Title
Cost-utility analysis of deferiprone for the treatment of β-thalassaemia patients with chronic
iron overload: a UK perspective
Journal
Pharmacoeconomics
Authors
Anthony Bentley1,4, Samantha Gillard1, Michael Spino2,3, John Connelly2, Fernando Tricta2.
1
Abacus International, Bicester, Oxfordshire, UK.
2
ApoPharma Inc., 200 Barmac Drive, Toronto, M9L 227, Canada.
3
Leslie Dan Faculty of Pharmacy, University of Toronto
4
Corresponding author: Abacus International, 01869 357223,
[email protected]
Supplementary appendix: Details of systematic review
Inclusion and exclusion criteria
Inclusion and exclusion criteria, based on the population, interventions and outcomes
reported, are shown in Table I.
Table I: Eligibility criteria used in search strategy
Description
Inclusion criteria
Population
Thalassaemia patients with chronic iron overload requiring blood
transfusions
Description
Interventions
Deferiprone or combination therapy of deferiprone and desferrioxamine
Deferasirox
Desferrioxamine
Outcomes
Liver iron concentration assessed by MRI T2*, liver biopsy, or
superconducting quantum-interference device (SQUID)
Cardiac iron concentration assessed by MRI T2*
Cardiac function assessed by left ventricular ejection fraction (LVEF) or
end diastolic volume
Total body iron excretion
Maintenance of iron balance as measured by serum ferritin levels
Induction of negative iron balance as measured by serum ferritin levels
Mortality rates
Adverse effects of treatment
Study design
Randomised controlled trials (RCTs), prospective controlled and
uncontrolled trials, observational studies (prospective and retrospective
cohort studies)
Language
restrictions
English language only
Exclusion criteria
Population
Patients with a haemoglobinopathy other than thalassaemia
Patients not requiring blood transfusions
Interventions
Desferrioxamine monotherapy single arm study
Deferasirox monotherapy single arm study
Non-Ferriprox® deferiprone
Conference proceedings were excluded if they did not include a
deferiprone monotherapy arm
Outcomes
Outcomes not listed in the inclusion criteria above
Study design
Case series and case studies. Any non-RCTs with < 100 participants.
Product and disease reviews
Editorials
Short surveys
Letters
Language
restrictions
Non-English language papers
Abbreviations: LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; SQUID,
Superconducting Quantum Interference Device.
Included studies
Following assessment and exclusion of studies based on title, abstract and full text, 20
studies were included in the final data set [1-20].
Twenty-two references were identified in total but Cohen 1998 [21] was a child record of
Cohen 2000 [6]. Additionally, Shashaty 2006 [22] was a child record of Cappellini 2006 [3].
Of the 11 included RCTs:

two trials examined DFP monotherapy as the intervention of interest with DFO
monotherapy as the comparator [11, 16];

one study examined combination therapy with DFO as the comparator [20];

one study examined DFP–DFO sequential therapy with DFO as the comparator [9];

one study examined DFP–DFO sequential therapy as the intervention of interest with
DFP monotherapy as the comparator [13];

one study consisted of four treatment arms: DFP–DFO sequential therapy,
combination therapy, DFP monotherapy, and DFO monotherapy [12];

four studies examined DFX monotherapy as the intervention of interest with DFO as
the comparator in three instances and placebo as the comparator in one instance [3,
7, 15, 19];

one study examined DFO as the intervention of interest with placebo as the
comparator [14].
Of the nine non-RCT studies included in the final data set:

four examined DFP as the only treatment arm;

two examined DFO versus DFP;

one evaluated DFP monotherapy, DFX monotherapy and DFO monotherapy;

two evaluated DFP monotherapy, DFO monotherapy, DFX monotherapy and
combination therapy.
Figure 1: Schematic for the systematic review of clinical evidence
Search strategy: clinical data
Databases searched

The Cochrane Library (incorporating the Central Register of Controlled Trials,
CENTRAL, NHSEED)
o
Cochrane Database of Systematic Reviews
o
Cochrane Central Register of Controlled Trials
o
NHS Economic Evaluation Database

OVID MEDLINE (including MEDLINE In-process)

OVID Embase
Date on which the search was conducted
Searches were conducted for all of the databases listed above on 9th February 2011.
Date span of the search
There were no restrictions on the time frame for searching. Databases were searched from
the commencement of the individual database up to 9th February 2011.
Search strategy
All the following searches were combined and inclusion/exclusion criteria applied.
The Cochrane Library, to present; Searched on 09/02/2011
ID
Search
Hits
#1
MeSH descriptor Thalassemia explode all trees
191
#2
MeSH descriptor beta-Thalassemia explode all trees
121
#3
thalass?emia
141
#4
MeSH descriptor Iron Overload explode all trees
129
#5
"chronic iron overload" or "iron overload"
194
#6
(#1 OR #2 OR #3 OR #4 OR #5)
433
#7
deferasirox or exjade or ICL670
91
#8
MeSH descriptor Deferoxamine explode all trees
133
#9
DFO or desferal or desferrioxamine
145
#10
deferiprone or ferriprox or L1
578
#11
MeSH descriptor Iron Chelating Agents explode all trees
331
#12
(#7 OR #8 OR #9 OR #10 OR #11)
959
#13
(#6 AND #12)
141
Cochrane Reviews [9] | Other Reviews [3] | Clinical Trials [109] | Methods Studies [1]
| Technology Assessments [4] | Economic Evaluations [14] | Cochrane Groups [1]
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to Present;
Searched on 09/02/2011
#
Searches
▲
1
2
exp thalassemia/ or exp beta-thalassemia/
thalass?emia.mp. [mp=protocol supplementary concept, rare disease supplementary concept,
title, original title, abstract, name of substance word, subject heading word, unique identifier]
Results
17207
17839
3
exp Iron Overload/ or chronic iron overload.mp.
10155
4
1 or 2 or 3
28525
5
deferasirox.mp.
322
(exjade or ICL670).mp. [mp=protocol supplementary concept, rare disease supplementary
6
concept, title, original title, abstract, name of substance word, subject heading word, unique
78
identifier]
7
deferoxamine.mp. or exp Deferoxamine/
6347
(DFO or desferal or desferrioxamine).mp. [mp=protocol supplementary concept, rare disease
8
supplementary concept, title, original title, abstract, name of substance word, subject heading
3955
word, unique identifier]
9
10
deferiprone.mp.
(ferriprox or L1).mp. [mp=protocol supplementary concept, rare disease supplementary concept,
title, original title, abstract, name of substance word, subject heading word, unique identifier]
691
18992
11 iron chelating agent.mp. or exp Iron Chelating Agents/
46035
12 5 or 6 or 7 or 8 or 9 or 10 or 11
66826
13 4 and 12
2140
Embase 1980 to 2011 Week 05; Searched on 09/02/2011
#
Searches
▲
1
2
exp thalassemia/ or exp beta thalassemia/ or exp thalassemia major/ or exp thalassemia minor/
thalass?emia.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
title, device manufacturer, drug manufacturer]
Results
19586
21076
3
iron overload/ or chronic iron overload.mp.
6637
4
1 or 2 or 3
26099
5
deferasirox.mp. or exp DEFERASIROX/
971
(exjade or ICL670).mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer]
7
8
9
10
exp DEFEROXAMINE MESYLATE/ or exp DEFEROXAMINE/ or deferoxamine.mp.
(DFO or desferal or desferrioxamine).mp. [mp=title, abstract, subject headings, heading word,
drug trade name, original title, device manufacturer, drug manufacturer]
deferiprone.mp. or exp DEFERIPRONE/
(ferriprox or L1).mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer]
366
10924
4972
1513
20457
11
iron chelating agent.mp. or exp iron chelating agent/
2508
12
5 or 6 or 7 or 8 or 9 or 10 or 11
33760
13
4 and 12
3489
Search strategy: quality of life data
Databases searched

The Cochrane Library

OVID MEDLINE (including MEDLINE In-process)

OVID Embase

CINAHL (EBSCO)
Date on which the search was conducted
Searches were conducted for all of the databases listed above on 10th February 2011.
Date span of the search
There were no restrictions on the time frame for searching. Databases were searched from
the commencement of the individual database up to the 10th February 2011.
Eligibility criteria
The aim of the review was to identify utility scores in patients with thalassaemia with iron
overload and without overload; disutilities associated with iron-chelation therapy; disutilities
with AEs associated with iron-chelation therapy. Non-English language studies were
excluded.
Search strategy
All the following searches were combined and inclusion/exclusion criteria applied.
The Cochrane Library, to present; Searched on 10/02/2011
ID
Search
Hits
#1
MeSH descriptor Thalassemia explode all trees
191
#2
MeSH descriptor beta-Thalassemia explode all trees
121
#3
thalass?emia
141
#4
MeSH descriptor Hemoglobinopathies explode all trees
492
#5
h?emoglobinopath*
61
#6
(#1 OR #2 OR #3 OR #4 OR #5)
566
#7
MeSH descriptor Quality of Life explode all trees
11643
#8
"short form 36" or "shortform 36" or "SF-36" or "SF36" or "SF 36"
3169
#9
"short form 12" or "shortform 12" or "SF12" or "SF-12" or "SF 12"
352
#10
"euroqol 5D" or "ED-5D" or "EQ5D" or Euroqol
764
#11
"health utility index" or HUI
2241
#12
"time trade off" or TTO
403
#13
"standard gamble" or SG
4254
#14
"quality of life"
26212
#15
MeSH descriptor Health Status explode all trees
4598
#16
"health status"
5812
#17
MeSH descriptor Health Status Indicators explode all trees
12992
#18
MeSH descriptor Health Surveys explode all trees
20168
#19
MeSH descriptor Quality-Adjusted Life Years explode all trees
2854
#20
QOL or HRQOL or WRQL or QALY or HYE
5889
#21
"quality of wellbieng index" or QWB
52
#22
"medical outcomes survey" or MOS
392
#23
"willingness to pay" or WTP
1142
#24
(#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR
#19 OR #20 OR #21 OR #22 OR #23)
56564
#25
(#6 AND #24)
83
Cochrane Reviews [25] | Other Reviews [4] | Clinical Trials [26] | Methods Studies [0] | Technology
Assessments [10] | Economic Evaluations [18] | Cochrane Groups [0]
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to Present;
Searched on 10/02/2011
#
Searches
▲
1
2
3
exp thalassemia/ or exp beta-thalassemia/
thalass?emia.mp. [mp=protocol supplementary concept, rare disease supplementary concept,
title, original title, abstract, name of substance word, subject heading word, unique identifier]
exp Hemoglobinopathies/
Results
17221
17845
32494
h?emoglobinopath*.mp. [mp=protocol supplementary concept, rare disease supplementary
4
concept, title, original title, abstract, name of substance word, subject heading word, unique
4992
identifier]
5
1 or 2 or 3 or 4
34797
(short form 36 or shortform 36 or SF-36 or SF36 or SF 36).mp. [mp=protocol supplementary
6
concept, rare disease supplementary concept, title, original title, abstract, name of substance
11011
word, subject heading word, unique identifier]
(short form 12 or shortform 12 or SF12 or SF-12 or SF 12).mp. [mp=protocol supplementary
7
concept, rare disease supplementary concept, title, original title, abstract, name of substance
1596
word, subject heading word, unique identifier]
(Euroqol 5D or EQ-5D or EQ5D or Euroqol).mp. [mp=protocol supplementary concept, rare disease
8
supplementary concept, title, original title, abstract, name of substance word, subject heading
2139
word, unique identifier]
(Health utilities index or HUI).mp. [mp=protocol supplementary concept, rare disease
9
supplementary concept, title, original title, abstract, name of substance word, subject heading
769
word, unique identifier]
(time trade off or TTO).mp. [mp=protocol supplementary concept, rare disease supplementary
10 concept, title, original title, abstract, name of substance word, subject heading word, unique
734
identifier]
(standard gamble or SG).mp. [mp=protocol supplementary concept, rare disease supplementary
11 concept, title, original title, abstract, name of substance word, subject heading word, unique
4628
identifier]
12 quality of life.mp. or *"Quality of Life"/
136574
13 health status.mp. or *Health Status/
78276
14 health status indicators.mp. or *Health Status Indicators/
15595
15 *"Activities of Daily Living"/
11506
16 *Health Surveys/ or health survey*.mp.
47233
17 *Quality-Adjusted Life Years/
1066
18 quality adjusted life year*.mp.
6411
19 *Psychometrics/ or psychometric*.mp.
50765
(QOL or HRQOL or HRQL or QALY).mp. [mp=protocol supplementary concept, rare disease
20 supplementary concept, title, original title, abstract, name of substance word, subject heading
20434
word, unique identifier]
(health* year* equivalent* or HYE*).mp. [mp=protocol supplementary concept, rare disease
21 supplementary concept, title, original title, abstract, name of substance word, subject heading
554
word, unique identifier]
22 (Quality of wellbeing index or QWB).mp. [mp=protocol supplementary concept, rare disease
136
supplementary concept, title, original title, abstract, name of substance word, subject heading
word, unique identifier]
(medical outcomes survey or MOS).mp. [mp=protocol supplementary concept, rare disease
23 supplementary concept, title, original title, abstract, name of substance word, subject heading
4047
word, unique identifier]
(willingness to pay or WTP).mp. [mp=protocol supplementary concept, rare disease
24 supplementary concept, title, original title, abstract, name of substance word, subject heading
1573
word, unique identifier]
25
6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or
24
26 5 and 25
297814
425
Embase 1980 to 2011 Week 05; Searched on 10/02/2011
#
Searches
▲
1
2
3
4
5
exp thalassemia/ or exp beta thalassemia/ or exp thalassemia major/ or exp thalassemia minor/
thalass?emia.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
title, device manufacturer, drug manufacturer]
exp HEMOGLOBINOPATHY/
h?emoglobinopath*.mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer]
1 or 2 or 3 or 4
Results
19586
21076
39949
6833
41559
(short form 36 or shortform 36 or SF-36 or SF36 or SF 36).mp. [mp=title, abstract, subject
6
headings, heading word, drug trade name, original title, device manufacturer, drug
15279
manufacturer]
(short form 12 or shortform 12 or SF12 or SF-12 or SF 12).mp. [mp=title, abstract, subject
7
headings, heading word, drug trade name, original title, device manufacturer, drug
2150
manufacturer]
8
9
(Euroqol 5D or EQ-5D or EQ5D or Euroqol).mp. [mp=title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer]
(Health utilities index or HUI).mp. [mp=title, abstract, subject headings, heading word, drug
trade name, original title, device manufacturer, drug manufacturer]
10 (time trade off or TTO).mp. [mp=title, abstract, subject headings, heading word, drug trade
2929
1626
897
name, original title, device manufacturer, drug manufacturer]
11
(standard gamble or SG).mp. [mp=title, abstract, subject headings, heading word, drug trade
name, original title, device manufacturer, drug manufacturer]
5498
12 quality of life.mp. or *"quality of life"/
196699
13 health status.mp. or *health status/
76135
14 health status indicators.mp.
262
15 activities of daily living.mp. or *daily life activity/
18708
16 *health survey/ or health survey*.mp.
127139
17 quality adjusted life years.mp. or *quality adjusted life year/
2983
18 psychometrics.mp. or *psychometry/
6461
19
20
21
22
23
(QOL or HRQOL or HRQL or QALY*).mp. [mp=title, abstract, subject headings, heading word, drug
trade name, original title, device manufacturer, drug manufacturer]
(health* year* equivalent* or HYE*).mp. [mp=title, abstract, subject headings, heading word, drug
trade name, original title, device manufacturer, drug manufacturer]
(Quality of wellbeing index or QWB).mp. [mp=title, abstract, subject headings, heading word,
drug trade name, original title, device manufacturer, drug manufacturer]
(medical outcomes survey or MOS).mp. [mp=title, abstract, subject headings, heading word, drug
trade name, original title, device manufacturer, drug manufacturer]
(willingness to pay or WTP).mp. [mp=title, abstract, subject headings, heading word, drug trade
name, original title, device manufacturer, drug manufacturer]
28189
820
152
5002
1981
24 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23
405880
25 5 and 24
895
CINAHL by EBSCO; Searched on 10/02/11
#
Query
Results
S1
MM thalassemia
583
S2
thalass?emia
217
S3
MJ hemoglobinopathies
122
S4
h?emoglobinopathy
34
S5
S1 or S2 or S3 or S4
763
S6
MJ short form 36
26
S7
"short form 36" or "shortform 36" or "SF-36" or "SF36" or "SF 36"
6558
S8
"short form 12" or "shortform 12" or "SF12" or "SF-12" or "SF 12"
592
S9
"euroqol 5D" or "ED-5D" or "EQ5D" or Euroqol
625
S10
"health utility index" or HUI
169
S11
"time trade off" or TTO
124
S12
"standard gamble" or SG
354
S13
MJ quality of life
17644
S14
"quality of life"
49390
S15
MJ health status
12015
S16
MJ health status indicators
1518
S17
MJ activities of daily living
3830
S18
MJ quality-adjusted life years
95
S19
QOL or HRQOL or HRQL or QALY or HYE
5568
S20
"quality of wellbieng index" or QWB
43
S21
"medical outcomes survey" or MOS
531
S22
"willingness to pay" or WTP
360
S23
(S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16
or S17 or S18 or S19 or S20 or S21 or S22)
67284
S24
(S5 and S23)
30
References
1.
2.
3.
4.
5.
6.
7.
Berdoukas V, Chouliaras G, Moraitis P, Zannikos K, Berdoussi E, Ladis V. The efficacy of iron
chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a
clinical observational study. J Cardiovasc Magn Reson. 2009;11:20.
Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et
al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with
thalassemia major. Blood. 2006 May 1;107(9):3733-7.
Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, et al. A phase 3 study of
deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia.
Blood. 2006 1;107 (9):3455-62.
Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, et al. The safety and
effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol.
2002 Jul;118(1):330-6.
Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term
therapy with the oral iron chelator deferiprone. Blood. 2003 Sep 1;102(5):1583-7.
Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F. Safety profile of the oral iron
chelator deferiprone: a multicentre study. Br J Haematol. 2000 Feb;108(2):305-12.
Cohen AR, Glimm E, Porter JB. Effect of transfusional iron intake on response to chelation
therapy in beta-thalassemia major. Blood. 2008 15;111 (2):583-7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
El Alfy M, Sari TT, Lee CL, Tricta F, El-Beshlawy A. The safety, tolerability, and efficacy of a
liquid formulation of deferiprone in young children with transfusional iron overload. J
Pediatr Hematol Oncol. 2010 Nov;32(8):601-5.
Galanello R, Kattamis A, Piga A, Fischer R, Leoni G, Ladis V, et al. A prospective randomized
controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the
treatment of iron overload in patients with thalassemia. Haematologica. 2006
Sep;91(9):1241-3.
Ladis V, Chouliaras G, Berdoukas V, Moraitis P, Zannikos K, Berdoussi E, et al. Relation of
chelation regimes to cardiac mortality and morbidity in patients with thalassaemia major: an
observational study from a large Greek Unit. Eur J Haematol. 2010 Oct;85(4):335-44.
Maggio A, D'Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, et al. Deferiprone versus
deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol
Dis. 2002 Mar-Apr;28(2):196-208.
Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, et al. Improving survival
with deferiprone treatment in patients with thalassemia major: a prospective multicenter
randomised clinical trial under the auspices of the Italian Society for Thalassemia and
Hemoglobinopathies. Blood Cells Mol Dis. 2009 May-Jun;42(3):247-51.
Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, et al. Long-term sequential
deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a
randomized clinical trial. Br J Haematol. 2009 Apr;145(2):245-54.
Modell B, Letsky EA, Flynn DM. Survival and desferrioxamine in thalassaemia major. British
Medical Journal. 1982;284 (6322):1081-4.
Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, et al.
Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: A randomised,
double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003 10;361 (9369):1597602.
Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A, et al. Randomized
controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with
asymptomatic myocardial siderosis. Blood. 2006 May 1;107(9):3738-44.
Pepe A, Meloni A, Capra M, Cianciulli P, Prossomariti L, Malaventura C, et al. Deferasirox,
deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and
function comparison determined by quantitative magnetic resonance imaging.
Haematologica. 2011 Jan;96(1):41-7.
Piga A, Gaglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and deferoxamine
on survival and cardiac disease in patients with thalassemia major: a retrospective analysis.
Haematologica. 2003 May;88(5):489-96.
Piga A, Galanello R, Forni GL, Cappellini MD, Origa R, Zappu A, et al. Randomized phase II
trial of deferasirox (Exjade*, ICL670), a once-daily, orally-administered iron chelator, in
comparison to deferoxamine in thalassemia patients with transfusional iron overload.
Haematologica. 2006 July;91 (7):873-80.
Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, et al. A randomized,
placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine
and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic
resonance. Circulation. 2007 Apr 10;115(14):1876-84.
Cohen A, Galanello R, Piga A, Vullo C, Tricta F. A multi-center safety trial of the oral iron
chelator deferiprone. Ann N Y Acad Sci. 1998 Jun 30;850:223-6.
Shashaty G, Frankewich R, Chakraborti T, Choudary J, Al-Fayoumi S, Kacuba A, et al.
Deferasirox for the treatment of chronic iron overload in transfusional hemosiderosis.
Oncology (Williston Park, N.Y.). 2006 Dec;20 (14):1799-806, 811; discussion 811-813, 817.