presentation slides - British Heart Foundation

Familial
Hypercholesterolaemia
The Role of Commissioners and
Service Providers in Improving
Quality of Care and Patient
Outcome
Session one: Why the
current patient pathway
needs to change
Chaired by Professor Peter
Weissberg, BHF Medical Director
Welcome and introduction
Professor Peter Weissberg,
Medical Director, BHF
Keynote speech
Professor Sir Bruce Keogh,
Medical Director, NHS England
Understanding FH
Professor Steve Humphries, BHF
Chair of Cardiovasular Genetics,
University College London
Understanding Familial Hypercholesterolaemia
Genetics, Pathology, Pediatrics
Professor Steve Humphries,
Cardiovascular Genetics, UCL, Director DH-FH Cascade Audit project.
Lead
Advisor to NICE Guideline Development Group and RCP FH UK Audit
,
•
•
•
•
Describe FH and known genes causing FH
Show clinical utility of DNA tests
Polygenic causes of “FH”
FH and Children
CVG - Ros Whittall, Marta Futema, Sarah Leigh, Ebele Usefo, KaWa Li, Philippa Talmud
UGI - Sonia Shah, Vincent Plagnol. Royal Free Lipid Clinic - Devi Nair, Mahtab Sharifi
ICH - Nick Lench, Alison Taylor. Simon Broome Study Group - Andrew Neil, Nigel
Capps, Ian McDowell, Mary Seed, Handrean Soran, John Betteridge, Paul Durrington.
NICE-recommended FH Diagnostic criteria
Cholesterol > 7.5mmol/l or LDL > 4.9mmol/l in adult
Cholesterol > 6.7mmol/l or LDL > 4.0mmol/l if < 16 yrs
PLUS family history of high cholesterol or MI (<55yrsM)
OR PLUS Tendon Xanthoma
OR FH-causing mutation
Corneal Arcus
Xanthelasma
Definite FH
•
•
•
•
•
Possible FH
Based on UK Simon Broome FH Register :
Tendon Xanthoma
Also Dutch Lipid
Clinic Criteria
scoring system & US
system MEDPED
What has gone wrong in FH ?
What has gone wrong in FH patients?
LIVER
Cholesterol
usedasinLDL
Circulates
in blood
building
membranes
of
particle
(“Bad
Cholesterol”)
new cells
“wrapped
up”and
by to
large
make important
hormones
protein ApoB
apoB binds
to receptor
Liver has special LDL-grabbing protein
called a “Receptor” – 7 fingered hand
What has gone wrong in FH patients?
LIVER
Cholesterol
usedasinLDL
Circulates
in blood
building
membranes
of
particle
(“Bad
Cholesterol”)
new cells
“wrapped
up”and
by to
large
make important
hormones
protein ApoB
LDL
removed
apoB
binds
from
Blood
to receptor
Liver hasReceptor
special LDL-grabbing
protein
internalised
called a “Receptor” – 7 fingered hand
What has gone wrong in FH patients?
Receptor
recycles
to surface
LIVER
Recycling controlled
by enzyme PCSK9
FH is due to :
•
•
•
LDL degraded
LDL removed
binds
andapoB
cholesterol
from
Blood
tointestine
receptor

lack of functional receptors,
poor LDL binding or
high degradation in recycling
Nobel Prize 1985
Most FH due to LDLR mutations, 5% by APOB, 2% PCSK9
Can LDL-C be lowered in FH patients?
Hadfield et al 2007
Pre-treatment LDL
Post-treatment LDL
40%
Overall
~ 50% reduction
3.3 mmol/l
35%
30%
6.7 mmol/l
25%
20%
15%
But 34% > 4.0mmol/l
and 12% > 5.0mmol/l
10%
5%
0%
<2
2-2.9
n = 249
•
•
3-3.9
4-4.9
5-5.9
6-6.9
7-7.9
8-8.9
9-9.9 10-10.9 ≥ 11
LDL (mmol/l)
Low potency (cheap) Simvastatin 40 is inadequate for >95% FH patients
Combination therapy eg Ezetimibe may be needed to achieve target
Do Statins reduce CHD mortality in FH?
Death rate in FH patients on Statins
Placebo-controlled trials not ethical in FH - have to treat!
Use Simon Broome Register Patients
•
•
•
Compare Mortality Rate versus general population
Look at 1988-1992 (lipid lowering by diet, resins)
After 1992 when FH patients were first to get statins
Registration Form
Co-ordination Centre
Death certificates
Follow up for mortality by NHS Central Registry
Continuous recruitment from up to 21 UK lipid clinics
1980
2012
Simon Broome Study Group - Andrew Neil, Gil Thompson, Nigel Capps, Ian McDowell, Mary Seed,
John Betteridge, Paul Durrington, Steve Humphries
Statins reduce CHD and ALL Deaths in FH
Neil et al E Heart J 2008
Age 20-79 years
CHD Mortality in those with/without CHD Cancer and Total Mortality
Secondary
1980-91 (25)
Cancer
1980-91 (14)
5.15
1991-06 (108)
0.96
1991-06 (76)
- 25%
- 34%
0.63
3.88
- 48%
1992-06 (45)
1.36
Total
1980-91 (55)
1.98
Primary
1980-91 (12)
- 29%
1992-06 (315)
0.94
1.03
0
1
2
3
4
SMR
Finding FH BEFORE CHD 
Life expectancy not lower
5
6
0
0.25
0.5
0.75
1
1.25
1.5
1.75
SMR
Because of low smoking rate,
good diet, annual checks
Based on 2766 (1456 M/1310 F) DFH + PFH patients. 190 CHD and 90 cancer deaths (37727 person years follow-up)
2
UK FH NICE Guidelines 2008
Wierzbicki, Humphries, Minhas, BMJ. 2008 27;337:a1095
Diagnosis
•
•
109 recommendations
all based on assessing published evidence
All individuals should be offered a DNA test to confirm the
diagnosis and to assist in Cascade testing of relatives
Issue date
In children at risk of FH (one affected parent) the following
: August 2008
Identification and
management of familial
hypercholesterolaemia
diagnostic tests should be carried out by age of 10 years :
- a DNA test if the family mutation is known
- LDL-C measurement if mutation not known
NICE clinical
Developed by the National
guideline 71
Collaborating
Centre for Primary Car
e
Identifying people with FH using cascade testing
•
Cascade testing - combination of DNA testing and LDL-C levels is recommended
to identify affected relatives of those with a clinical FH.
Knowing the family mutation is a key piece of information for cascade
testing and for starting statin therapy in childhood.
2013 UK FH NICE Quality Standard 41
No. Final Quality Statements
1
2
3
4
5
6
7
8
Adults with a baseline total cholesterol above 7.5mmol/l are assessed for a clinical
diagnosis of FH
People with a clinical diagnosis of FH are referred to a specialist with expertise in FH.
People with a clinical diagnosis of FH are offered DNA testing.
Children at risk of FH are offered diagnostic tests by the age of 10 years.
Relatives of people with a confirmed diagnosis of FH are offered testing through a
nationwide, systematic cascade process.
Adults with FH receive lipid-modifying drug treatment to reduce LDL-C concentration by
more than 50% from baseline.
Children with FH are offered lipid-modifying drug treatment by a healthcare professional
with expertise in FH in a child-focused setting by the age of 10 years.
People with FH are offered a structured review at least annually.
Knowing the family mutation is a key piece of information for cascade
testing and for starting statin therapy in childhood.
How Common is FH ?
• It is Common - Frequency FH ~1/500
120,000 in UK
Same as childhood diabetes
• It is underdiagnosed < 15,000 known Marks, et al 2004 , HEARTUK 2008,
particularly in the < 35 years group Neil, et al BMJ 2000
Survey UK Lipid Clinics and UK 2010 Audit
Missing 85%
of predicted
It runs in Families
-autosomal dominant trait
-50% of children of
-an FH parent will have FH
Family studies are efficient way
of finding more FH patients
“Cascade Testing”
Cascade Testing in FH Family
Referred to Cardiology Royal
Free. Chest pains 52 yrs, Chol 7.5
Father Early MI?
Mrs A
?
Diagnosis: Possible FH
Action: Test brothers and sisters and children
Family A
Approach Father’s
relatives
High
Chol
High
Chol
High
Chol
Mrs A
FH Relatives identified
?
Action: Test ONLY at-risk
children
What does genetic
Testing cost?
Offer statin therapy to adults, and life-style,
diet, smoking cessation to all
DNA tests for FH GOSH Regional DNA lab since 1997
To date > 2000 reports.
•
•
•
First in world
Up until now costs ~£5-600 and takes 2-4 months
Test of single mutation in relative ~ £70.
Cholesterol test ~£10, ECG ~£300
Have now developed Next Generation Sequencing methods
which allow all the FH genes to be sequenced in one go !
and soon  96 samples to be analysed in one run!
Cost falling to under £250!!!
North East Thames Regional Genetics Laboratory - contact Alison
Taylor-Beadling Genetics.Lab@gosh.nhs.uk to discuss cost of
testing.
The Overlap Problem
Collaboration with John Kastelein et al Amsterdam
Data from Starr et al 2008
FH vs. Not FH LDL levels, Ages 5-15
2.2mmol/l
16.00%
14.00%
Data on 2469 non-carriers
and 825 carriers of family
mutation.
Analyse by age
12.00%
4.6mmol/l
10.00%
Not FH - Histogram
FH - Histogram
Not FH - Normal Dist
FH - Normal Dist
8.00%
FH
6.00%
False +ve = 8%
False –ve = 15%
4.00%
2.00%
Gets worse
with age!
4.44 + 1.43mmol/l
0.00%
0.6
1
1.4
1.8
2.2
2.6
3
3.4
3.8 4.2
4.6
5
5.4 5.8
6.2
6.6
7
7.4
7.8
8.2 8.6
9
LDL mmol/l
3.2mmol/l
DNA test avoids false –ve diagnosis
DNA testing for identification of relatives
Starr et al Clin Chem Lab Med 2008
FH vs. Not FH LDL levels, Ages 45-54
FH vs. Not FH LDL levels, Ages 5-15
5-15 years
45-54 years
12.00%
16.00%
3.1 mMol/l
2.2 mMol/l
14.00%
10.00%
12.00%
4.6 mMol/l
10.00%
8.00%
4.6 mMol/l
Not FH - Histogram
FH - Histogram
Not FH - Normal Dist
FH - Normal Dist
6.00%
8.00%
6.00%
4.00%
4.00%
2.00%
2.00%
0.00%
0.6
1
1.4
1.8
2.2
2.6
3
3.4
3.8
4.2
4.6
5
5.4
5.8
6.2
6.6
7
7.4
7.8
LDL mmol/l
False +ve = 8%, False –ve = 15%
8.2
8.6
9
0.00%
4.2mmol/l
0.6 1 1.4 1.8 2.2 2.6 3 3.4
3.8 4.2 4.6 5 5.4 5.8 6.2 6.6 7 7.4 7.8 8.2 8.6 9
LDL mmol/l
False +ve = 16%, False –ve = 46%
As mean LDL-C rises with age in non-FH, overlap increases.
DNA testing gives an unambiguous result
What is overall mutation detection rate?
Taylor et al Clin Genet 2010
100 patients with a clinical diagnosis of FH
(DFH+PFH or DLCN score > 3)
66 with PFH
34 with DFH
(DLCN score > 3)
(DLCN score > 8)
Detection rate 20-30%
Detection rate 70-80%
Mutation in 13-20
Mutation in 24-27
Overall find a monogenic molecular cause in 35-47% of patients
No mutation patients?
Detection Rate of ~80% in DFH patients compares favourably with the 20-30%
seen in BRCAI/2 in familial breast cancer- also fewer “unclassified” variants

Technical reasons – No method detects all mutations.
Sequencing introns may find > mutations

Genetic heterogeneity – May be 4th or 5th gene to be found.
Predict prevalence < PCSK9 ie < 2%

Over-Diagnosis – Many patients do not have “true” FH. Family
history of hypercholesterolaemia and early CHD not very specific.
Many have polygenic cause
Polygenic Cause of no mutation FH
Talmud et al Lancet 2013
Hypothesis
Having a large number of common genetic variants that each
raise LDL-C by a small amount could mimic Monogenic FH



Used 12 common variants (SNPs) in 321 Mutation negative FH patients
from UK, 451 from Belgium and compared with 3000 healthy men and
women from the Whitehall II Study
Results in UK non mutation FH patients show that in at least 80% a
“polygenic” cause of their elevated LDL-C is most likely explanation
Results confirmed in Belgium patients and now in samples from 6
other countries - Futema et al Clin Chem in press
Why is the polygenic explanation important?
•
•
•
•
Research: Searching for a monogenic cause of FH in high
score patients will not be successful!!!
Money : 2008 NICE Guideline CG71 Cascade testing should be
done in all patients with a clinical diagnosis of FH using DNA
where available and LDL-C where not.
But Cascade testing those with polygenic hypercholesterolemia
 much less cost effective – fewer than 30% “affected” relatives
Treatment : Predict polygenic patients will have less severe
disease and can be easily managed by statin treatment in
general practice (not expensive tertiary referral centres)
Important for FH Guidelines and we are testing these hypotheses
NICE, Children and statins
•
•
There are 7,000,000 children <10years in UK.
Predict 14, 000 FH children
Roughly 7,000,000 between 10-18 years in UK.
Predict 14,000 FH Teenageers
At most 600 currently known !
- HEARTUK Survey Jan 2008, UK FH Audit 2010
NICE CG71 Recommendation
Lipid-modifying drug therapy for a child or young person with FH should
usually be considered by the age of 10 years.
What is Evidence to support this recommendation?
Carotid intima-media thickness (cIMT)
IMT
IMT
•
•
•
Thickness of intima and media of blood
vessel wall
Associated with Coronary
atherosclerosis, predictive of future CVD
events
Easily measured using ultrasound
At what age is cIMT thicker in children with FH?
NICE, Children and statins - The Evidence
Wiegman et al JAMA 2004
Wiegman et al Lancet 2004
Statin
Placebo
0.51
0·005 mm/year vs
<0·001 mm/year.
N
Carotid IMT (mm)
FH
0.5
p = 0.01
0.49
0.48
Baseline
Difference in mean carotid IMT in 201 children with
FH vs 80 unaffected siblings plotted against age
Detectable atherosclerosis
by age 10-12 years
2 Year
FH (8-8yrs) 102 on 20mg/d pravastatin,106 placebo.
LDL 6.18  4.7mmol/l. No safety or growth problems
Progression prevented by
low dose statin
Supports NICE guidance to identify at risk children using DNA testing
by age 10 years and to consider statin use
The UK Paediatric FH Register
Aims :
 To collect SB-type information on all identified FH children in UK
 To update information annually wrt growth/statin use/side effects etc
Clinicians still reluctant to prescribe statins in case of some long term risk
 Reduce loss to follow up as children  adult clinics
 Steering group of clinicians, Colleges, charities and patient reps
 Obtained research Ethics in January 2013
Have >50 registered clinicians and>200 enrolled children to date
Paediatric FH Register – Preliminary data
56% of the children are treated with statin
Age (SD)
% Male (no)
% CHD in parent (no)
% CHD in relative (no)
Diagnostic T-Chol
Diagnostic LDL-C
On Treat T-Chol
On Treat LDL-C
No N=31
11.7 (3.7)
51.6% (16)
9.7% (3)
22.6% (7)
7.66 (1.42)
5.55 (1.25)
7.66 (2.03)
5.75 (2.67)
Yes N=40
13.4 (3.2)
57.5% (23)
38.5% (15)
55.0% (22)
8.08 (2.06)
6.23 (2.14)
5.53 (1.30)
4.26 (3.16)
P value
0.08
0.62
0.007
0.008
0.54
0.22
0.0001
0.0002
Equal number boys and girls on statin
Treated group have higher LDL-C and worse family history
Statin use  30% LDL-C lowering
Number FH known
Finding all the FH patients
140000
Cascade Testing – BHF Nurses
120000
Each FH  5 living relatives of whom 50%
have FH so 15,000 known  ~30,000 new
100000
80000
60000
From Genomics England
40000
100,000 people having genomes sequenced
Expect >200 to carry FH-causing mutation
All can be fed into Cascade testing
20000
0
2004
2008
2012
2016
2020
2024
From General Practice/ Vascular Health Check/Chem Path “flag” of high Chol
Each will have 2-3 families. Find by note search  refer to FH Nurses 1000/yr?
From Young MI
All MIs on MINAP register. 5-10% of those <45yrs may be FH  1000/yr?
From cholesterol testing Children at immunisation
Proposed by Wald et al BMJ 2008 Being piloted now  1000/yr?
Lots more work to do! – Educate GPs, Train Nurses
FH Research - the Time Line
Dequker et al 2004, Medical Archaelogy IMAJ
1503 - 24 years
Madonna Lisa Maria di Gherardini
Born Florence 1479
Died 1516 age 37 years
Xanthoma?
Xanthelasma?
With DNA testing, BHF Nurses and Cascading in families can
find all 120,000 FH patients in UK in next 10 years
The current patient pathway
experienced by most FH
patients– why it needs to
change
Dr Robert Cramb, Consultant
Chemical Pathologist/Director of
Pathology Services, Birmingham
The current patient pathway
experienced by most FH patients–
why it needs to change
Dr Rob Cramb
Chemical Pathologist
Queen Elizabeth Hospital Birmingham
Referral to Clinic:
Information to GP
• Causes of lipid disorders are reviewed in the
clinic
Familial Hypercholesterolaemia
Familial Hypertriglyceridaemia
Muscle pain with lipid lowering drugs
Refractory Hyperlipidaemia
Secondary Hyperlipidaemia
• Procedures Performed:
Blood tests prior to follow-up appointments
Fasting blood tests in clinic
Secondary CVD investigations as required
Referral to Clinic:
Information to GP
• Exclusions:
 children under 16
• Suggested Investigations:
 Venous fasting blood check:
•
•
•
•
•
•
Cholesterol
Triglyceride
HDL-cholesterol
Glucose
Thyroid function
ACR
• Administrative Requirements:
• please ensure that any medication taken by the patient
is listed in the referral letter
Referral to Clinic:
Information to GP
• Service Notes:
 Consultant who see patients in this clinic:
 Dr Robert Cramb
 New patients are automatically seen by a Dietitian as part of their
appointment.
 The Joint British Society Guidelines (Version 2; Heart Supplement
2005) and NICE Guidelines (CG71; Familial hypercholesterolaemia and
CG67; lipid modification)are followed.
 Familial causes of lipid disorders and secondary hyperlipidaemias are
reviewed in the clinic and treated.
 Diabetic patients who have refractive lipid problems are seen in the
combined Diabetic/Lipid Clinic.
 Patients with muscle pains or intolerance of lipid lowering drugs are also
reviewed.
 Lipid apheresis is offered to patients with homozygous familial
hypercholesterolaemia in conjunction with renal services
Referral
Referral- 2
Referral- 2 (cont)
Referral - 3
Non – referral to Clinic
• Admission Details
This 54 year old gentleman presented to CDU
with chest pain. The chest pain was left sided and
sharp in nature, it worse on inspiration but no
radiation. He denied cough/fever/S.O.B/sweaty/
clammy.
On examination: chest was clear, left side chest
was tender on palpation, heart sounds were
normal,abdomen was soft, non tender.
Investigations: Bloods were normal, serial
troponin were normal, D-dimer was negative,
ECG was SR
Non – referral to Clinic
•
•
•
•
•
•
•
•
•
•
Date Na K Urea Creat Ca Alb Bili
AlkP AST ALT Hb (g/
dL)
Hb (g/L)
13/02/2014 136 4.5 4.2 90 2.40 48
8 80 29 144
14/02/2014 137 4.5 4.3 96 2.15 46
7 76 24 143
Date WBC Plat Folate B12
13/02/2014 9.5 355
14/02/2014 7.8 333
Date TSH fT4
No Results
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Date Chol
No Results
Date HbA1cIFCC
No Results
Date Trop-T HS
Trop-T 6
14/02/2014
Date INR Warfarin
(mg)
13/02/2014 1.0
14/02/2014 1.0
Date CK CRP Gluc
13/02/2014 <3
14/02/2014
Non – referral to Clinic
•
•
•
•
•
•
•
•
•
•
Date Na K Urea Creat Ca Alb Bili
AlkP AST ALT Hb (g/
dL)
Hb (g/L)
13/02/2014 136 4.5 4.2 90 2.40 48
8 80 29 144
14/02/2014 137 4.5 4.3 96 2.15 46
7 76 24 143
Date WBC Plat Folate B12
13/02/2014 9.5 355
14/02/2014 7.8 333
Date TSH fT4
No Results
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Date Chol
No Results
Date HbA1cIFCC
No Results
Date Trop-T HS
Trop-T 6
14/02/2014
Date INR Warfarin
(mg)
13/02/2014 1.0
14/02/2014 1.0
Date CK CRP Gluc
13/02/2014 <3
14/02/2014
Non – referral to Clinic
•
•
•
•
•
•
•
•
•
•
Date Na K Urea Creat Ca Alb Bili
AlkP AST ALT Hb (g/
dL)
Hb (g/L)
13/02/2014 136 4.5 4.2 90 2.40 48
8 80 29 144
14/02/2014 137 4.5 4.3 96 2.15 46
7 76 24 143
Date WBC Plat Folate B12
13/02/2014 9.5 355
14/02/2014 7.8 333
Date TSH fT4
No Results
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Date Chol
No Results
Date HbA1cIFCC
No Results
Date Trop-T HS
Trop-T 6
14/02/2014
Date INR Warfarin
(mg)
13/02/2014 1.0
14/02/2014 1.0
Date CK CRP Gluc
13/02/2014 <3
14/02/2014
Non – referral to Clinic
•
•
•
•
•
•
•
•
•
•
Date Na K Urea Creat Ca Alb Bili
AlkP AST ALT Hb (g/
dL)
Hb (g/L)
13/02/2014 136 4.5 4.2 90 2.40 48
8 80 29 144
14/02/2014 137 4.5 4.3 96 2.15 46
7 76 24 143
Date WBC Plat Folate B12
13/02/2014 9.5 355
14/02/2014 7.8 333
Date TSH fT4
No Results
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Date Chol
No Results
Date HbA1cIFCC
No Results
Date Trop-T HS
Trop-T 6
14/02/2014
Date INR Warfarin
(mg)
13/02/2014 1.0
14/02/2014 1.0
Date CK CRP Gluc
13/02/2014 <3
14/02/2014
GP Measurement of Cholesterol = 9.0 mmol/L
Lifelong exposure to high LDL-C levels result in high
CHD risk and imperative to treat early
Heterozygous FH
Homozygous FH
Untreated TC levels of 12–30 mmol/L (460–1160
mg/dL)
typically develop CHD very early in life
Untreated
Treat at 10yrs
Non FH
Treat at 18yrs
200
200
Cumulative LDL-C, mmol
Cumulative LDL-C (mmol)
HOZ
If untreated, TC levels are typically between 8–15 mmol/L
(310–580 mg/dL) and at high risk of CAD before age 55/60
years
12.5yrs
150
150
Start lowdose statin
Threshold
for CHD
35yrs
48yrs
Start highdose statin
53yrs
55yrs
100
100
5050
Without FH (estimable via
Framingham and/or SCORE)
00
00 33 66 99 12
12 15
15 18
18 21
21 24
2427
27 30
3033
3336
3639
3942
42 45
4548
4851
5154
5457
57 60
60
Age in years
Years Age
Nordestgaard BG, et al. Eur Heart J 2013. doi:10.1093/eurheartj/eht273
Support for statin use in FH primarily comes from transferable
evidence from major cardiovascular diseases …
… but also directly from FH:
Cumulative eventfree survival, %
Dutch subjects with heterozygous familial
hypercholesterolaemia on or off statin treatment
Versmissen J. BMJ 2008;337:a2423
n=413
p<0.001
n=1537
Cholesterol Tests
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• Total Numbers
46362
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• Total Numbers
46362
• GP Tests
38170
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• Total Numbers
46362
• GP Tests
38170
• GP Tests >7.4 mmol/L
614
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• Total Numbers
46362
• GP Tests
38170
• GP Tests >7.4 mmol/L
614
1.61%
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• GP Testing
• Women >7.4 mmol/L
408
• Men >7.4 mmol/L
206
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• GP Testing
• Women >7.4 mmol/L
408
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• Women >7.4 mmol/L
408
• Women <50
71; mean cholesterol – 8.9 mmol/L
• Women >50
337; mean cholesterol – 8.0 mmol/L
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• Women >7.4 mmol/L
408
• Women <50
71; mean cholesterol – 8.9 mmol/L
• Women >50
337; mean cholesterol – 8.0 mmol/L
• 31 Women > 9.0 mmol/L; 7 Seen in clinic
Cholesterol testing
1 Nov 2013 – 31 Oct 2014
• GP Testing
• Men >7.4 mmol/L
206
• Men >9.0 mmol/L
17; 3 seen in clinic
7 with associated hypertriglyceridaemia
• Apo E2 homozygosity, DM and xs EtOH
HEART UK: The cholesterol charity
http://heartuk.org.uk
Thank you for your attention
One family’s perspective on
FH
David, Gill and Bethan Collings,
Wales
Questions and discussion
Refreshment break
Session two: Commissioning
a cost effective FH cascade
testing service
Chaired by Professor Huon Gray,
National Clinical Director for Cardiac
Care, NHS England
Welcome back
Professor Huon Gray,
National Clinical Director for Cardiac Care,
NHS England
What does an effective FH
cascade testing service
look like?
Dr Ian McDowell, Chair
Professional Advisory Group
Welsh FH Service
FH Service Implementation in Wales
including Family Cascade testing
Dr Ian McDowell
British
Soc
Human
Genetics
Dept of
Health
FH project
England
Cardiac
Networks
& CHD
NSF
NICE FH
Guideline
Welsh
Cardiova
scular
Society
Public
Health
Welsh
Endo
Diabetes
Society
BHF
Welsh
Cardiac
Rehab
Nursing
Wales FH
Special Interest
Group
LDL
Paediatrics
BIMDG
All Wales
Medicines
Advisory
Group
Apheresis
Service
Dutch FH
Project
HEART
UK
Inequalities
in Health
Projects
Clinical
Genetics
AWMGS
Molecular
Genetics
Wales
Gene
Park
SSAGCC&
Welsh
Chemical
Path
Group
Genetic
Interest
Group
FH Patient
Forum
Cascade Testing Pilots 2006
Cardiff - Bridgend
Familial
hypercholesterolaemia
Implementing NICE guidance
2008
NICE clinical guideline 71
Have a vision!
Launch of Wales FH Service December 2010
Implementation Phases
•
•
•
•
•
•
•
Project management
Patient pathway consultation
Genotyping
Software procurement
Nurses and GC appointments
Education
Paediatric services
Patient Pathway with Cascade Testing
???FH
??FH
General
Practice
Family Cascade Programme
Full Pedigree
Family registration
Family Tracing
Test 1st degree relatives
Hospital
(eg Cardiology)
Lipid Clinic
Clinical and lipid assessment Provisional
diagnosis of FH using SB criteria
Genotype
positive
Cascade from
relatives
FH 
FH X
Document family history
Genotyping
Consultation to
advise on FH
treatment
options
Treat hyperlipidaemia
Continuing care
Primary care (most)
Continuing care
Secondary care(some)
FH
diagnosed
Referred to
lipid clinic
FH excluded
in relative
Discharged from cascade
programme:
Continuing care
Paediatrics (some)
PASS Software
1. Pedigree drawing function
2. Workflow management
3. Templates and archiving
4. Multisite working
5. Audit and research
Family
History
1st/2nd degree relative:
 known with premature (<60yrs) CHD
 known with premature (<45yrs) CHD
 known with LDL-C > 4.9mmol/l (or total chol > 7.5mmol/l)
 <18yrs with LDL-C > 4.0mmol/l (or total chol > 6.7mmol/l)
1
2
1
2
………….
Please specify relation to index case
Physical
Examination
Clinical
History


Tendon xanthomata (in patient or 1st/2nd degree relative)
Premature corneal arcus (no score for arcus senilis)



Patient with premature CHD (<45 yrs)
Patient with premature CHD (<50 yrs)
Patient with premature CHD (<60 yrs)
 Patient with premature (<60yrs) strokes and/or
peripheral vascular disease
Untreated or
corrected
LDL- Cholesterol
Concentrations
(mmol/l)
Fasting
Triglycerides
(mmol/l)

LDL-C ≥ 8.5

LDL-C 6.5 – 8.4

LDL-C 5.0 – 6.4

LDL-C 4.0 – 4.9
If untreated LDL- C values are unobtainable see attached sheet
(Correction Factor Table) and calculate estimated value.
 Triglyceride 2.5 – 3.4
 Triglyceride 3.5 – 4.9
 Triglyceride ≥ 5.0
Please record in the narrative box any 2 causes that predispose to raised
triglycerides, e.g. diabetes.
6
4
4
3
2
1
8
5
3
1
minus 2
minus 3
minus 4
10
Genotype of first 624 index patients
100.0%
90.0%
85 %
Percentage of patients
80.0%
67 %
70.0%
60.0%
50.0%
46 %
38 %
40.0%
30.0%
20.0%
14 %
10 %
10.0%
4%
0.0%
5 or less
(n=101)
6
(n=137)
7 to 8
(n=126)
9 to 10
(n=114)
11 to 12
(n=56)
13 to 14
(n=36)
Score Group
No variant found
VUS
Pathogenic variant
15 to 20
(n=54)
Genetic Testing Results
2073
individuals
genotyped
1409 index
patients
433+ ve
(31%)
116 are VUS
664
relatives
349 + ve
313 - ve
What has gone well
• More FH patients
• Improved quality of care
• All Wales approach
• Partnership with BHF
Cascading is happening
• Paediatric service
What could go better
• More effective
cascading
• Some clinic
bottlenecks
• Recognition/ referral
from primary care
• Utilise PASS fully
• Patient and family
support
www.fhwales.co.uk
The costs associated with
an FH cascade testing
service
Mr Robert Pears,
Consultant in Public Health,
Hampshire County Council
FH services:
Associated costs
Implications for commissioning
Robert Pears
Consultant in Public Health
Content
• Revising NICE costings
– Method
– Results
– Limitations
• Implications for commissioning
SHIP
Method
Not method acting
NICE costings
• 3 year model
– 20% in years 1-3
• Extended
– 20% in years 1-3
– 10% in years 4-7
• Generic
atorvostatin
3 models of care: same entry
Potential FH case identified by
GP, lipidologist or cardiologist
FH Coorindator assesses
Diagnostic criteria met:
Genetic testing
Diagnostic criteria not met:
Referred back
Mutation identified:
1st, 2nd and 3rd degree
relatives cascade testing
Diagnostic criteria not met:
Management of phenotype
Specialist led model
• Treatment decisions:
– 70% GP
– 30% specialist
• Annual review:
– 80% GP
– 20% specialist
GP led model
• Treatment decisions:
– 100% GP
• Annual review:
– 100% GP
Dual mode
• Treatment decisions:
– 80% GP
– 20% specialist
• Annual review:
– 80% GP
– 20% specialist
Paediatric patients
• Treatment:
– 100% specialist
• Annual review:
– 100% specialist
Results
Not election results
Costs of 10yr programme
• Atorvastatin 40 or 80mg
– Formally £367.74 p.a.
– At generic simvastatin cost £60.36 p.a.
• Drug costs:
– 68% of total on patent
– 50% off patent
Costs and benefits over 10yrs
43% less
expensive
SHIP modification to costs
• Drugs:
– NICE: 20% simva, 40% atorva, 40% rosuva
– SHIP: 20% simva, 72% atorva, 8% rosuva
• Cascade testing:
– NICE: 4 1st degree, 8 2nd degree, 12 3rd degree
– SHIP: 3 1st degree, 6 2nd degree, 9 3rd degree
• DNA testing:
– NICE: £400 index case, £50 already identified
– SHIP: £250 index case, £70 already identified
Model costs and benefits over 10 years
Costs more
than
halved!
Study limitations
Nobody’s perfect
Limitations
• Could not calculate QALYs
• Referrals may be front
ended
• GPs and lipidologists
– Will need FH/genetic
support
– may not participate
• Costs lost in other budgets
Commissioners
The art of
persuasion
Forward planning during cuts
• Not cost saving
• 8 years for investment to be realised
• Continued commissioner support needed
The economic case
Priorities within FH service
• Dual model in SHIP
• Polygenic: to cascade or not to
cascade?
– Almost 2/3 savings Year 1
– Almost 3/4 savings Year 3
• Assertive case finding in
general practice
• Access to specialists
Scaling up
•
•
•
•
•
•
•
•
Strategic fit
Cultural fit
Strategic implementation
Equal access
Quality assurance
Shared database
Evaluation
Good for morale
Paper published
• More detail
• Free access
• Open Heart/PubMed
Thanks for listening
Any questions?
Robert.pears@hants.gov.uk
Building consensus across
geographical and
organisational boundaries
Dr Guy Pilkington, Clinical Chair,
Newcastle West, CCG
Building Consensus
across the North East
Dr Guy Pilkington
NHS Newcastle West
Clinical Commissioning Group
Northern Lipid Forum
in association with
FH: can we deliver the new
NICE Quality Standard?
Hilton Newcastle Gateshead Hotel
Bottle Bank, Gateshead,
Newcastle upon Tyne NE8 2AR
Tuesday 15th October 2013
NICE Quality Standard (QS41 August 2013)
Familial Hypercholesterolaemia
8 prioritised statements derived from CG71, designed to drive
measurable quality improvements
Statement 1. Diagnosis
Statement 2. Specialist referral
Statement 3. DNA testing
Statement 4. Diagnosis in children under 10 years
Statement 5. Cascade testing
Statement 6. Drug treatment in adults
Statement 7. Drug treatment in children
Statement 8. Annual review
North East FH Service Developments
•
•
•
•
•
•
•
•
•
•
•
Adult specialist lipid clinics well established in 6 Trusts
– Durham, Gateshead, Hartlepool, Newcastle, Northumbria, Sunderland
Adult FH patients also seen in outpatients in Carlisle, Middlesbrough
Paediatric Lipid clinics in 2 Trusts
– Newcastle and Sunderland, both signed up for RCP National Paediatric FH Register
Regional experience of FH Genetic Diagnosis and Family Cascade Testing
- Newcastle Clinic and Regional Genetics participated in National Pilot Study of FH Genetic Diagnosis
and Family Cascade Testing 2005-2008, 145 probands genotyped
Regional Genetic Service agree to continue support for FH mutation testing
- continue to accept requests for of relatives of FH probands with known mutations.
Specialist Lipid Clinics Network created in 2008
- agreed NICE CG71 compliant FH identification and management pathway
NECVN Lipid Specialists Advisory Group (LSAG) established 2009
NECVN endorsed proposal for Implementation of NICE CG71
- rejected by commissioners 2009, 2010
FATS Primary Care Guidelines for Identification of FH
- developed, promoted and implemented in Newcastle and Northumbria 2009
FATS Primary Care Guidelines for Identification of FH
- adopted by NECVN but not widely promoted not yet fully implemented
NECVN Standards for identification of FH in Acute Cardiology patients
- developed by LSAG, launched Jan 2013
Key Findings from the RCP FH Audit
The clinical management in lipid clinics is of a good standard for
individual patients who have been diagnosed with FH.
Current resources are inadequate to cope with the identification of the
predicted additional FH cases UK wide.
There is a major lack of family “cascade” testing, whether carried out
on the basis of lipid levels, or more effectively by a DNA diagnosis.
While there is good access to DNA diagnosis and funding for DNA
testing in the Devolved Provinces, access and funding in England is
poor.
There is a shortfall in child-focused services throughout the country,
with only 26% of sites offering paediatric FH services.
FH Services in the North East – Gap Analysis
• No centralised disease register for Adult FH probands and families in
North East
• No Specialist nurses in Adult or Paediatric FH Clinics
• No regional infrastructure for FH Family cascade testing available to
support Clinics
• No access to DNA mutation testing for new FH probands
• No clinical management database software (e.g. PASS) available to FH
Clinics
• Adult specialist lipid clinics capacity shortfall, particularly in the south of
the Region
• Paediatric Lipid clinics not available in south of the Region
• FATS/NECVN Primary Care FH Guidelines not fully implemented in
south of Region
• No access to LDL Apheresis
Northern CCG Forum
• 13 CCGs
– North East SHA area plus Cumbria CCG
• Long history of collaboration across the area
– E.g. Clinical Innovation Teams
• Strong and independently minded forum
• Academic Health Sciences Network
– Co terminus
– Need for CCG engagement
Selling Idea To The CCGs
•
•
•
•
•
•
Prevention
Innovation
Implementing NICE guidance
Best practice
Population
The human touch
The Funding
• British Heart Foundation
– Nursing team for running regional FH cascade
testing service
• AHSN
– Next generation chip and sequence genetics
• AstraZeneca
– PASS software licence
• Northern Forum CCGs
A Population Approach
•
•
•
•
3.1 million people
5,000 people living with FH mutations
Only 15% known
Perhaps 50 preventable cardiac deaths
per year
• CCGs agreed to risk share / population
approach
The Money
• Total requested funding from CCGs
• Year 1 £134,122
• £4,327 per 100k pop.
• Year 2 £294,277
• £9,493 per 100k pop.
• Year 3 £368,520
• £11,887 per 100k pop.
£11,887 per 100k
population
300 proband, 800 cascade
The North East FHG Consortium
•
•
•
•
•
•
•
•
•
North East Cardiovascular Network LSAG (10 clinics)
Northern CCG Forum (13 CCGs)
Northern Regional Genetics Service (genotyping)
NewGene Ltd (genotyping)
Academic Health Sciences Network (AHSN) (genetics)
City Hospitals Sunderland (CHS FT, nurses host Trust)
Newcastle NIHR Diagnostic Evidence Co-operative (DEC)
AstraZeneca Ltd (PASS software licences)
Heart UK – Patient Support Groups
British Heart Foundation Support for FHG Nurses
Questions and discussion
Lunch and networking
First floor, Edwards room
Session three:
Service delivery
Chaired by Dr Mike Knapton,
BHF Associate Medical Director
Welcome back
Dr Mike Knapton, BHF Associate
Medical Director
Delivering an FH cascade
testing service in England
Melanie Watson, Consultant
Genetic Counsellor, Southampton
From NICE Guidance to Clinical Practice:
the Challenge of Setting up a Service for
Familial Hypercholesterolaemia
Melanie Watson
Wessex Clinical Genetics Service
Implementation of the NICE Clinical
Guideline CG71 on Familial Hypercholesterolaemia
A report for the South Central Cardiovascular Network
October 2009
Martin Allaby
Michael Griffin
The CCGs
Funding & Support
• South Central Cardio Vascular Network funding
FH Specialist Nurse - 2 years.
• Wessex Clinical Genetics Service
• PASS database and licences - 3 years
CVD Outcome Strategy
Cardiovascular Disease Outcomes Strategy
Improving outcomes for people with or at
risk of cardiovascular disease (5 Mar 2013).
Action 5
“The National Clinical Director for Heart Disease
will work with all relevant stakeholders to
develop and spread good practice in relation to
FH and sudden cardiac death”
https://www.gov.uk/.../9387-2900853-CVD-Outcomes_web1.pdf
Further Funding
28th January 2014 BHF awarded Wessex
FH Cascade Testing Service £168,000.
• Darren Alderson
Public Health Nurse
• Angela Cazeaux
Senior Sister Coronary Care
• Subhashini Balasingham Genetic Counsellor
• Sabrina Ait-Boudaoud
Patient Pathway Co-ord
The Pathway: Dual Model
Patient visits GP/ referred as a result of a routine blood test indicating high lipids
or early CVD: GP assesses if patient meets SC referral criteria 1(clinical
examination and exclusion of secondary causes of hyperlipidaemia) 2 full fasting
lipid profiles ( 3 months apart)
Secondary care specialist identifies patient
meets SC referral criteria
GP CVD assessment & commencement of statins2 (using secondary care
protocols and lipid clinic advice); offer primary/secondary prevention
Ref to FH Co-ordinator using proforma ( seek advice from FH specialist prn))
FH Co-ordinator/Specialist Nurse
Patient does not meet referral
criteria- rejection letter to
referrer
Checks meets SC referral criteria: discuss FH and
implication for patient and family; discuss limitations of DNA
and LDL- C testing/Draw up family pedigree/Gain consent for
genetic testing Entry of own and family details on national
genetic database/Initiate genetic testing mutation)
Genetic test
positive
Genetic test positive and total
cholesterol satisfactorily reduced by
50% by GP
Start of NICE pathway
for index case
FH co-ordinator to coordinate cascade testing
to family
Test for known familial
mutation negative.
Patient does not have
Genetic test
negative
Genetic test positive but GP
unable to reduce lipid levels by
50% (assumed to be about
20% of cases)
Refer to lipid clinic (or use
choose and book) for lipid
management advice
Genetic test
identifies mutation
of unknown
significance
Discussion between clinical
genetics and FH specialist to
consider if patient’s phenotype is
sufficiently suggestive of FH to
cascade test to family using lipids
The model in practice
GP/Consultant/ refers
Patient with possible FH to
Wessex FH Cascade Testing
Service using referral form
Referral triaged according to
local SB adapted criteria
FH Clinic Appointment:Information RE Condition of FH
Family history taken and pedigree drawn
Genetic Testing – Utility & Limitations
Consent form completed/Bloods
Health promotion and resources given
Entered into the National FH PASS database
Blood Sample sent to Bristol for NGS
Mutation +ve
Clinic appointment
Genetic Test result given
and explanation result.
Genetic report & letter
cc GP & Referrer
Patient enters into
Cascade work flow
Mutation –ve
Letter to confirm that
no alteration was found
and discharged back to
referrer/GP.
VUS
Clinic appointment given
Genetic Test result given
and explanation of result.
Genetic report & letter cc.
GP & Referrer
The model in practice: cascade
• Direct Contact: The FH service will attempt to
contact relatives directly.
• Indirect contact: The patient takes responsibility
for contacting relatives. The service provides
letters/information
*A combination of both methods can be used
Local variation
• West Berkshire: Virtual lipid Clinic
(South Reading; Newbury & District; North & West Reading).
• IOW: Genetic testing requested by Consultant
Chemical Pathologist. „Eclipse‟ to identify patients
with possible FH in GP practices.
Regional Clinics
• Southampton
(Paed/Adult)
• Isle of Wight
• North Hampshire
• Portsmouth
• West Berkshire
(Paed/Adult)
Clinic Appointment
• Condition of FH
• Pedigree
• Genetic Testing; utility
& limitations
• Consent for Genetic
Testing & PASS
Database
Lifestyle Advice
• Diet & Exercise
• Smoking Cessation
• Education & Support
Acknowledgements
Clinical Team
Bristol Genetics Laboratory
Prof Chris Byrne (Lipidologist)
Dr Maggie Willliams
Dr Paul Cook (Lipidologist)
Dr Nikki Davis (Paediatric Endocrine)
Charities
Dr Ali Al-Bahrani (Lipidologist)
Dr Tim Wang (Metabolic Medicine)
Dr Jose Cabrera-abreu (Lipidology)
Prof Mike Cummings (Metabolic Medicine)
Melanie Watson (Lead Genetic Counsellor)
Darren Alderson (Specialist Nurse)
Angela Cazeaux (Specialist Nurse)
Subhashini Balasingham (Genetic Counsellor)
National Leadership
Steering Group
Prof Huon Gray
Prof Steve Humphries (UCL)
National Clinical Director (Cardiac)
Dr Richard Jones (Cardiologist/SCN)
NHS England
Dr Andrew Douglas (GP/CCG)
Robert Pears (Public Health)
Beverley Meeson (CCG)
Jules Payne (Heart UK)
Using PASS software as an
FH database
Kate Haralambos, Welsh FH
Service
Using PASS software as an FH
database
Kate Haralambos
• 2007:
• 2008 -10: pilot & develop
PASS for Wales
• 2010: Wales FH Service
• 2013: AZ/HUK funded
licenses In England
• 2014: BHF Project (0.5 wte)
NICE quality standard #5:
Relatives of people with a confirmed diagnosis of
monogenic FH are offered DNA testing through a
nationwide, systematic cascade process.
Licences, connections, hosting
•
•
•
•
•
1 central database for all users in England
50 licenses funded for PASS
Hosted by Asckey on N3 network
On the cloud:
– assessable via
internet or intranet
Key Features of PASS
1. Pedigree drawing function
2. Workflow management
3. Templates and archiving
4. Multisite working
5. Audit and research
A lot more than just a register!
Bristol Relative Workflow (Page 1)
Refer out
of area
New
Relative
1st direct
letter
sent
BRISTOL
2nd direct
letter
sent
Relative
MAKE
appt.
Relative
appt.
MADE
Relative
sent for
genotyping
Indirect
letter
given
Relative NOT
sent for
genotyping
FH Nurse
Workflow
Lab Workflow
Clinical and Operational data
Age- and gender-specific diagnostic cut-offs
Family and Professional
Linkage
• Family linkage
• Professional linkage – multiple FH nurses
working off 1 pedigree
• Transfer patients to colleagues out of area
Reporting from centres
Examples:
•
•
•
•
Index patients registered/month
Index patients tested/month
# of patients with mutations detected
# of relatives tested
Other such operational or clinical reports can be created.
How I work with the centres?
• Database administrator
• On site training
• SOP
• Workflows
• Template letters
Who’s using PASS?
• 180 families registered to date
• Centres with access and registered
patients• Royal Free, Wessex, Bristol & Bath, Plymouth
• Centres with access to PASS
• Cornwall, Dorset, UCL, West Midlands, Royal
Brompton & Harefield
• Centres in process of getting access
• Manchester, Sheffield, Sunderland & several more.
Conclusions
• Working well in Wales to support a nationwide,
systematic cascade testing service.
• Ability to link up all FH services in England to
allow cascade testing of families spread out
geographically.
• Allows FH services to be evaluated and audited.
• I have been supporting the implementation of
PASS in England and will continue to do so.
The role of the GP in
identifying which patients
should be referred to a
specialist FH service
Professor Nadhim Qureshi,
Professor of Primary Care,
University of Nottingham
The role of the GP in identifying which
patients should be referred to a
specialist FH service
Professor Nadeem Qureshi
University of Nottingham, Division of Primary Care
Opportunities & Tools in Primary Care
• Integrate with national policy
• Computer records
–
–
–
–
Patient-specific reminders
Mailout
Audit & Feedback
Software toolkit
But also consider barriers
Familial
hypercholesterolaemia
Implementing NICE guidance
2008
NICE clinical guideline 71
NICE Quality Standard for FH
Statement 1. Adults with a baseline total cholesterol above
7.5 mmol/l are assessed for a clinical diagnosis of
familial hypercholesterolaemia (FH).
Statement 2. People with a clinical diagnosis of familial
hypercholesterolaemia (FH) are referred for specialist
assessment.
FAMCHOL study
Feasibility of improving identification of familial hypercholesterolaemia
in general practice: intervention development study
Identification of FH:
Simon Broome diagnostic criteria (adults)
Dx for possible FH:
cholesterol > 7.5 mmol/l (LDL
4.9 mmol/l) Computer Search
& at least one of the following:
FHx of MI < 50 years in second-degree relative, or < 60 years in first-degree
OR
relative
FHx of raised total cholesterol > 7.5 mmol/l ( LDL 4.9 mmol/l*) in adult first or
second- degree relative OR > 6.7 mmol/l in child, brother or sister aged < 16
years.
Collect Family History
t
Marks et al (2003) A review on the diagnosis, natural history, and treatment of familial
hypercholesterolaemia. Atherosclerosis 168 (1): 1–14.
NICE clinical guideline 71 – Identification and management of familial
hypercholesterolaemia
FAMCHOL study
Feasibility of improving identification of familial hypercholesterolaemia
in general practice: intervention development study
Patient specific reminders
FAMCHOL study
Feasibility of improving identification of familial hypercholesterolaemia
in general practice: intervention development study
Practice recruitment
Practice geographical area
001 – Inner city
002 – Inner city
003 – Suburban
004 – Inner city
005 – Inner city
006 - Rural
Total recruitment
oo3
Opportunistic
Mail out
33 (14%)
91(10%)
Total = 124
FAMCHOL study
Feasibility of improving identification of familial hypercholesterolaemia
in general practice: intervention development study
No. of eligible patients aged > 18 years:
31377
No. with cholesterol > 7.5 mmol/l:
927
No. participate in the study:
124 (13%)
No. of possible FH identified:
27 (3%)
Unclear if possible FH, due to lack of information on
family history:
16
Familial Hypercholesterolaemia Audit & Feedback
Total no. of eligible patients in Practice
2932
No. of patients with Total Cholesterol > 7.5 ever
No. of those patients with Primary Cause recorded
No. of those patients with Secondary Cause recorded
No. of those patients with Possible Drug Cause recorded
No. of those patients with Thyroid or Diabetes Rx recorded
No. of those patients whose most recent cholesterol before 1/3/2013 < 4
No. of those patients with no primary exclusions
54
11
15
15
14
5
43
Potential participants
No. of patients recruited
No. of patients with Latest Total Cholesterol > 7.5
No. of patients with Total Cholesterol in last 6 months
No. of patients with TSH recorded
No. of patients with Dietary Advice recorded
No. of patients with Weight Management advice recorded
No. of patients with GPPAQ exercise advice recorded
No. of patients with Smoking Cessation advice recorded
No. of patients with Statin prescribed
19
9
10
12
5
0
6
14
14
Medical coding for Familial
Hypercholesterolaemia
& Diagnostic criteria
Medical coding for diagnostic criteria
e.g. Tendon Xanthomata
Genetic testing
FAMCAT study
Improving ascertainment of familial
hypercholesterolaemia in General Practice
electronic records
Improving Identification of Familial
Hypercholesterolemia in General Practice
Computer Medical Records
Rationale
From feasibility study large number of case identified
using Serum Cholesterol > 7.5 filter: ? Rationalise
resources
95% Confidence Interval
Diagnostic Variables
Adjusted Odds Ratio (AOR)
Lower Confidence Limit
Gender
Male
Ref
-Female
1.24
1.16
Highest TC or LDL recorded (mmol/L)
Ideal (TC ≤ 5 OR LDL ≤ 3.3)
Ref
-High (TC > 5 to ≤ 6.5 OR LDL > 3.3 to ≤ 4.1)
2.60
2.26
Very High (TC > 6.5 to ≤ 7.5 OR LDL > 4.1 to ≤ 4.9)
8.29
7.17
Extremely High (TC > 7.5 OR LDL > 4.9)
42.74
37.24
Age during cholesterol measurement (years)
0.95
0.94
Triglycerides during cholesterol measurement (mmol/L)
Ideal (< 1.7)
Ref
-Borderline High (≥ 1.7 to < 2.3)
0.96
0.88
High (≥ 2.3 to < 5.6)
0.83
0.76
Very High (≥ 5.6)
0.68
0.57
Not Recorded
0.43
0.38
Lipid lowering drug usage during cholesterol measurement
No lipid lowering drugs prescribed
Ref
-Prescribed fibrate, bile acid sequestrant, or nicotinic acid
4.51
3.51
Prescribed low potency statins1
2.67
2.11
Prescribed medium potency statin2
3.98
3.53
Prescribed high potency statins3
8.30
7.31
Family history of familial hypercholesterolemia
None recorded/No
Ref
-Yes
9.13
8.12
Family history of myocardial infarction
None recorded/No
Ref
-Yes
1.81
1.61
Family history of raised cholesterol
None recorded/No
Ref
-Yes
3.20
2.75
Any diagnosis of diabetes
No
Ref
-Yes
0.37
0.32
Any diagnosis of kidney disease
No
Ref
-Yes
0.71
0.62
1 Fluvastatin or Pravastatin ≤ 40 mg/day; Simvastatin ≤ 10 mg/day
2 Fluvastatin or Pravastatin 80 mg/day; Simvastatin 20 mg/day or 40 mg/day; Atorvastatin ≤ 10 mg/day; Rosuvastatin 5 mg
3 Simvastatin 80 mg; Atorvastatin ≥ 20 mg/day; Rosuvastatin ≥ 10 mg/day
Upper Confidence Limit
-1.33
-3.00
9.59
49.07
0.96
-1.05
0.91
0.82
0.50
-5.80
3.37
4.48
9.43
-10.26
-2.05
-3.72
-0.42
-0.81
AUC c-statistic*
Standard Error+
95% Confidence Interval
R2
Simon-Broome
0.749
0.007
0.735 - 0.763
0.105
FAMCAT
0.860
0.006
0.848 - 0.871
0.179
FAMCAT excluding secondary disease causes1
0.858
0.006
0.845 - 0.869
0.173
FAMCAT with comprehensive family history of MI2
0.894
0.005
0.884 - 0.904
0.232
FAMCAT excluding family history variables3
0.820
0.007
0.807 - 0.834
0.137
Model Performance
Primary Analysis
Sensitivity Analysis
*Harrell’s c concordance index
+Bootstrap standard errors using jack-knife procedure
1 Excluded kidney disease and diabetes
2 Assumes 80.3% of familial hypercholesterolemia cases and
9.3% of non-cases have positive family history of myocardial infarction
3 Excluded family history of myocardial infarction, raised cholesterol
and familial hypercholesterolemia
What about PMH of Premature CHD
• Secondary care
• Opportunistic
• Computer records
– Patient-specific reminders
– Mailout
– Audit & Feedback
Finally, acknowledge research team
• Dr Stephen Weng
• Ms Jennifer Tranter
• Ms Christine Brindley
• Professor Joe Kai
• Professor Steve Humphries
• Professor Andrew Neil
• Mr Phil Rowlands
END of PRESENTATION
12/3/2014
197
Improving Identification of Familial
Hypercholesterolaemia (FH) in English
Family Practice using
Electronic Medical Records
EXTRA SLIDES
Professor Nadeem Qureshi
University of Nottingham, Division of Primary Care
Risk Assessment in Primary Care
Professor Nadeem Qureshi
University of Nottingham, Division of Primary Care
The role of pathology in
identifying FH in primary
care
Professor Jo Martin, National
Clinical Director for Pathology,
NHS England
The role of pathology in diagnosing FH
in primary care
Jo Martin
Testing
Interpreting
Alerting
Sharing
Teaching
Learning
Testing
MDTs
Audit
Guidelines
Training
Workforce
development
User
feedback
Quality
Standards
Surveillance
Performance
Indicators
Peer
review
Proficiency
test EQA
Accreditation
Oversight
‘Laboratory processes should be
harmonised so that patients can be
confident about the consistency of their
test results, especially as they start to
gain access to their personal health
records that may contain reports from
different pathology services’
Press Release, Pathology Quality Assurance Review
Female, 45y, 55kg
Method Mean Creatinine (μmol/l)
C&G (ml/min)
Carboplatin (mg)
Enzymatic
50
108.5
801
Kinetic Jaffe
64
85.4
663
Jaffe - Compensated
60
90.8
695
O'Leary
67
81.2
637
Endpoint Jaffe
68
80.8
635
IDMS Value
50
109.2
805
34%
34%
26%
Variability
2
1
1
Interpretation and alerting


Interpretative commenting was associated
with a significant additional LDL-c reduction
and increased specialist referrals compared
with controls.
However, only a minority of individuals
received a specialist referral.
al 2013
Bell et
Sharing and teaching
•
•
•
•
•
Data between labs
Working with patient groups to understand their
requirements for access to pathology testing
Publication of data
Patient understanding - lab tests on line
development
Letting patients know about FH will drive clinical
behaviour
Learning
Data
Total
cholesterol



More awareness
More training
More information
Questions?
Questions and discussion
BHF FH funding criteria
Professor Peter Weissberg, BHF
Medical Director
Supporting FH Cascade
Testing Services
BHF Funding November 2014
Funding available
• BHF will fund FH nurses salaries and
admin staff provide the need for the latter
is clear
• 100% salary in year 1 and 50% salary in
year 2
• Approximately £100K to £150K per trust
Funding will not be
available for:
• Genetic testing
• PASS software
• Any additional running costs for the
service
Key Points
• There must be a named lead clinician
• There must be a named paediatrician
• You must commit to delivering an FH
cascade testing service:
– Target family members of known index cases
– Identify new index cases
Key Points
• You must have secured funding for the
genetic tests before the funding for the
nurse(s) will be released by BHF
• You must commission genetic tests from
an accredited laboratory where nextgeneration sequencing technologies are
used
Guidance notes
• Please read the guidance notes (sent by
email to each applicant) carefully before
you commence the application process
Further information
• Contact Heidi Mayhew at
mayhewh@bhf.org.uk