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Cost-benefit of Prophylactic
Treatment in Hemophilia
Angelika Batorova
National Hemophilia Center, Dept. of Hematology,
University Hospital, Bratislava,
Slovak Republic
Modern Haemophilia Care
 Major advances
Safe products
Prophylaxis
radical change of the natural history of hemophilia
 Challenges of hemophilia treatment
 Cost of treatment
 Unmet needs and benefits
 Disparities in the availability o modern treatment
Prophylaxis - treatment of choice in children
recommended by the WHO and the WFH since 1994
Modern treatment of haemophilia.
Berntorp E, Boulyjenkov V, Brettler D, Chandy M, Jones P, Lee C, Lusher J, Mannucci P, Peak I, Rickard K, et al.
Bull World Health Organ. 1995; 73 (5): 691-701
Evidence for clinical effect of prophylaxis
1976-2003 Observational studies  a strong clinical effect1,2
 75% - 95% reduction of joint bleeds
 long-term preservation of physical capability
 reduction of orthopedic surgery

improved psychosocial development and QoL
2006 - Cochran Collaboration review conlusion3:
 paucity of randomised studies
 insufficient evidence supporting prophylaxis
!
Prospective randomised studies - US Joint Outcome Study4
Canadian prophylaxis study5
ESPRIT study6
PK tailored prophylaxis7
1.Nilsson IM Acta PaediatrScand 1976; 65: 129–35.
2.Fischer et al. Haemophilia 2007; 13:345-350
3.Stobart et al. Cochran Database Syst Rev 2006, CD003429
4.Manco-Johnson et al. NEJM 2007; 357:535-544
5. Feldman et al. JTH 2006; 4: 1228-1236
6. Gringeri et al. JTH 2011;9:700-710
7. Valentino et al, JTH 2012;10:357-367
Prophylaxis- prospective randomized studies
2007; 357:535-544
Prophylaxis versus Episodic Treatment to Prevent Joint Disease
in Boys with Severe Hemophilia
MJ Manco-Johnson, TC Abshire, AD Shapiro et al.
Age at start: 1.6 yrs;
Prophylaxis
n=32
Enhanced on demand n=33
MRI score
2011
Age at start: 4 (1-7) yrs; Prophylaxis n=21
On demand n=19
Comparison of two prospective studies
Joint bleeds/yr (n)
<0.001
Prophylaxis dosage
Pts with radiological arthropathy (%)
<0.001
<0.02
<0.05
Manco-Johnson
Gringeri
25 IU/kg e.o.d.
25 IU/kg/ 3x/week
Prophylaxis dose /yr
4,450 IU/kg
On demand initial dose
40 IU/kg
3,041 IU/kg
25 IU/kg
Swedish v.s. Dutch Prophylactic Strategy - Results
Outcome
Swedish
HD protocol
Dutch
ID protocol
p
Start of prophylaxis (yrs)
1.5 (1.2-2.5)
4.5 (3.1-5.7)
<0.01
4273
2120
<0.001
Joint bleeds (n/yr)
0 (0-2)
1 (0-3)
<0.01
HJHS score (max.128)
4 (1-6)
7.5 (3-15.3)
<0.01
HAL scores (max.100)
99 (89-100)
92 (81-99)
<0.01
EQ5D-values
1.0 (0.8-1.0)
0.8 (0.7-1.0)
p=0.7
€ 188 896
€ 97 311
FVIII consumption (IU/kg/yr)
Health-care costs /yr
Conclusion:
 outcome was good in both cohorts
 HD protocol  small, significant improvement in outcome
 however with a doubling of cost
Fischer et al. JTH 2011; 9 (S2): O-TH-073
Prophylaxis in adults
Prophylaxis
 initiated in adulthood (>18 years)
 significant arthropathy often already exists
 aim: to arrest the clinical effects of arthropathy
& prevent other complications
Prophylaxis in adults- studies
Author, yr
Pats
(n)
Age (yrs)
(M; range)
Miners ,1998
25
30 (4- 63)
4
-
Saba, 2000
7
37 (29- 49)
Coppola, 2005
19
29 (17- 46)
Tagliaferri, 2008
84
28 (13- 76)
Loverin, 2000
Collins, 2010
19
30 - 45
Joints bleeds/yr
(n)
Main results
before
after
37
50
13
 of bleedings
 89%
 joint status
0.48
 71%
32.4
15
 QoL
3.3
34.6 → 3.0 days lost
 orthopaedic scores
0
 orthopedic scores
 factor consumption
1630 vs. 4552 IU/kg/yr
Effects of secondary prophylaxis started in adolescent and adult haemophiliacs.
Tagliaferri A, Franchini M, Coppola A et al.
Haemophilia 2008; 14: 945–51.
84 severe haemophilia A or B
on-demand
prophylaxis because of frequent bleeding
30 adolescents >10 years & 54 adults  18 years
Parameter
On demand
Prophylaxis
p
All hemorrhages (n/yr)
35.8
4.2
<0 .01
Joint bleedings (n/yr)
32.4
3.3
< 0.01
Days lost from school/work
34.6
3.0
<0.01
Adolescents
Entire cohort
significant  clinical orthopaedic scores
improvement in QOL
Blood Transfus DOI 10.2450/2012.0147-11
Treatment for life- a „gold standard of care“
Heterogeneity of bleeding phenotypes
Limitations: Cost, Pts adherence
Individualised approach
UK 2010/2011: Median FVIII (IU/kg/yr) used in severe
hemophilia A according to age
Prophylaxis
UK: FVIII (IU/kg/yr)- severe hemophilia A according to age
Children/adolescents 0-24 yrs v.s. adults 25-64 yrs
 27 IU/kg
3xW
19 IU/kg
3xW
17IU/kg 22IU/kg
3xW
3xW
Some patients receive as large annual dose on demand as on prophylaxis.
Hay C.
Hemophilia Care In Europe 2011- Survey in 35
countries - Availability of Prophylaxis
Children
% of the centres
Survey 2011 vs. 2009
% of the centres
Adults
18% increase in reported FVIII use in Europe
10% increase in Western Europe
35% increase in Central and Eastern Europe
O´Mahony EHC Survey 2011
FVIII Supply (IU/cap) v.s. GDP (€) in Europe 2011
Slovakia – 2011
FVIII supply - real FVIII supply
5.4 IU/cap  over GDP by 64%
if corresponding to the GDP 1.8 IU/cap
Cost of therapy- major challenge of prophylaxis
Factor concentrates  63 - 96% of total cost of hemophilia treatment
Cost of prophylaxis v.s. on demand
Author
Age (yrs)
Prophylaxis
On-demand
Smith, 1996
< 18
$ 75,574
$ 24,435
Bohn, 1998
15 ( 6.9)
$ 87,865
$ 30,820
15- 25
[4,012
Manco-Johnson, 2007
<2.5
$ 300,000
$125,000
Steen-Carlsson, 2008
> 18
$147,939
$ 51,518
Gringeri, 2011
1-7
€ 79,668
€ 35,829
Fischer, 2003
IU/kg/yr 1,612]
Prophylaxis is about 3 times more costly than on-demand
Predicted average annual cost
of prophylaxis v.s. on-demand by age
Steen Carlsson et al., Haemophilia 2004;10:515-526
Measurement of outcomes of hemophilia
management
Clinical outcomes and benefits
 Number of bleeds / Bleed avoided



Number of joint bleeds / Joint bleed avoided
Joint Health Score / Arthropathy avoided / Disability avoided
Survival
Quality of life
•
36-SF, EQ-5D, HAL - Hemophilia activity list
Economic measurements

Cost-of-illness (COI) analysis (direct and indirect costs)

Cost-effectiveness analysis (CEA)

Cost utility analysis (CUA) – utility values (SF-6D)

QALY - Quality Adjusted Life Years (= Health utility value x Years)

ICER – Incremental Cost Effectiveness Ratio  Cost per QALY
$ 50,000 – Accepted threshold of ICER per QALY
Direct and indirect costs of hemophilia treatment
Direct costs
Factor concentrates
Healthcare service(s)
• Comprehensive care visits
• Outpatient procedure
• Hospitalization, Surgery,Prostheses
• Laboratory tests
• Diagnostics – X-ray, CT scan MRI, Ultrasound
• Other hemophilia-related medication(s)
• Medical device(s)
Nonmedical costs
Indirect costs



Lost work time
Lost work time by family and friends
Unpaid caregiving services - family and friends
ASH 2011
Costs of six major invasive procedures
€
Steen Carlsson et al., Haemophilia 2004
Senstitivity analysis of prices for adults
Mean annual cost by different prices of products.
Annual cost (€)
Product
On demand
(x SD)
Prophylaxis
(x SD)
Most expensive factor
concentrate brand
65 876  47 050
190 736  83 481
Cheapest factor
concentrate brand
45 013  31 656
118 835  52 328
Steen Carlsson et al. Haemophilia 2004;10:515-526
Cost benefits of prophylaxis v.s. on demand
On demand
(n=61)
Prophylaxis
(n=94)
Days lost from work /patient
5.25
2.59
Surgeries/patient
1.98
0.51
Total number of procedures
121
48
Arthrodeses
21
3
Joint replacements/extractions
42
4
Synovectomies
13
2
Radioactive isotope
12
0
Port-A-cath
0
16
Steen Carlsson et al., Haemophilia 2003
Prophylaxis:
 resources are needed to compensate disabilities
Equipment
On demand
(n=61)
31
Prophylaxis
(n=94)
3
Wheel chairs
13
6
Adjustable furniture
6
0
Cars
Steen Carlsson et al., Haemophilia 2003
Health state  QoL
EQ-5D descriptive system
• 5 dimensions
• Each 5 levels of perceived problems
Scoring the EQ VAS
Level 1: no problem
2: slight problems
3: moderate problems
4: severe problems
5: extreme problems
Health state
defined by combining 1 level from each of
the 5 dimensions „12345“
The EuroQol Group (1990). EuroQol-a new facility for the measurement of
health-related quality of life. Health Policy 16(3):199-208.
Prophylaxis in adults - impact on the QoL
Costeffectiveness
Cost-utility
Tagliaferri et al.Haemophilia (2008), 14, 945–951
Comparison of health utility value by the time
spent on prophylaxis.
Always on
prophylaxis
>50%
on prophylaxis
<50%
on prophylaxis
Always
on demand
New trend: Hemophilia treatment over whole life
- need for mew cost utility assesment
Ageing hemophilia population
 bleeding problems re-emerge
 re-induction of prophylaxis is often necessary
New cost effectivity analyses of prophylaxis
Key features:
• Pharmacokinetic dosage
• Effect on inhibitors
• Inclusion of soft tissue bleeds, intracranial bleeds
• Comorbidities increasing the risk of bleeding
• Management of comorbidities requiring normal hemostasis
A.Farrugia et al., EHC Roundtable, Brussels 2012
Pharmacokinetic assesment for cost- effective
prophylaxis
Effect of half-life on factor (FVIII) level
following a single bolus infusion 30 IU/kg
Median half life: 10.4 h
Join bleeds/yr according to time < 1%
In pats with joint score 0
7.5h (5th percentile of normal range)
16.5h (95th percentile of normal range)
Difference
in FVIII Level
at 48h
59h difference
0
10
20
30
40
50
60
70
Effect of half-life on factor (FVIII) level following a single
bolus infusion 30 IU/kg
Median half life: 10.4 h
Importance for keeping FVIII  1%
T1/2 & frequency of injections
Collins P et a. Haemophilia (2011), 17, 2–10
>
IVR & dose
J. Ahnstrom et al. Haemophilia (2004), 10, 689–697
.
Daily and standard prophylaxis regimes - Factorconsumption,
cost of treatment and QoL measured by EQ-5D
Standard
prophylaxis
(n=9)
Daily
prophylaxis
(n=9)
5863
4025
305 671
209 864
Mean cost/yr
208,467 €
143,127 €
QoL (EQ-5D)
0.904
0.85
Mean IU/week
Mean IU/yr
Journal of Thrombosis and Haemostasis 2012; 10: 359–367
.
n
66
Standard prophy
32
PK tailored prophy 34
Annualized bleeding rate
OD
dose
ABR (Median)
FVIII IU/kg/yr
43.9
2152.2
20-40IU/kg 486h
1.0
5768.2
20-80IU/kg 726h
1.1
5197.8
Relative reduction in median ABR
with any prophylaxis v.s. OD
99.4 % < 0.0001
CONCLUSION
“The dilemma in managing haemopilia is not whether to
use prophylaxis or episodic treatment
BUT
how to manage prophylaxis to provide
the optimal, most cost-effective treatment.”
„Quality of life is the most important value for patients,
and it is difficult to translate it into data“
Future perspectives
Individualized prophylaxis
Pharmacokinetic dosage
Long acting products
Treatment for All & for Life
European Parliament - Brussels
Thank you
QALY- Quality Adjusted Life Year
A measure of benefit of health care based on
 the lenght of life
 quality of life (health utility value
QALY´s gained
= Health utility value x years
QALY´s gained 6. 8 =
0.93
x
10
 of the 10 years 6.8 would be in perfect health
Average FVIII consumption per year in different age groups
of patients with hemophilia
Peyvandi et al. Haemophilia 2012
Conclusions
 The cost of prophylaxis is about 3 fold higher than on
demand
 Prophylaxis over life  ICER well under the threshold
currently applied by health authorities
 Using current criteria
cost- effectiveness : prophylaxis > on-demand
 Future perspectives
 Individualized prophylaxis
 Pharmacokinetic dosage
 Long acting products
 Treatment for All & for Life
Potential aims of tertiary prophylaxis
Prevent life-threatening bleeds
 Bleeding frequency
 Bleeding in target joints
 The worsening of arthropathy
 Bleeding risk due to comorbidities
Control pain
Permit physiotherapy
 QoL
 Social participation and maintain
working activity and independence
 Activity/autonomy levels
Gringeri at al. Haemophilia (2012), 18, 722-728
Current dilemma of hemophilia management
“The dilemma in managing haemopilia is not whether to
use prophylaxis or episodic treatment
BUT
how to manage prophylaxis
to provide
the optimal, most cost-effective treatment.”
„Quality of life is the most important value for patients,
and it is difficult to translate it into data“
The EuroQol Group (1990). EuroQol-a new facility for the measurement of healthrelated quality of life. Health Policy 16(3):199-208.
Estimates of the cost effectiveness of prophylaxis in
haemophilia
Study
ICER for prophylaxis
v.s. on demand
*Threshold ICER
Miners 2002
£ 46,500
£ 30,000
Miners 2009
£ 37,000
£ 30,000
Lippert 2005
€ 1,2 mio- 2,4 mio
n.a.
Roosendaal 2007
€ 300,000
n.a.
Risebrough 2008
Escalated dose
Prophylaxis
CDN $ 524,938
CDN $ 1,000,000
CDN $ 50,000
CDN $ 100,000
* Maximum ICER that healthcare providers will pay for an intervention or
treatment for QALY
Adherence to therapeutic regimen by age
category
S. GERAGHTY et al.Haemophilia (2006), 12, 75–81
Incremental costs and clinical effectiveness of 5 degrees of
hemophilia treatments
Incremental cost curve
Effectiveness/ Benefit
5
4
3
2
Intervention
1
1. Treatment of life threathening bleeds
2.
non-life treathening bleeds
3. Orthopedic operations
4. Inhibitors
5. Prophylaxis & Social integration
Units cost
Schramm W. Haemophilia 2003,9,S1:111-116
©1990 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group.
THE FREQUENCY OF INHIBITORS IN HAEMOPHILIA A PATIENTS
INCREASES IN SWEDEN
Frida Holmberg, Pia Petrini, Rolf Ljung
JTH 2011; 9 (S2): P-WE-529
1980-1999 Inhibitors 19%
1980s pd-FVIII  1990s r-FVIII
62 children born 2000- 2009, FVIII<1%
•
•
•
•
•
inhibitor status
FVIII mutations
family history
ethnicity
medical history
50%
40%
30%
37%
26%
20%
10%
3%
0%
All inhibitors
High titre
Risk factor: ‘Null mutation’ p=0.0039
intron 22 inv inhibitor frequency 61%
Transient
The economic perspective
The major cost generators (prices in Euro)
Steen Carlsson et al., Haemophilia 2004
Number of hospital days and invasive procedures were
significantly higher in the on demand than in the
prophylaxis group
On demand
61
Prophylaxis
94
Total number of hospital days
320
246
Number of days divided by group size
5.25
2.59
Total number of
invasive procedures
Arthrodeses
21
3
Prostheses implantations/extractions
42
4
Synovectomies
13
2
Radioactive isotope
12
0
Port-á-Cath and percuseal port implantations/extractions
0
16
Others
33
23
Total number of procedures
121
48
Total number of procedures divided by group size
1.98
0.51
Steen Carlsson et al., Haemophilia 2003
Distribution of cost sources
Factor concentrate
Other healthcare costs
Lost production
Other non-healthcare costs
Total
Steen Carlsson et al., Haemophilia 2004
On demand
EUR (%)
Prophylaxis
EUR (%)
30 825 (46.5%)
97 615 (80.5%)
2523 (3.8%)
2127 (1.8%)
31 096 (46.9%)
13 004 (10.7%)
1874 (2.8%)
8516 (7.0%)
66 327 (100%)
121 263 (100%)
Prophylaxis – for how long?
•
Current Swedish regimen (Malmö)
prophylaxis throughout the life
•
Current Dutch regimen*
In some patients prophylaxis can be stopped
47%
31%
n= 49
M age: 23,4 yrs
22%
Never stopped (n=15)
Discontinued 1-2x, are back on prophylaxis (n=23)
Stopped prophylaxis (11)
*M.v.d. Berg et al. Haemophilia 2006; 12, (S3): 159-168
SPINART
Secondary prophylaxis with rFVIII vs on demand
in severe hemophilia A adult subjects
2008-2013
Bayer
Clinical Trials. gov web site.
Available at: http://www.clinicaltrials.gov/ct2/show/NCT00623480
?term=hemophilia+and+prophylaxis+and+adults& rank=2.