITT
High
4-5
0-3
Intermediate
Low
Score =1
30-50% fall or
platelet nadir 1019 x 109L
Onset of
thrombocytopenia
after 10 days
Score = 0
Fall <30% or
platelet nadir <10 x
109L
Platelet count fall
too early (without
recent heparin
exposure)
Progressive or
recurrent
thrombosis,
erythematous skin
lesions or
suspected
thrombosis not yet
proven
Possible other
cause is evident
None
Definite other
cause is present
Action
Inform haematology. If appropriate treat as
detailed in HIT guideline.
Discuss with haematologist
May continue heparin but review diagnosis
frequently
Patient name
DOB
Hospital number
Ward
Haematologist
contacted
Form completed by:
Name/Signature
Date
Contact number
Page 9 of 16
Appendix 3: Calculation of Cockroft Gault Creatinine Clearance
CrCl (ml/min) =
(140 – age) x weight (kg) x 1.04 (female) or 1.23 (male)
serum creatinine (micromol/l)
Appendix 4: Argatroban dosing for anticoagulation during haemodialysis for
patients with acute or previous HIT
Argatroban can be used for haemodialysis anticoagulation though there is limited
data for its use
Use initial bolus of 250microgram/kg followed by continuous infusion of
2microgram/kg/min. See page 4 for information on how to prepare the infusion and
the table below for dosing.
Stop infusion 1 hour before the end of dialysis
Target Activated Clotting Time (ACT) range is 170-230 seconds using the Haemotec
device. In patients already on argatroban no bolus dose is required (i.e. continue the
infusion at the existing rate).
Argatroban is not extensively cleared during haemodialysis and continuous
venovenous haemofiltration.
Body
weight
(kg)
(round to
nearest
10kg)
50
60
70
80
90
100
110
120
130
140
Haemodialysis bolus dose
of
250microgram/kg
given over 3-5 minutes
Bolus dose
Volume of
(microgram)
1mg/ml
solution
(mL)
12500
12.5
15000
15
17500
17.5
20000
20
22500
22.5
25000
25
27500
27.5
30000
30
32500
32.5
35000
35
Infusion rate of
Argatroban 1mg/mL
(mL/hr)
2microgram/kg/min
6
7
8
10
11
12
13
14
16
17
Page 10 of 16
Appendix 5: Argatroban in patients with HIT undergoing PCI
There is limited data for HIT patients undergoing PCI.
Dilute argatroban to give a solution of 1mg/ml. See page 4 for information on how to
prepare the infusion.
A bolus dose of 350microgram/kg over 3-5 minutes followed by an infusion of
25microgram/kg/min has been used.
Check Activated Clotting Time (ACT) 5-10 minutes after bolus dose completed and
proceed with procedure if ACT greater than 300seconds.
ACT value
If ACT below 300 seconds
Action
Give additional bolus dose of 150microgram/kg
and
increase infusion rate to 30microgram/kg/min
and
re-check ACT 5-10 minutes later
If therapeutic ACT of 300-450
seconds achieved
If ACT higher than 450 seconds
Continue infusion for duration of procedure
Decrease infusion rate to 15microgram/kg/min
and
re-check ACT 5-10 minutes later
There is no data on use of argatroban in combination with GPIIb/IIIA inhibitors
Dosing schedules as in tables below:
Bolus Doses:
Body
weight
(kg)
(round to
nearest
10kg)
50
60
70
80
90
100
110
120
130
140
Initial bolus dose of
350microgram/kg
given over 3-5 minutes
Bolus dose
(microgram)
17500
21000
24500
28000
31500
35000
38500
42000
45500
49000
Volume of
1mg/ml
solution
(mL)
17.5
21
24.5
28
31.5
35
38.5
42
45.5
49
If ACT<300 seconds
additional bolus dose of
150microgram/kg
given over 3-5 minutes
Bolus dose
Volume of
(microgram)
1mg/ml
solution
(mL)
7500
7.5
9000
9
10500
10.5
12000
12
13500
13.5
15000
15
16500
16.5
18000
18
19500
19.5
21000
21
Page 11 of 16
Infusion Rates:
Body
weight
(kg)
Initial infusion
25microgram/kg/min
(ACT 300-450 seconds)
If ACT<300 seconds
Dose adjust infusion to
30microgram/kg/min
If ACT >450 seconds
Dose adjust to
15microg/kg/min
Infusion
rate
(ml/hr)
See above table for
150microgram/kg dose
See table above for
350microgram/kg dose
(round to Initial Infusion Infusion Bolus Infusion Infusion
Infusion
nearest Bolus
dose
rate
dose
dose
rate
dose
10kg)
dose (microgram/ (ml/hr)
(microgram/ (ml/hr) (microgram/
min)
min)
min)
50
1250
75
1500
90
750
60
1500
90
1800
108
900
70
1750
105
2100
126
1050
80
2000
120
2400
144
1200
90
2250
135
2700
162
1350
100
2500
150
3000
180
1500
110
2750
165
3300
198
1650
120
3000
180
3600
216
1800
130
3250
195
3900
234
1950
140
3500
210
4200
252
2100
Page 12 of 16
45
54
63
72
81
90
99
108
117
126
Appendix 6: Acute HIT treatment summary
Positive diagnosis of HIT
Requiring anticoagulation
treatment
Creatinine clearance
>30ml/min
Treat with fondaparinux s/c
once daily
See guideline page 4 for full
information
Creatinine clearance
<30ml/min or undergoing
dialysis or PCI
Treat with argatroban iv infusion:
reduced infusion rate for patients with
moderate hepatic impairment (ChildPugh class B), after cardiac surgery
and critically ill patients.
Contraindicated in patients with
severely impaired hepatic function,
uncontrolled bleeding and
hypersensitivity to argatroban or any of
the excipients (ethanol and sorbitol).
See guideline page 5 for full
information and appendices 4 or 5 as
applicable
ALL patients to be started on oral coumarin anticoagulants unless contra-indicated.
Fondaparinux should be continued until INR >2 on 2 consecutive days.
Argatroban should be continued until INR >4 on 2 consecutive days.
(Concomitant use of warfarin and argatroban produces a combined effect on the INR
test so when INR>4 this correlates with an INR of 2-3 with warfarin alone.)
Page 13 of 16
Appendix 7
Anticoagulation in patients with a history of HIT
Subsequent Event
VTE
Either
fondaparinux 7.5mg s/c OD
if <50kg
fondaparinux 5mg s/c OD
Or
Treatment doses of
argatroban (as above)
and warfarinisation
if >100kg
fondaparinux 10mg s/c OD
(reduced to 7.5mg on day 2
if CrCl 30-50ml/min)
and warfarinise
Thromboprophylaxis
(e.g. for surgery)
N.B. Fondaparinux C/I if
CrCl <30ml/min
fondaparinux 2.5mg s/c OD
(if CrCl = 20-30ml/min
fondaparinux 1.5mg s/c OD)
N.B. Fondaparinux C/I if
CrCl <20ml/min
fondaparinux 2.5mg s/c OD
Non-ST elevation acute
coronary syndromes (i.e.
ACS; unstable angina
[UA] and non-ST
elevation [non-Q wave]
myocardial infarction
[NSTEMI])
N.B. Fondaparinux C/I if
CrCl <20ml/min
Page 14 of 16
Equality Impact Assessment Report
1.
Name of Policy or Service
Response to external best practice policy
2.
Responsible Manager
Owen Bennett (Clinical Quality, Risk and Safety Manager)
3.
Name of person Completing EIA
Julian Holmes
4.
Date EIA Completed
2.8.15
5.
Description and Aims of Policy/Service
Treatment of heparin induced thrombocytopenia (HIT)
6.
Brief Summary of Research and Relevant Data
BCSH guideline on diagnosis and management of acute HIT 2nd edition Oct
2012
7.
Methods and Outcome of Consultation
N/A
8.
Results of Initial Screening or Full Equality Impact Assessment:
Equality Group
Assessment of Impact
Age
No Impact Identified
Gender
No Impact Identified
Race
No Impact Identified
Sexual Orientation
No Impact Identified
Religion or belief
Argatroban contains alcohol
Disability
No Impact Identified
Dignity and Human Rights
No Impact Identified
Working Patterns
No Impact Identified
Social Deprivation
No Impact Identified
Page 15 of 16
9.
Decisions and/or Recommendations (including supporting rationale)
From the information contained in the procedure, and following the initial
screening, it is my decision that a full assessment is not required at the
present time.
10.
Equality Action Plan (if required)
N/A
11.
Monitoring and Review Arrangements
Review September 2018
Page 16 of 16