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Management of Thalassemia Iron chela-

tion therapy, Bisphosphonates and Zinc


supplementation i

Guideline Panel Members


Saudi Expert Panel
Prof. Abdulkareem Almomen
Prof. Soad Al-Jaouni
Dr. Abdullah Al-Jefri
Dr. Mustafa Al Kalaf
Dr. Fawaz Abdulaziz Al-Kasim
Dr. Hussein Al-Saeed
Dr. Ahmed Al-Suliman
Dr. Fahad Al Tamimi
Dr. Azzah Al-Zahrani

McMaster University Working Group


Claudia Bollig, MSc, Joerg J Meerpohl, MD, Elie A Akl, MD PhD, Jan L Broek, MD PhD, and
Holger J Schnemann, MD PhD, on behalf of the McMaster Guideline Working Group

Acknowledgements
We acknowledge Mrs. Haya Al-Mazyad and Dr. Tarek Owaidah for their contribution to this
work.

We gratefully acknowledge Dr Yasser Sami Amer, from King Saud University for
peer reviewing this final report.

Disclosure of potential conflict of interest:

Dr. Al-Jefri declares to have received speaker honoraria from Novartis. Dr. Al-Saeed declares
to have received speaker honoraria from Novartis and Apotex. Other co-authors have no
conflict of interest to declare.

Funding:
This clinical practice guideline was funded by the Ministry of Health, Kingdom of Saudi Ara-
bia.

Address for correspondence:


Saudi Center for Evidence Based Health Care
E-mail: ebhc@moh.gov.sa
Web: http://www.moh.gov.sa/endepts/Proofs/Pages/home.aspx
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation ii

Contents
The Saudi Center for Evidence Based Health Care (EBHC) .................................................................... iii
Executive Summary................................................................................................................................. 1
Introduction ........................................................................................................................................ 1
Methodology....................................................................................................................................... 1
How to use these guidelines ............................................................................................................... 2
Key questions ...................................................................................................................................... 2
Recommendations .............................................................................................................................. 3
Scope and purpose.................................................................................................................................. 6
Introduction ............................................................................................................................................ 6
Methodology........................................................................................................................................... 7
How to use these guidelines ................................................................................................................... 8
Key questions .......................................................................................................................................... 8
Recommendations .................................................................................................................................. 8
Question 1: Should deferasirox versus deferoxamine be used for iron overload in thalassemia
patients? ............................................................................................................................................. 8
Question 2: Should deferoxamine versus deferiprone be used for iron overload in thalassemia
patients? ........................................................................................................................................... 10
Question 3: Should deferoxamine alone versus deferoxamine in combination with deferiprone be
used for iron overload in thalassemia patients? .............................................................................. 12
Question 4: Should deferoxamine in combination with deferiprone versus deferiprone alone be
used for iron overload in thalassemia patients? .............................................................................. 13
Question 5: Should bisphosphonates versus no bisphosphonates be used for management of
thalassemia-associated osteoporosis? ............................................................................................. 15
Question 6: Should zinc supplements versus no zinc supplements be used in children and
adolescents with beta thalassemia major? ...................................................................................... 16
References ............................................................................................................................................ 19
Appendices............................................................................................................................................ 22
Appendix 1: Evidence to Decision Frameworks ................................................................................ 23
Guideline Question 1: Should deferasirox versus deferoxamine be used for iron overload in
thalassemia patients? ................................................................................................................... 23
Guideline Question 2: Should deferoxamine versus deferiprone be used for iron overload in
thalassemia patients? ................................................................................................................... 34
Guideline Question 3: Should deferoxamine alone versus deferoxamine in combination with
deferiprone be used for iron overload in thalassemia patients ................................................... 45
Guideline Question 4: Should deferoxamine in combination with deferiprone versus
deferiprone alone be used for iron overload in thalassemia patients? ....................................... 55
Guideline Question 5: Should bisphosphonates versus no bisphosphonates be used for
management of thalassemia-associated osteoporosis? ............................................................... 66
Guideline Question 6: Should zinc supplements versus no zinc supplements be used in children
and adolescents with beta thalassemia major? ........................................................................... 77
Appendix 2: Search Strategies and Results ....................................................................................... 86
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation iii

The Saudi Center for Evidence Based Health Care (EBHC)

The Saudi Centre for Evidence Based Health Care has managed and supported the coordination of
the process of clinical practice guideline (CPG) development between the methodological team from
McMaster University and the local clinical expert panel members in Saudi Arabia.

The EBHC staff members recruited local clinical experts through contacting Saudi specialist societies
and also independent experts interested in developing reliable and most up-to-date CPGs to harmo-
nize the treatment and provide the highest quality of health care in the kingdom of Saudi Arabia.
These experts were health care professionals of multidisciplinary backgrounds. As much as possible,
patients representatives were also included in panels.

In an effort to make national recommendations, the participating experts were professionals from
the Ministry of Health (MoH), National Guard Hospitals, King Faisal Specialist Hospital and Research
Centre (KFSHRC), University Hospitals, Security Forces Hospitals, Prince Sultan Military Medical City
(PSMMC) and from some private hospitals.

Based on a preselection of available evidence syntheses, the EBHC provided a list of potential topics
to be addressed in CPGs after thorough consultations with the local stakeholders. These topics were
further discussed with the McMaster team for important selection criteria and agreed on 12 topics
for wave 2.

The guideline panel meetings were held in Riyadh on 15th-18th March 2015 where about 96 local
experts working in Saudi Arabia participated with the methodological support from 20 experts from
McMaster University and its partners from the American University of Beirut, Lebanon, and the Uni-
versity of Freiburg, Germany, in providing high quality recommendations for common and important
clinical conditions in the Kingdom.

The Saudi Centre for EBHC supports the efforts for dissemination of the CPGs by publishing online
the full reports of the CPGs, facilitates writing concise versions of the CPGs for publication in peer
reviewed medical journals, sending hard copies to hospitals and health care centers. Finally, a mo-
bile App has been introduced in KSA to facilitate the dissemination efforts of the completed practice
guidelines.

The staff members at the Saudi Centre for EBHC:


Dr Zulfa Al Rayess, Consultant Family Medicine, Head of Saudi Center for EBHC
Dr Yaser Adi, Scientific Advisor for the Saudi Centre for EBHC
Miss Nourah Al Moufarreh, Project Manager, Saudi Center for EBHC
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 1

Given the importance of this topic, the Minis-


Executive Summary try of Health of the Kingdom of Saudi Arabia
with the support of the McMaster University
Introduction working group produced practice guidelines
to assist health care providers in evidence-
Thalassemia, a group of inherited blood dis- based decision-making on management of
eases, is caused by mutations in hemoglobin thalassemia patients.
genes. Marked variable frequencies of beta-
thalassemia have been reported in different Methodology
areas and populations of the Kingdom of Saudi
Arabia (KSA).1-5 Due to a lack of a mandatory This practice guideline is a part of the larger
screening program, prevalence in the KSA is initiative of the Ministry of Health of the King-
not precisely known.6 Based on data of the dom of Saudi Arabia (KSA) to establish a pro-
National Premarital Screening Program in the gram of rigorous development of guidelines.
KSA from 2004-2009, the mean prevalence of The ultimate goals are to provide guidance for
couples testing positive for beta-thalassemia clinicians and other healthcare decision mak-
was 18.0 for carriers and 0.5 for cases per ers and reduce unnecessary variation in clini-
1000 examined persons.4 cal practice across the Kingdom.

This document focuses on iron chelation, The Saudi expert guideline panel selected the
bisphosphonates and zinc supplementation in topic of this guideline and all healthcare ques-
thalassemia patients. The guideline does not tions addressed herein using a formal prioriti-
address patients with thalassemia and co- zation process. For all selected questions we
morbidities other than thalassemia-associated updated the literature search of existing sys-
osteoporosis. The guideline has this focused tematic reviews on management of thalasse-
scope as the chosen methodological approach mia patients8-13 by searching MEDLINE, Em-
for the synthesis of evidence consisted of up- base and CENTRAL. According to the inclusion
dating existing systematic reviews. criteria of underlying systematic reviews, we
only regarded randomised controlled trials
Beta-thalassemia major, the more severe sub- (RCT). Risk of bias assessment of primary stud-
type, requires lifelong frequent red blood cell ies included in the existing systematic reviews
(RBC) transfusions. As a result of the additional was double-checked and adopted if appropri-
iron load caused by transfusions, iron chela- ate. We also conducted systematic searches
tion therapy is essential. However, iron chela- for information that was required to develop
tors, in turn, may cause zinc deficiency.7 Zinc full guidelines for the KSA, including searches
has an important influence on growth and the for information about patients values and
immune system. preferences, and costs and resource use spe-
cific to the Saudi context. Based on the sys-
While life expectancy can be increased tematic reviews we prepared summaries of
through improved transfusion programs com- available evidence supporting each recom-
bined with iron chelation therapy, several co- mendation following the GRADE (Grading of
morbidities such as osteopenia or osteoporo- Recommendations, Assessment, Development
sis may occur. Accordingly, bisphosphonates and Evaluation) approach.14 We used this
use has been suggested in thalassemia pa- information to prepare GRADE evidence-to-
tients. decision frameworks that served the guideline
panel to follow the structured consensus pro-
The objective of this document is to provide cess and transparently document all decisions
guidance for the management of patients made during the meeting (see Appendix 1).
with thalassemia living in Saudi Arabia. The guideline panel met in Riyadh on March
17 & 18, 2015 and formulated all recommen-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 2

dations during this meeting. Potential con- that we are very confident that the true effect
flicts of interests of all panel members were lies close to that of the estimate of the effect.
managed according to the World Health Or- Moderate quality evidence indicates moder-
ganization (WHO) rules.15 ate confidence, and that the true effect is
likely close to the estimate of the effect, but
As a quality measure for any practice guide- there is a possibility that it is substantially
line prior to publication, the final report have different. Low quality evidence indicates that
been externally peer reviewed by a methodo- our confidence in the effect estimate is lim-
logical expert who has not been involved in ited, and that the true effect may be substan-
this guideline development. tially different. Finally, very low quality evi-
dence indicates that the estimate of effect of
How to use these guidelines interventions is very uncertain, the true effect
is likely to be substantially different from the
The guideline working group developed and effect estimate and further research is likely
graded the recommendations and assessed to have important potential for reducing the
the quality of the supporting evidence accord- uncertainty.
ing to the GRADE approach.16 Quality of evi-
dence (confidence in the estimates of effects) The strength of recommendations is ex-
is categorized as: high, moderate, low, or very pressed as either strong (guideline panel
low based on consideration of risk of bias, recommends) or conditional (guideline
indirectness, inconsistency, imprecision and panel suggests) and has explicit implications
publication bias of the estimates as well as (see Table 1).17 Understanding the interpreta-
factors that lead to upgrading the quality of tion of these two grades is essential for saga-
the evidence. High quality evidence indicates cious clinical decision making.

Table 1: Interpretation of strong and conditional (weak) recommendations

Implications Strong recommendation Conditional (weak) recommendation


For patients Most individuals in this situation The majority of individuals in this situa-
would want the recommended tion would want the suggested course
course of action and only a small of action, but many would not.
proportion would not. Formal deci-
sion aids are not likely to be needed
to help individuals make decisions
consistent with their values and pref-
erences.
For clinicians Most individuals should receive the Recognize that different choices will be
intervention. Adherence to this rec- appropriate for individual patients and
ommendation according to the that you must help each patient arrive
guideline could be used as a quality at a management decision consistent
criterion or performance indicator. with his or her values and preferences.
Decision aids may be useful helping
individuals making decisions consistent
with their values and preferences.
For policy makers The recommendation can be adapted Policy making will require substantial
as policy in most situations debate and involvement of various
stakeholders.

Key questions
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 3

1. Should deferasirox versus deferox- Patients need to be adequately edu-


amine be used for iron overload in cated and trained for deferoxamine
thalassemia patients? administration
2. Should deferoxamine versus defer- For patients treated with deferox-
iprone be used for iron overload in amine: regular ophthalmologic exam-
thalassemia patients? ination and audiometry needs to be
3. Should deferoxamine alone versus ensured
deferoxamine in combination with de- In patients with severe iron overload
feriprone be used for iron overload in and/or significant cardiac/endocrine
thalassemia patients impairment or non-responsiveness to
4. Should deferoxamine in combination monotherapy intensified chelation
with deferiprone versus deferiprone therapy (e.g. combination therapy)
alone be used for iron overload in tha- needs to be considered
lassemia patients?
5. Should bisphosphonates versus no Recommendation 2:
bisphosphonates be used in manage-
ment of thalassemia-associated oste- For thalassemia patients with iron overload,
oporosis? the panel suggests treatment with deferox-
6. Should zinc supplements versus no amine rather than treatment with defer-
zinc supplements be used in children iprone. (conditional recommendation, very
and adolescents with beta thalasse- low quality of evidence)
mia major?
Remarks:
Recommendations Informed patient choice is of para-
mount importance
Recommendation 1: Iron overload, compliance and side ef-
fects should be monitored in patients
For thalassemia patients with iron overload, while on chelation therapy, for details
the panel suggests treatment with defer- see Regional consensus opinion
asirox rather than treatment with deferox- (Qari et al)6
amine. (conditional recommendation, low Dose of iron chelation drug needs to
quality of evidence) be tailored according to iron overload
Patients need to be adequately edu-
Remarks: cated and trained for deferoxamine
Informed patient choice is of para- administration
mount importance For patients treated with deferox-
Iron overload, compliance and side ef- amine: regular ophthalmologic exam-
fects should be monitored in patients ination and audiometry needs to be
while on chelation therapy, for details ensured
see Regional consensus opinion For patients treated with deferiprone:
(Qari et al)6 easy access to monitoring facilities
Dose of iron chelation drug needs to (e.g. FBC), in particular in remote set-
be tailored according to iron overload tings, needs to be ensured
Deferoxamine should be considered Deferiprone should be considered as
as an alternative treatment in pa- an alternative treatment in patients
tients with adverse effects of defer- with severe cardiac iron overload,
asirox treatment or non- cardiac and/or endocrine impairment,
responsiveness to deferasirox therapy adverse effects of deferoxamine
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 4

treatment or non-responsiveness to Recommendation 4:


deferoxamine
In patients with severe iron overload For thalassemia patients with iron overload,
and/or significant cardiac/endocrine the panel suggests against treatment with
impairment or non-responsiveness to deferoxamine in combination with defer-
monotherapy intensified chelation iprone rather than treatment with defer-
therapy (e.g. combination therapy) iprone alone. (conditional recommendation
needs to be considered against, very low quality of evidence)

Recommendation 3: Remarks:
Informed patient choice is of para-
For thalassemia patients with iron overload, mount importance
the panel suggests treatment with deferox- Iron overload, compliance and side ef-
amine alone rather than treatment with fects should be monitored in patients
deferoxamine in combination with defer- while on chelation therapy, for details
iprone. (conditional recommendation, very see Regional consensus opinion
low quality of evidence) (Qari et al)6
Dose of iron chelation drug needs to
Remarks: be tailored according to iron overload
Informed patient choice is of para- For patients treated with deferiprone:
mount importance easy access to monitoring facilities
Iron overload, compliance and side ef- (e.g. FBC), in particular in remote set-
fects should be monitored in patients tings, needs to be ensured
while on chelation therapy, for details For patients treated with deferox-
see Regional consensus opinion amine: regular ophthalmologic exam-
(Qari et al)6 ination and audiometry needs to be
Dose of iron chelation drug needs to ensured
be tailored according to iron overload Patients need to be adequately edu-
Patients need to be adequately edu- cated and trained for deferoxamine
cated and trained for deferoxamine administration
administration Combination therapy should be con-
For patients treated with deferox- sidered as an alternative treatment in
amine: regular ophthalmologic exam- patients with severe cardiac iron over-
ination and audiometry needs to be load, cardiac and/or endocrine im-
ensured pairment or non-responsiveness to
For patients treated with deferiprone: monotherapy
easy access to monitoring facilities
(e.g. FBC), in particular in remote set-
tings, needs to be ensured
Combination therapy should be con-
sidered as an alternative treatment in
patients with severe cardiac iron over-
load, cardiac and/or endocrine im-
pairment or non-responsiveness to
monotherapy
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 5

Recommendation 5:

For patients with thalassemia-associated


osteoporosis, the panel suggests against
treatment with bisphosphonates. (condition-
al recommendation against, very low quality
of evidence)

Remarks:

Vitamin D, calcium and bone density


should be monitored in patients with
thalassemia
Prevention and first line treatment of
thalassemia-associated osteoporosis
should be based on vitamin D and
calcium supplementation
Patients with a history of fractures
and/or proven severe osteoporosis
should be referred to an endocrinol-
ogist; jointly, a decision about treat-
ment with bisphosphonates in se-
lected patients should be made.

Recommendation 6:

For children and adolescents with thalasse-


mia major, the panel suggests zinc supple-
mentation rather than no zinc supplementa-
tion. (conditional recommendation, very low
quality of evidence)

Remarks:
Practically all patients with thalas-
semia major are receiving (or will re-
ceive) iron chelation therapy which
can interact with zinc metabolism
Serum zinc levels should be moni-
tored in patients with iron chelation
therapy
Patients with proven zinc deficiency
should receive zinc supplementation
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 6

lence of beta-thalassemia trait among neo-


Scope and purpose nates in the same area was 0.96% (8/834).1
Based on data of the National Premarital
The purpose of this document is to provide Screening Program in the KSA from 2004-
guidance about the management of thalasse- 2009, the mean prevalence of couples testing
mia patients focusing on iron chelation thera- positive for beta-thalassemia was 18.0
py, bisphosphonates and zinc supplementa- (28,235/1,572,140) for carriers and 0.5
tion. The target audience of this guideline (771/1,572,140) for cases per 1000 examined
includes both paediatric and adult haematolo- persons.4
gists in the Kingdom of Saudi Arabia (KSA).
Other health care professionals and policy This document focuses on iron chelation,
makers may also benefit from these guide- bisphosphonates and zinc supplementation in
lines. thalassemia patients. The guideline does not
address patients with thalassemia and co-
Given the importance of this topic, the Minis- morbidities other than thalassemia-associated
try of Health (MoH) of Saudi Arabia with the osteoporosis. The guideline is focused on this
support of the McMaster University working limited scope as the chosen methodological
group produced practice guidelines to assist approach for the synthesis of evidence con-
health care providers in evidence-based deci- sisted of updating existing systematic reviews.
sion-making. This practice guideline is a part
of the larger initiative of the Ministry of Beta-thalassemia major, the more severe sub-
Health of Saudi Arabia to establish a program type, is usually diagnosed in children between
of rigorous adaptation and de novo develop- 6 months and one year. Observable symptoms
ment of guidelines in the Kingdom; the ulti- are pallor, irritability, growth retardation, ab-
mate goal being to provide guidance for clini- dominal swelling, hepatosplenomegaly and
cians and other healthcare decision makers jaundice.
and reduce unnecessary variability in clinical
practice across the Kingdom. A therapy with regular red blood cell transfu-
sions is required to reach sufciently high he-
Introduction moglobin levels for adequate growth and de-
velopment in children with thalassemia major
and has a beneficial effect on life expectancy.
Thalassemia, a group of inherited blood dis- Transfusion therapy has to be commenced
eases, is caused by mutations in hemoglobin within the first years of life. But as a result of
genes. the additional iron load caused by transfusions
The worldwide birth rate for children with iron chelation therapy is essential. However,
symptomatic thalassemia is about 0.44 per iron chelators, in turn, may cause zinc defi-
1000 births18 summing up to more than ciency.7 Zinc has an important influence on
40,000 newborns per year19. Marked variable growth and the immune system.
frequencies of beta-thalassemia have been
reported in different areas and populations of While life expectancy can be increased
the Kingdom of Saudi-Arabia.1-5 The preva- through improved transfusion programs com-
lence in the KSA is not precisely known, due to bined with iron chelation therapy, several co-
a lack of a mandatory screening program.6 In morbidities such as osteopenia or osteoporosis
2004, a 3.4% (307/8918) beta-thalassemia may occur. Accordingly, bisphosphonates use
trait prevalence in premarital couples living in has been suggested in thalassemia patients.
the Al-Hassa area was observed.2 Additionally,
a screening of 6750 healthy persons in Jeddah, The objective of this document is to provide
western Saudi Arabia, showed that 316 guidance for the management of patients with
(4.69%) had beta-thalassemia trait. The preva- thalassemia living in Saudi Arabia. Given the
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 7

importance of this topic, the Ministry of lished evidence was lacking. The final step
Health of the Kingdom of Saudi Arabia with consisted of an in-person meeting of the
the methodological support of the McMaster guideline panel in Riyadh on March 17 & 18,
University working group produced practice 2015 to formulate the final recommendations.
guidelines to assist health care providers in We used the GRADE evidence-to-decision
evidence-based decision-making on manage- frameworks to follow a structured consensus
ment of thalassemia patients. process and transparently document all deci-
sions made during the meeting. Potential con-
flicts of interests of all panel members were
Methodology managed according to the World Health Or-
ganization (WHO) rules.15
To facilitate the interpretation of these guide-
lines; we briefly describe the methodology we Grading of the quality of evidence
used to develop and grade recommendations The GRADE working group defines the quality
and quality of the supporting evidence. of evidence as the extent of our confidence
that the estimate of an effect is adequate to
The Saudi expert guideline panel selected the support a particular decision or recommenda-
topic of this guideline and all healthcare ques- tion.16 We assessed the quality of evidence
tions addressed herein using a formal prioriti- using the GRADE approach.
zation process. In the case of this guideline on
management of patients with thalassemia, the Quality of evidence is classified as high,
scope and choice of questions to be addressed moderate, low, or very low based on
was limited due to the paucity of existing sys- decisions about methodological characteris-
tematic reviews evaluating management op- tics of the available evidence for a specific
tions in thalassemia patients. For the chosen health care problem. The definition of each
questions we updated the existing systematic category is as follows:
reviews on iron chelation therapy, bisphos-
phonates and zinc supplementation in the High: We are very confident that the
management of thalassemia patients8-13 by true effect lies close to that of the es-
searching MEDLINE, Embase and CENTRAL to timate of the effect.
identify new randomised controlled trials. Risk Moderate: We are moderately confi-
of bias assessment of primary studies included dent in the effect estimate: The true
in the existing systematic reviews was double- effect is likely to be close to the esti-
checked and adopted if appropriate. Where mate of the effect, but there is a pos-
possible, the meta-analyses were updated. sibility that it is substantially different.
We also conducted systematic searches for Low: Our confidence in the effect es-
information that was required to develop full timate is limited: The true effect may
guidelines for the KSA, including searches for be substantially different from the es-
information about patients values and pref- timate of the effect.
erences, and costs and resource use specific Very low: We have very little confi-
to the Saudi context (see Appendix 2). dence in the effect estimate: The true
effect is likely to be substantially dif-
Next, we developed for each question an evi- ferent from the estimate of effect.
dence profile and an evidence-to-decision
(EtD) table following the GRADE (Grading of Grading of the strength of recommendations
Recommendations, Assessment, Development The GRADE working group defines the
and Evaluation) approach and shared them strength of recommendation as the extent to
with the panel members (see Appendix 1).14,20 which we can be confident that desirable ef-
The guideline panel was invited to provide fects of an intervention outweigh undesirable
additional information, particularly when pub- effects. According to the GRADE approach, the
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 8

strength of a recommendation is either strong The reader should base dosing on product
or conditional (also known as or called weak) specific doses and factors that require dose
and has explicit implications.17 Understanding adjustments.
the interpretation of these two grades ei-
ther strong or conditional of the strength of
recommendations is essential for sagacious Key questions
clinical decision-making. (see Table 1)
The following is a list of the clinical questions
As a quality measure for any practice guide- selected by the Saudi expert panel and ad-
line prior to publication, the final report have dressed in this guideline.
been externally peer reviewed by a methodo-
logical expert who has not been involved in 1. Should deferasirox versus deferox-
this guideline development. amine be used for iron overload in
thalassemia patients?
2. Should deferoxamine versus defer-
How to use these guide- iprone be used for iron overload in
thalassemia patients?
lines 3. Should deferoxamine alone versus
deferoxamine in combination with de-
The Ministry of Health of Saudi Arabia and feriprone be used for iron overload in
McMaster University Practice Guidelines pro- thalassemia patients?
vide clinicians and their patients with a basis 4. Should deferoxamine in combination
for rational decisions about the treatment with deferiprone versus deferiprone
with iron chelators, bisphosphonates and zinc alone be used for iron overload in tha-
in thalassemia patients. Clinicians, patients, lassemia patients?
third-party payers, institutional review com- 5. Should bisphosphonates versus no
mittees, other stakeholders, or the courts bisphosphonates be used in manage-
should never view these recommendations as ment of thalassemia-associated oste-
dictates. As described in other guidelines fol- oporosis?
lowing the GRADE approach, no guideline or 6. Should zinc supplements versus no
recommendation can take into account all of zinc supplements be used in children
the often-compelling unique features of indi- and adolescents with beta thalasse-
vidual clinical circumstances. Therefore, no mia major?
one charged with evaluating clinicians actions
should attempt to apply the recommenda- While initially identified during the prioritiza-
tions from these guidelines by rote or in a tion process as potentially relevant, the ques-
blanket fashion. tion Should deferoxamine bolus injection
versus subcutaneous deferoxamine infusion be
Statements about the underlying values and used for iron overload in thalassemia patients
preferences, resources, feasibility, equity, was determined by the panel to be irrelevant
acceptability as well as other qualifying re- to the KSA setting and it is not addressed in
marks accompanying each recommendation this guideline.
are its integral parts and serve to facilitate an
accurate interpretation. They should never be
omitted when quoting or translating recom-
mendations from these guidelines if they in-
fluence the strength or direction of the rec- Recommendations
ommendation. The guideline panel did not
specify doses for medications in its recom- Question 1: Should deferasirox versus
mendations as they may differ by product. deferoxamine be used for iron overload in
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 9

thalassemia patients? 95% CI: 1.68 to 3.07; moderate quality of evi-


dence). Data from this trial reflect the dose-
Summary of Findings: response and ratio effect: at a ratio of 1:1.18
The summary of evidence is based on two deferasirox showed a significantly higher effi-
Cochrane systematic reviews by Fisher9 and cacy than deferoxamine in the subgroup of
Meerpohl10, including two randomised con- highly iron overloaded people, while deferox-
trolled trials21,22. We found two additional amine showed higher efficacy in the other
trials23,24 in the updated literature search. One three subgroups at ratios of 1:2.2, 1:3.6 and
of these trials23, published in Chinese lan- 1:5.5. In addition, the reduction in serum ferri-
guage, has not been considered in this analysis tin (g/l) at 8 and 12 months was significantly
yet. An additional trial25 was identified as part higher in the deferoxamine group (3 trials;
of an updated version of the Cochrane sys- 873 patients; MD 415.72, 95% CI: 295.07 to
tematic review by Meerpohl10. The overall 536.37; moderate quality of evidence). Data
quality of evidence for our prioritised patient- from one trial (563 patients) showed a clear
important critical outcomes was judged as dose-response effect for serum ferritin levels.
low. The search strategy for values and pref- At a ratio of less than 1:2.2 of deferasirox to
erences led to the inclusion of one study26 deferoxamine, the latter was statistically more
conducted in the Middle East. effective; equal efficacy was achieved only in
the highly iron-overloaded subgroup at a
Benefits & Harms of the Option: mean ratio of 1:1.8.
Mortality at 48 weeks and 1 year was report-
ed to be not significantly different between Values and Preferences:
treatment groups (3 trials; 844 patients; RR Given the different modes of application and
0.48, 95% CI: 0.09 to 2.63; absolute effect: 5 the differing spectrum of possible adverse
fewer patients per 1000, 95% CI: from 9 fewer effects, a variability of patients values and
to 16 more; low quality of evidence). Data preferences seems likely. Although this might
from one trial (172 patients) were unclear not be true for all patients (e.g. small children,
with regard to left ventricular ejection fraction patients experiencing adverse effects of de-
(%) at 12 months (MD -0.1, 95% CI: -1.84 to ferasirox, etc.), probably the majority of pa-
1.64; low quality of evidence). The same trial tients would prefer oral application of iron
demonstrated non-inferiority of deferasirox in chelation. This assumption is supported by a
myocardial iron removal (myocardial T2*) and study26 including iron-overloaded thalassemia
a trend for superiority which, however, was patients from the Middle-East, who had not
not statistically significant at 12 months (low achieved successful iron chelation with
quality of evidence). The evidence showed no deferoxamine and/or deferiprone (n=237)
significant difference between treatment before. Treatment with deferasirox for one
groups in the number of serious adverse year led to high compliance and satisfaction.
events at 12 months (2 trials, 773 patients; RR
0.78, 95% CI: 0.44 to 1.38; absolute effect: 13 In government insured population of thalas-
serious adverse events fewer per 1000, 95% semia patients, both treatment options are
CI: from 22 more to 32 fewer; low quality of covered, this is not the case for patients not
evidence). Compliance (% of dose taken by insured through a government plan. For these
patients) at 12 months was not significantly patients, no chelation treatment is covered,
different (1 trial, 187 patients; MD -1.4, 95% so cost considerations will influence choice of
CI: -3.75 to 0.95; low quality of evidence). treatment.

Reduction in liver iron concentration (mg Fe/g Acceptability:


dry weight) evaluated by biopsy or SQUID was Most patients would likely prefer oral applica-
significantly higher in the deferoxamine group tion.
at 12 months (1 trial; 541 patients; MD 2.37,
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 10

Feasibility: amine: regular ophthalmologic ex-


No obvious barriers to implementation were amination and audiometry needs to
identified. be ensured
In patients with severe iron overload
Resource Use: and/or significant cardiac/endocrine
We found no economic evaluation addressing impairment or non-responsiveness
the use of deferasirox versus deferoxamine in to monotherapy intensified chelation
the KSA setting. therapy (e.g. combination therapy)
needs to be considered
Balance between desirable and undesirable
consequences: Implementation Considerations:
The panel assumed based on low quality of There were no specific considerations relevant
evidence a rather close balance between de- for implementation of this recommendation.
sirable and undesirable consequences. Due to
longer half-life of deferasirox suggesting bet- Research Priorities:
ter protection against free iron and probable Ideally, further RCTs evaluating the benefits
better compliance due to oral administration, and harms of the alternatives including long-
the panel suggests treatment with defer- er-term patient-relevant outcomes should be
asirox. conducted. Also, appropriate cost-
effectiveness analyses in the KSA setting
Recommendation 1: should be considered.

For thalassemia patients with iron overload, Question 2: Should deferoxamine versus
the panel suggests treatment with defer- deferiprone be used for iron overload in tha-
asirox rather than treatment with deferox- lassemia patients?
amine. (conditional recommendation, low
quality of evidence) Summary of Findings:
The summary of evidence is based on two
Remarks: Cochrane systematic reviews by Fisher8,9, in-
Informed patient choice is of para- cluding eight randomised controlled trials 27-34.
mount importance We found no additional trials in the updated
Iron overload, compliance and side literature search. The overall quality of evi-
effects should be monitored in pa- dence based on our prioritized patient-
tients while on chelation therapy, for important critical outcomes was judged as
details see Regional consensus very low.
opinion (Qari et al)6
Dose of iron chelation drug needs to Benefits & Harms of the Option:
be tailored according to iron over- Only one trial (13 patients) reported data on
load mortality. One death occurred after 6 months
Deferoxamine should be considered in the deferiprone group which, however, was
as an alternative treatment in pa- not thought to be related to the deferiprone
tients with adverse effects of defer- treatment (very low quality of evidence). Data
asirox treatment or non- from one trial (36 patients) were unclear with
responsiveness to deferasirox thera- regard to liver fibrosis (Ishak score) at 12
py months (MD 0.1; 95% CI: -0.78 to 0.98; low
Patients need to be adequately edu- quality of evidence). Data from one trial (57
cated and trained for deferoxamine patients; very low quality of evidence) showed
administration no superiority of deferoxamine compared to
For patients treated with deferox- deferiprone for change in liver iron concentra-
tion (mg/g dry weight) using SQUID at 12
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 11

months (MD -0.61; 95% CI: -2.02 to 0.8). A ment and physicians, but many patients would
meta-analysis of five trials (307 patients; very likely prefer deferiprone due to its oral admin-
low quality of evidence) evaluated change in istration.
serum ferritin concentration (ng/ml) at 6, 12
and 24 months. It remains unclear (MD - Feasibility:
133.82; 95% CI -313.12 to 45.49) whether one No obvious barriers to implementation were
drug is superior to the alternative with regard identified.
to change of serum ferritin (ng/ml). Data from
one trial (144 patients) suggest a significantly Resource Use:
lower number of participants experiencing an We found no economic evaluation addressing
adverse event in the deferoxamine group at the use of deferoxamine versus deferiprone in
12 months (RR: 0.45; 95% CI: 0.24 to 0.84; the KSA setting. Comparing deferoxamine
absolute effect: 186 fewer participants per drug cost including administration cost to
1000, 95% CI: from 54 fewer to 257 fewer; low deferiprone drug cost, the panel supposes
quality of evidence). Data from one trial (61 that deferiprone might be cheaper. However,
patients; very low quality of evidence) were due to the need for close monitoring of possi-
unclear with regard to patient compliance (%) ble side effects in deferiprone treatment,
at 12 months (MD -1; 95% CI: -4.88 to 2.88). combined resources required for patients on
deferiprone are likely higher.
A meta-analysis of three trials (227 patients;
very low quality of evidence) suggests a signif- Balance between desirable and undesirable
icant difference in mean change from baseline consequences:
for left ventricular ejection fraction (%) at 12 The panel considered that for thalassemia
and 24 months between both groups in favour patients with iron overload, the benefit of a
of deferiprone (MD -1.56; 95% CI: -2.94 to - better safety profile and the lower overall
0.17). resource utilization using deferoxamine rather
than deferiprone probably outweighs the in-
Values and Preferences: crement of the burden of parenteral admin-
Given the different modes of application and istration and the possibly lower compliance.
the differing spectrum of possible adverse
effects, a variability of patients values and Recommendation 2:
preferences seems likely. Although, probably
the majority of patients would prefer oral For thalassemia patients with iron overload,
application of iron chelation, this might not be the panel suggests treatment with deferox-
true for all patients (e.g. small children, pa- amine rather than treatment with defer-
tients experiencing adverse effects of defer- iprone. (conditional recommendation, very
iprone, etc.). low quality of evidence)

In the government insured population of tha- Remarks:


lassemia patients, both treatment options are Informed patient choice is of para-
covered, this is not the case for patients not mount importance
insured through a government plan. For these Iron overload, compliance and side
patients, no chelation treatment is covered, effects should be monitored in pa-
so the cheaper treatment option with tients while on chelation therapy, for
deferoxamine would likely be the preferred details see Regional consensus
choice. opinion (Qari et al)6
Dose of iron chelation drug needs to
Acceptability: be tailored according to iron over-
The panels judgement was that treatment load
with deferoxamine is acceptable to govern- Patients need to be adequately edu-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 12

cated and trained for deferoxamine important critical outcomes was judged as
administration very low.
For patients treated with deferox-
amine: regular ophthalmologic ex- Benefits & Harms of the Option:
amination and audiometry needs to One patient in the combination arm died with-
be ensured in a year after one trial was ended while still
For patients treated with defer- on deferiprone (1 trial; 20 patients, very low
iprone: easy access to monitoring fa- quality of evidence). Liver damage was not
cilities (e.g. FBC), in particular in re- reported in any of the trials. Only very low
mote settings, needs to be ensured quality evidence was available for myocardial
Deferiprone should be considered as T2* (ms) at 12 months (2 trials). There are
an alternative treatment in patients unclear data for this outcome. One trial
with severe cardiac iron overload, (number of patients at end of study was not
cardiac and/or endocrine impair- clear, but 65 patients were randomised at the
ment, adverse effects of deferox- beginning) reported a significant benefit on
amine treatment or non- myocardial T2* in the combination group,
responsiveness to deferoxamine with an estimate of a 10% increase in myocar-
In patients with severe iron overload dial T2* compared with the monotherapy
and/or significant cardiac/endocrine group. Whereas, another trial (11 patients)
impairment or non-responsiveness found that the mean change in myocardial
to monotherapy intensified chelation T2* (ms) was nearly identical in the two
therapy (e.g. combination therapy) treatment groups. A clear inferiority of
needs to be considered deferoxamine alone on change in liver iron
concentration using SQUID at 12 months
Implementation Considerations: (mg/g wet weight) was not demonstrated
There were no specific considerations relevant when compared to combination treatment (1
for implementation of this recommendation. trial; 59 patients; MD 0.17; 95% CI: -0.45 to
0.11; very low quality of evidence). There was
Research Priorities: no significantly different change in serum
Ideally, further RCTs evaluating the benefits ferritin concentration (ng/ml) between both
and harms of the alternatives including long- groups at 6 and 12 months (3 trials; 107 pa-
er-term patient relevant outcomes should be tients; MD -136.86; 95% CI -469.61 to 195.89;
conducted. Also, appropriate cost- very low quality of evidence). A significantly
effectiveness analyses in the KSA setting lower number of patients experiencing ad-
should be considered. verse events at 12 months was reported in the
group treated with deferoxamine alone (2
trials; 119 patients; RR 0.33, 95% CI 0.13 to
Question 3: Should deferoxamine alone ver- 0.84; absolute effect: 170 fewer participants
sus deferoxamine in combination with defer- per 1000, 95% CI: 41 fewer to 221 fewer; low
iprone be used for iron overload in thalasse- quality of evidence).
mia patients?
The meta-analysis of two trials (118 patients)
Summary of Findings: found evidence for significantly lower left
The summary of evidence is based on two ventricular ejection fraction (%) in patients
Cochrane systematic reviews by Fisher8,9, in- treated with deferoxamine alone(MD -6.22;
cluding nine randomised controlled trials27- 95% CI -8.12 to -4.32; very low quality of evi-
30,35-39
. We found one additional trial40 in the dence) when compared to the combination
updated literature search. The overall quality therapy group at 12 months.
of evidence based on our prioritized patient-
Values and Preferences:
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 13

In government insured population of thalas- amine alone rather than treatment with
semia patients, monotherapy and combina- deferoxamine in combination with defer-
tion are covered, this is not the case for pa- iprone. (conditional recommendation, very
tients not insured through a government plan. low quality of evidence)
For these patients, no chelation treatment is
covered, so the cheaper treatment option Remarks:
with deferoxamine alone would likely be the Informed patient choice is of para-
preferred choice. mount importance
Iron overload, compliance and side
Acceptability: effects should be monitored in pa-
The panels judgement was that many pa- tients while on chelation therapy, for
tients would likely prefer monotherapy. Addi- details see Regional consensus
tionally, combination therapy requires more opinion (Qari et al)6
resources. Dose of iron chelation drug needs to
be tailored according to iron over-
Feasibility: load
No obvious barriers to implementation were Patients need to be adequately edu-
identified. cated and trained for deferoxamine
administration
Resource Use: For patients treated with deferox-
We found no economic evaluation addressing amine: regular ophthalmologic ex-
the use of deferoxamine alone versus amination and audiometry needs to
deferoxamine in combination with defer- be ensured
iprone in the KSA setting. However, the panel For patients treated with defer-
supposes that combination therapy requires iprone: easy access to monitoring fa-
more resources than monotherapy. cilities (e.g. FBC), in particular in re-
mote settings, needs to be ensured
Balance between desirable and undesirable Combination therapy should be con-
consequences: sidered as an alternative treatment
The panel considered that for thalassemia in patients with severe cardiac iron
patients with iron overload, the desirable overload, cardiac and/or endocrine
consequences (i.e. the lower overall resource impairment or non-responsiveness
utilization, better safety profile, more conven- to monotherapy
ient application and possibly higher compli-
ance using deferoxamine alone rather than Implementation Considerations:
deferoxamine in combination with defer- There were no specific considerations relevant
iprone) probably outweigh the undesirable for implementation of this recommendation.
consequences in most settings.
Research Priorities:
Ideally, further RCTs evaluating the benefits
and harms of the alternatives including long-
er-term patient-relevant outcomes should be
conducted. Also, appropriate cost-
effectiveness analyses in the KSA setting
should be considered.
Question 4: Should deferoxamine in combi-
Recommendation 3: nation with deferiprone versus deferiprone
alone be used for iron overload in thalasse-
For thalassemia patients with iron overload, mia patients?
the panel suggests treatment with deferox-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 14

concentration (ng/ml) at 6 and 12 months was


Summary of Findings: evident in the data (3 trials; 193 patients; MD
The summary of evidence is based on two -219.25; 95% CI: -468.87 to 30.36; very low
Cochrane systematic reviews by Fisher8,9, in- quality of evidence). Lastly, no significant dif-
cluding five randomised controlled trials27- ference in risk for leucopenia, neutropenia
29,41,42
. We found no additional trials in the and/or agranulocytosis was found (3 trials;
updated literature search. The overall quality 217 patients; RR 1.41; 95% CI: 0.76 to 2.61;
of evidence based on our prioritized patient- absolute effect: 54 more cases per 1000; 95%
important critical outcomes was judged as CI: 32 fewer to 213 more; very low quality of
very low. evidence).

Benefits & Harms of the Option: Values and Preferences:


Mortality was reported in two trials (237 pa- In government insured population of thalas-
tients; very low quality of evidence). One trial semia patients, monotherapy and combina-
(duration: 12 months) reported that one par- tion are covered, this is not the case for pa-
ticipant, randomised to combination therapy, tients not insured through a government plan.
died at the beginning of the trial due to ar- For these patients, no chelation treatment is
rhythmia-induced congestive heart failure. covered, so the cheaper treatment option
The other trial reported one death in 5 years, with deferiprone alone would likely be the
due to arrhythmia in the group treated with preferred choice.
combination therapy. The same trial also re-
ported five further deaths in patients who Acceptability:
were relocated to treatment with deferox- The panels judgement was that many pa-
amine alone due to adverse events of the tients would likely prefer monotherapy. Addi-
treatment they were initially randomised to; tionally, combination therapy requires more
these patients died 11 to 60 months after resources.
withdrawal of the randomised treatment. A
higher or lower left ventricular ejection frac- Feasibility:
tion (%) in the combination therapy group was No obvious barriers to implementation were
not clearly evident when compared to mono- identified.
therapy at 12 months (1 trial; 20 patients, MD
5.2; 95% CI: -1.99 to 12.39; very low quality of Resource Use:
evidence). The liver fibrosis Ishak score did not We found no economic evaluation addressing
change significantly in either treatment arm at the use of deferoxamine in combination with
12 months (1 trial; 20 patients; very low quali- deferiprone versus deferiprone alone in the
ty of evidence; only graphic presentation of KSA setting. The panel, however, supposes
data). A benefit or harm of combination ther- that a combination therapy requires more
apy compared to deferiprone alone on liver resources than a monotherapy.
iron concentration (mg/g dry weight) at 12
months could not be demonstrated clearly (1 Balance between desirable and undesirable
trial; 33 patients; MD -1; 95% CI -3.42 to 1.42; consequences:
very low quality of evidence). Myocardial T2* The panel considered that for thalassemia
was reported by one trial (54 patients; very patients with iron overload, the undesirable
low quality of evidence), but calculating the consequences (i.e. the burden of administra-
mean change was not possible, due to varia- tion, possibly lower compliance, higher re-
ble durations of follow up. However, the trial source utilization and worse safety profile)
reported no significant differential T2* signals using deferoxamine in combination with de-
of the heart between both groups. No clear feriprone rather than deferiprone alone prob-
benefit or harm of combination therapy com- ably outweigh the desirable consequences in
pared to deferiprone alone on serum ferritin most settings.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 15

conducted. Also, appropriate cost-


Recommendation 4: effectiveness analyses in the KSA setting
should be considered.
For thalassemia patients with iron overload,
the panel suggests against treatment with
deferoxamine in combination with defer- Question 5: Should bisphosphonates versus
iprone rather than treatment with defer- no bisphosphonates be used for manage-
iprone alone. (conditional recommendation ment of thalassemia-associated osteoporo-
against, very low quality of evidence) sis?

Remarks: Summary of Findings:


Informed patient choice is of para- The summary of evidence is based on two
mount importance systematic reviews11,12 including five random-
Iron overload, compliance and side ised controlled trials43-47. The follow-up48 after
effects should be monitored in pa- cross-over of one trial47 was not considered.
tients while on chelation therapy, We found no additional trial in the updated
for details see Regional consensus literature search. The overall quality of evi-
opinion (Qari et al)6 dence based on our prioritized patient-
Dose of iron chelation drug needs important critical outcomes was judged as
to be tailored according to iron very low.
overload
For patients treated with defer- Benefits & Harms of the Option:
iprone: easy access to monitoring Comparing bisphosphonates to no bisphos-
facilities (e.g. FBC), in particular in phonates the estimate for the difference in
remote settings, needs to be en- number of participants experiencing at least
sured one vertebral or non-vertebral fracture at 12
For patients treated with deferox- and 24 months was very imprecise (3 trials,
amine: regular ophthalmologic ex- 207 patients; RR 0.31, 95% CI: 0.01 to 6.85;
amination and audiometry needs to absolute effect: 7 fewer patients per 1000,
be ensured 95% CI: from 10 fewer to 60 more; very low
Patients need to be adequately ed- quality of evidence). Two trials (184 patients)
ucated and trained for deferox- reported only narratively on back or bone pain
amine administration at 12 months (low quality of evidence). In the
Combination therapy should be first trial, patients treated with zoledronic acid
considered as an alternative treat- showed a high reduction of pain scores,
ment in patients with severe cardiac whereas patients in the control group showed
iron overload, cardiac and/or endo- no change during the study period. In the
crine impairment or non- other trial, mean back pain scale score was
responsiveness to monotherapy also significantly improved in patients treated
with neridronate. Regarding flu-like symptoms
Implementation Considerations: after a first infusion of neridronate 100mg,
For this recommendation against a combina- the evidence did not preclude a lower or
tion therapy, implementation considerations higher incidence of symptoms compared to no
are not considered to be relevant by the panel bisphosphonate treatment (one trial, 118
members. patients; RR 8.27, 95% CI: 0.44 to 156.70; low
Research Priorities: quality of evidence). A significantly higher
Ideally, further RCTs evaluating the benefits lumbar spine bone mineral density (g/cm) in
and harms of the alternatives including long- patients treated with bisphosphonates using
er-term patient-relevant outcomes should be DXA at 12 and 24 months was reported (3
trials, 191 patients MD 0.03, 95% CI: 0.02 to
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 16

0.05; low quality of evidence). A significantly consequences (i.e. burden of administration,


higher femoral neck bone mineral density resource utilization, possible side-effects)
(g/cm) using DXA at 12 or 24 months was using bisphosphonates rather than using no
seen under treatment with bisphosphonates bisphosphonates probably outweigh the de-
(3 trials, 191 patients; MD 0.05 , 95% CI: 0.02 sirable consequences given unclear health
to 0.08; low quality of evidence). benefits.

A significantly higher number of patients with Recommendation 5:


fever after first infusion zoledronic acid 4 mg
was observed compared to placebo group (2 For patients with thalassemia-associated
trials, 89 patients; RR 10.72, 95% CI: 1.49 to osteoporosis, the panel suggests against
76.96; low quality of evidence). treatment with bisphosphonates. (condi-
tional recommendation against, very low
Values and Preferences: quality of evidence)
No published evidence with regard to the
considered outcomes was identified. Howev- Remarks:
er, panel members assumed some variability Vitamin D, calcium and bone densi-
in values within the KSA thalassemia popula- ty should be monitored in patients
tion with regard to the considered outcomes. with thalassemia
Treatment with bisphosphonates is covered in Prevention and first line treatment
government insured thalassemia patients with of thalassemia-associated osteopo-
osteoporosis. This is not the case for patients rosis should be based on vitamin D
not insured through a government plan; and calcium supplementation
therefore health inequities might be in- Patients with a history of fractures
creased. and/or proven severe osteoporosis
should be referred to an endocri-
Acceptability: nologist; jointly, a decision about
For more severely affected thalassemia pa- treatment with bisphosphonates in
tients (e.g. pain, fractures) acceptability seems selected patients should be made
likely. As prophylactic measure, given the ad-
verse effects and potential costs for non- Implementation Considerations and Monitor-
government insured people, acceptability will ing:
likely vary. Standardized criteria for the use of bisphos-
phonates in high-risk patients should be es-
Feasibility: tablished and its application monitored. Moni-
No obvious barriers to implementation were toring of benefits and adverse effects in pa-
identified. tients treated with bisphosphonates should be
established.
Resource Use:
We found no economic evaluation addressing Research Priorities:
the use of bisphosphonates versus no Ideally, further RCTs evaluating the benefits
bisphosphonates in the KSA setting. Specific and harms of the alternatives and of bisphos-
cost data for various bisphosphonate drugs phonates compared to exercises or Vitamin D
and respective doses were not available at the + calcium including longer-term patient-
meeting, but were judged to be moderate. relevant outcomes should be conducted. Also,
appropriate cost-effectiveness analyses in the
Balance between desirable and undesirable KSA setting should be considered.
consequences:
The panel considered that for thalassemia
patients with osteoporosis, the undesirable Question 6: Should zinc supplements versus
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 17

no zinc supplements be used in children and er, panel members assumed some variability
adolescents with beta thalassemia major? in values within the KSA thalassemia popula-
tion with regard to the considered outcomes,
Summary of Findings: in particular given the prophylactic nature of
The summary of evidence is based on a this intervention.
Cochrane systematic review by Swe13, includ- Cost of zinc supplements are likely low, but
ing two randomised controlled trials49,50. We limited access to measurement and monitor-
found two additional randomised controlled ing of zinc levels might increase health inequi-
trials51,52 in the updated literature search. The ties.
overall quality of evidence based on our prior-
itized patient-important critical outcomes was Acceptability:
judged as very low. Treatment with zinc supplements was as-
sumed to be acceptable for government and
Benefits & Harms of the Option: physicians due to no/little side effects and low
Benefit of zinc supplements on height (cm or cost. However, it might well be that some
z-score) at 9 months, 18 months and 1-7 years patient subgroups in the KSA setting will deem
could not be demonstrated by a meta-analysis this prophylactic intervention rather unac-
of three trials (124 patients; SMD - 0.11 , 95% ceptable given the unclear benefits.
CI: -0.47 to 0.25; very low quality of evidence).
No significantly higher or lower body mass Feasibility:
index (kg/m) at 3 months was observed (1 No obvious barriers to implementation identi-
trial; 60 patients; MD 0.6, 95%CI: -0.65 to fied.
1.85; low quality of evidence). Data from two
trials were unclear with regard to bodyweight Resource Use:
(kg or z-score) at 9 and 18 months (92 pa- We found no economic evaluation addressing
tients; SMD 0.22, 95% CI: -0.19 to 0.63; low the use of zinc versus no zinc in the KSA set-
quality of evidence). Three trials reported ting.
adverse events (138 patients, very low quality Costs are likely to be low. Monitoring zinc
of evidence). One trial did not observe signifi- uptake is not available at all medical centers in
cant differences in adverse events including the KSA, therefore additional resources in
diarrhea, stomach upset and nausea at 18 these cases are required.
months. The second trial reported that no
visible side effects were observed at 1-7 years. Balance between desirable and undesirable
The third trial mentioned gastrointestinal dis- consequences:
turbances in 1-8% of the study population at 9 Due to very low quality of evidence for bene-
months. Two studies reported serum zinc fits of zinc supplementation, relevance of
levels (g/dl). In one trial (60 patients), the health benefits is somewhat uncertain. How-
use of 220 mg zincsulfate led to a higher se- ever, due to no relevant side effects, feasible
rum zinc at 3 months (MD 47.30, 95% CI: implementation, moderate to small resource
16.16 to 78.44) compared to no treatment use and prevention of zinc deficiency, the
with zinc supplements, while dispensing 30 panel suggests offering this option in children
mg zincsulfate showed no difference (60 pa- and adolescents with thalassemia major.
tients, MD 0.60, 95% CI: -12.83 to 14.03) in
the other trial at 9 months (low quality of
evidence). No trial reported haemoglobin Recommendation 6:
levels.
For children and adolescents with thalasse-
Values and Preferences: mia major, the panel suggests zinc supple-
No published evidence with regard to the mentation rather than no zinc supplementa-
considered outcomes was identified. Howev- tion. (conditional recommendation, very
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 18

low quality of evidence) There were no specific considerations relevant


for implementation of this recommendation.
Remarks:
Practically all patients with thalas- Research Priorities:
semia major are receiving (or will Ideally, further RCTs evaluating the benefits
receive) iron chelation therapy and harms of zinc supplementation stratified
which can interact with zinc metab- by baseline zinc levels including longer-term
olism patient-relevant outcomes and research of
Serum zinc levels should be moni- prevalence in zinc deficiency should be con-
tored in patients with iron chelation ducted. Also, appropriate cost-effectiveness
therapy analyses in the KSA setting should be consid-
Patients with proven zinc deficiency ered.
should receive zinc supplementation

Implementation considerations and Monitor-


ing:
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 19

References
1. Al Jaouni S. Prevalence of thalassemia disorders and hemoglobinopathies in Jeddah, western
Saudi Arabia. Journal of Applied Hematology 2010;1:43-6.
2. Al-Suliman A. Prevalence of beta-thalassemia trait in premarital screening in Al-Hassa, Saudi
Arabia. Ann Saudi Med 2006;26:14-6.
3. El-Hazmi MA, Warsy AS. Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia. East
Mediterr Health J 1999;5:1147-53.
4. Memish ZA, Owaidah TM, Saeedi MY. Marked regional variations in the prevalence of sickle
cell disease and beta-thalassemia in Saudi Arabia: findings from the premarital screening and genetic
counseling program. J Epidemiol Glob Health 2011;1:61-8.
5. Alhamdan NA, Almazrou YY, Alswaidi FM, Choudhry AJ. Premarital screening for thalassemia
and sickle cell disease in Saudi Arabia. Genet Med 2007;9:372-7.
6. Qari MH, Wali Y, Albagshi MH, et al. Regional consensus opinion for the management of
Beta thalassemia major in the Arabian Gulf area. Orphanet J Rare Dis 2013;8:143.
7. Erdogan E, Canatan D, Ormeci AR, Vural H, Aylak F. The effects of chelators on zinc levels in
patients with thalassemia major. Journal of trace elements in medicine and biology : organ of the
Society for Minerals and Trace Elements (GMS) 2013;27:109-11.
8. Fisher SA, Brunskill SJ, Doree C, Chowdhury O, Gooding S, Roberts DJ. Oral deferiprone for
iron chelation in people with thalassaemia. Cochrane Database Syst Rev 2013;8:Cd004839.
9. Fisher SA, Brunskill SJ, Doree C, Gooding S, Chowdhury O, Roberts DJ. Desferrioxamine
mesylate for managing transfusional iron overload in people with transfusion-dependent
thalassaemia. Cochrane Database Syst Rev 2013;8:Cd004450.
10. Meerpohl JJ, Antes G, Rucker G, et al. Deferasirox for managing iron overload in people with
thalassaemia. Cochrane Database Syst Rev 2012;2:Cd007476.
11. Giusti A. Bisphosphonates in the management of thalassemia-associated osteoporosis: a
systematic review of randomised controlled trials. J Bone Miner Metab 2014;32:606-15.
12. Mamtani M, Kulkarni H. Bone recovery after zoledronate therapy in thalassemia-induced
osteoporosis: a meta-analysis and systematic review. Osteoporos Int 2010;21:183-7.
13. Swe KM, Abas AB, Bhardwaj A, Barua A, Nair NS. Zinc supplements for treating thalassaemia
and sickle cell disease. Cochrane Database Syst Rev 2013;6:Cd009415.
14. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of
evidence and strength of recommendations. BMJ 2008;336:924-6.
15. WHO Handbook for Guideline Development. World Health Organization, 2012. (Accessed
February 7, 2014, at http://apps.who.int/iris/bitstream/10665/75146/1/9789241548441_eng.pdf.)
16. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of
evidence. J Clin Epidemiol 2011;64:401-6.
17. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to
recommendations: the significance and presentation of recommendations. J Clin Epidemiol
2013;66:719-25.
18. Angastiniotis M, Modell B. Global epidemiology of hemoglobin disorders. Annals of the New
York Academy of Sciences 1998;850:251-69.
19. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service
indicators. Bulletin of the World Health Organization 2008;86:480-7.
20. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence
profiles and summary of findings tables. J Clin Epidemiol 2011;64:383-94.
21. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily
oral iron chelator, in patients with beta-thalassemia. Blood 2006;107:3455-62.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 20

22. Piga A, Galanello R, Forni GL, 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;91:873-80.
23. Peng P, Long LL, Huang ZK, et al. Comparison of deferasirox and deferoxamine treatment in
iron-overloaded patients: Liver iron concentration determined by quantitative MRI-R2*. [Chinese].
Chinese Journal of Radiology (China)2013:55-9.
24. Pennell DJ, Porter JB, Piga A, et al. A 1-year randomized controlled trial of deferasirox vs
deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). Blood
2014;123:1447-54.
25. Molavi MA DH, Nazemi A, Evazi R, Mansoori F. Comparison of therapeutic response and
complications of oral Osveral and injection Desfereal chelating agent in patient with thalassemia
major. Asian Journal of Medical and Pharmaceutical Researches 2013;3:93-7.
26. Taher A, Al Jefri A, Elalfy MS, et al. Improved treatment satisfaction and convenience with
deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial.
Acta haematologica 2010;123:220-5.
27. Aydinok Y, Evans P, Terzi A, Cetiner N, Porter JB. Randomised Prospective Evaluation of Iron
Balance, Chelation Efficiency, Urine Excretion and NTBI Progression with Deferiprone (DFP) or
Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. ASH Annual Meeting Abstracts
2005;106:2698-.
28. El-Beshlawy A, Manz C, Naja M, et al. Iron chelation in thalassemia: combined or
monotherapy? The Egyptian experience. Ann Hematol 2008;87:545-50.
29. Gomber S, Saxena R, Madan N. Comparative efficacy of desferrioxamine, deferiprone and in
combination on iron chelation in thalassemic children. Indian Pediatr 2004;41:21-7.
30. Ha SY, Chik KW, Ling SC, et al. A randomized controlled study evaluating the safety and
efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Hemoglobin
2006;30:263-74.
31. Maggio A, D'Amico G, Morabito A, et al. Deferiprone versus deferoxamine in patients with
thalassemia major: a randomized clinical trial. Blood Cells Mol Dis 2002;28:196-208.
32. Olivieri NF, Koren G, Hermann C, et al. Comparison of oral iron chelator L1 and
desferrioxamine in iron-loaded patients. Lancet 1990;336:1275-9.
33. Olivieri NF BG. Final results of the randomized trial of deferiprone (L1) and deferoxamine
(DFO) [abstract]. Blood 1997;90:264a.
34. Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial of deferiprone or
deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood
2006;107:3738-44.
35. Abdelrazik N. Pattern of iron chelation therapy in Egyptian beta thalassemic patients:
Mansoura University Children's Hospital experience. Hematology 2007;12:577-85.
36. Galanello R, Kattamis A, Piga A, 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;91:1241-3.
37. Mourad FH, Hoffbrand AV, Sheikh-Taha M, Koussa S, Khoriaty AI, Taher A. Comparison
between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron
overloaded thalassaemia patients. Br J Haematol 2003;121:187-9.
38. Tamaddoni A RM. Comparison between deferoxamine and combined therapy with
deferoxamine and deferiprone in iron overloaded thalassemia patients. Iranian Red Crescent
Medical Journal 2010;12:655-9.
39. Tanner MA, Galanello R, Dessi C, 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;115:1876-84.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 21

40. Porter JB, Wood J, Olivieri N, et al. Treatment of heart failure in adults with thalassemia
major: response in patients randomised to deferoxamine with or without deferiprone. J Cardiovasc
Magn Reson 2013;15:38.
41. Aydinok Y, Ulger Z, Nart D, et al. A randomized controlled 1-year study of daily deferiprone
plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with
thalassemia major. Haematologica 2007;92:1599-606.
42. Maggio A, Vitrano A, Capra M, et al. Long-term sequential deferiprone-deferoxamine versus
deferiprone alone for thalassaemia major patients: a randomized clinical trial. Br J Haematol
2009;145:245-54.
43. Forni GL, Perrotta S, Giusti A, et al. Neridronate improves bone mineral density and reduces
back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2, randomized,
parallel-arm, open-label study. Br J Haematol 2012;158:274-82.
44. Gilfillan CP, Strauss BJ, Rodda CP, et al. A randomized, double-blind, placebo-controlled trial
of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia. Calcif Tissue
Int 2006;79:138-44.
45. Morabito N, Lasco A, Gaudio A, et al. Bisphosphonates in the treatment of thalassemia-
induced osteoporosis. Osteoporos Int 2002;13:644-9.
46. Pennisi P, Pizzarelli G, Spina M, Riccobene S, Fiore CE. Quantitative ultrasound of bone and
clodronate effects in thalassemia-induced osteoporosis. J Bone Miner Metab 2003;21:402-8.
47. Voskaridou E, Anagnostopoulos A, Konstantopoulos K, et al. Zoledronic acid for the
treatment of osteoporosis in patients with beta-thalassemia: results from a single-center,
randomized, placebo-controlled trial. Haematologica 2006;91:1193-202.
48. Voskaridou E, Christoulas D, Konstantinidou M, Tsiftsakis E, Alexakos P, Terpos E. Continuous
improvement of bone mineral density two years post zoledronic acid discontinuation in patients
with thalassemia-induced osteoporosis: long-term follow-up of a randomized, placebo-controlled
trial. Haematologica 2008;93:1588-90.
49. Arcasoy A, Cavdar A, Cin S, et al. Effects of zinc supplementation on linear growth in beta-
thalassemia (a new approach). Am J Hematol 1987;24:127-36.
50. Rashidi M, Aboomardani M, Rafraf M, Arefhosseini SR, Keshtkar A, Joshaghani H. Effects of
Vitamin E and Zinc Supplementation on Antioxidants in Beta thalassemia major Patients. Iran J
Pediatr 2011;21:8-14.
51. Fung EB, Kwiatkowski JL, Huang JN, Gildengorin G, King JC, Vichinsky EP. Zinc
supplementation improves bone density in patients with thalassemia: a double-blind, randomized,
placebo-controlled trial. Am J Clin Nutr 2013;98:960-71.
52. Ghahramanlu E, Banihashem A, Mirhossini NZ, et al. Effect of zinc supplementation on
serum antibody titers to heat shock protein 27 in patients with thalassemia major. Hematology
2014;19:113-9.
53. Bentley A, Gillard S, Spino M, Connelly J, Tricta F. Cost-utility analysis of deferiprone for the
treatment of beta-thalassaemia patients with chronic iron overload: a UK perspective.
Pharmacoeconomics 2013;31:807-22.
54. Scalone L, Mantovani LG, Krol M, et al. Costs, quality of life, treatment satisfaction and
compliance in patients with beta-thalassemia major undergoing iron chelation therapy: the ITHACA
study. Current medical research and opinion 2008;24:1905-17.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 22

Appendices
1. Appendix 1: Evidence-to-Decision Tables
2. Appendix 2: Search Strategies and Results
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 23

Appendix 1: Evidence to Decision Frameworks

Guideline Question 1: Should deferasirox versus deferoxamine be used for iron overload in thalassemia patients?

Problem: Thalassemia patients with iron overload re- Background and Objective: Deferoxamine, the standard iron chelating drug, is linked to poor compliance when adminis-
quire treatment with iron chelators tered subcutaneously over 8-12 h/day by continuous infusions using a battery-operated portable pump. Oral chelation
Option: Deferasirox therapy with deferasirox is suggested to be at least similarly effective, leading to increased patient compliance due to the
more convenient application.
Comparison: Deferoxamine
Setting: KSA
Perspective: Clinical or health system
Criteria Judgements Research evidence Additional considerations

No "The incidence of beta-thalassemia in Arabian Gulf countries is not exactly known due
to lack of mandatory screening programs."6
Probably no
In 2004, a 3.4% (307/8918) beta-thalassemia trait prevalence in premarital couples
Is there a Uncertain living in the Al-Hassa area was observed.2
Problem problem pri-
ority?
Probably yes A screening of 6750 healthy persons in Jeddah, western Saudi Arabia, showed that
316 (4.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait
Yes among neonates in the same area was 0.96% (8/834).1

Varies

The relative importance or values of the main outcomes of interest: Long term experience with defer-
No included asirox is limited.
Relative Certainty of the
What is the studies Outcome Given the different modes of ap-
Benefits & importance evidence (GRADE)
harms of the
overall cer- Very low plication and the differing spec-
trum of possible adverse effects, a
tainty of this
options
evidence? Low Mortality at 48 weeks and 1 year CRITICAL
LOW
variability of patients values and
preferences seems likely. Alt-
hough this might not be true for
Moderate all patients (e.g. small children,
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 24

patients experiencing adverse


High End-organ damage - Cardiac: Left ven-
effects of deferasirox, etc.), prob-
tricular ejection fraction (%) - at 12 CRITICAL ably the majority of patients
months LOW
would prefer oral application of
iron chelation. This assumption is
Important Myocardial T2* (ms) - mean change from supported by a study26 including
CRITICAL
uncertainty or baseline - at 12 months LOW iron-overloaded thalassemia pa-
variability tients from the Middle-East, who
Mean change in liver iron concentration had not achieved successful iron
Possibly im- (mg Fe/g dw) evaluated by biopsy or CRITICAL
chelation with deferoxamine
MODERATE and/or deferiprone (n=237) be-
portant uncer- SQUID - at 12 months fore. Treatment with deferasirox
Is there im- tainty or variabil- for one year led to high compli-
portant un- ity Mean change in serum ferritin (g/l) - at ance and satisfaction.
certainty IMPORTANT
about how Probably no 8 and 12 months MODERATE

much people important uncer-



value the tainty of variabil- Any serious adverse event - at 12 months IMPORTANT
LOW
main out- ity
comes?
No important Compliance (% of dose taken by pa-
IMPORTANT

uncertainty of tients) - at 12 months LOW
variability

No known Summary of findings: Deferasirox compared to deferoxamine for iron overload in


thalassemia patients
undesirable
Relative
effect
With Difference
No Outcome
deferoxamine
With deferasirox
(95% CI)
(RR)
(95%
Probably no CI)

Are the desir- Uncertain Mortality at


5 fewer per
RR 0.48
able antici- 5 per 1000 1000 (from
pated effects Probably yes 48 weeks and 10 per 1000
1 year
(1 to 26) 9 fewer to
(0.09 to
2.63)
large? 16 more)
Yes
End-organ Left ventricular Left ventricular ejec- MD 0.1
Varies damage - ejection fraction tion fraction (%) at lower
-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 25

No Cardiac: Left (%) at 12 months 12 months in the (1.84 lower


ventricular in the control intervention group to 1.64
Probably no ejection frac- group was 66.4 was 0.1 lower (1.84 higher)
tion (%) - at lower to 1.64 higher)
Are the unde- Uncertain 12 months
sirable antici-
pated effects Probably yes "In the per-protocol population, Gmean (coefficient of variance)
small? myocardial T2* improved after 1 year of treatment with deferasirox
Yes by 12 % (11.2 [32.6] ms at baseline to 12.6 [42.6] ms at EOS) and
Varies Myocardial
T2* (ms)-
by 7% for DFO (11.6 [30.7] ms to 12.3 [34.7] ms). The ratio of the
Gmeans of deferasirox over DFO was 1.056 (repeated 95% CI 0.998,
mean change 1.133). Because the lower bound of the 95% CI was greater than
from baseline prespecified margin of 0.9, noninferiority of deferasirox compared
- at 12 with DFO for myocardial iron removal was demonstrated. A trend for
months superiority of deferasirox compared with DFO was observed, alt-
hough this did not reach statistical significance. An analysis of the
intention-to-treat population showed similar results to the per-
protocol population" (Pennell 2014)

No The range for Change in LIC (mg


change in LIC (mg Fe/g dw) (evaluated
Probably no Mean change
Fe/g dw) (evaluat- by biopsy or SQUID at
Are the desir- ed by biopsy or 12 months) in the
able effects Uncertain in liver iron
concentration
SQUID at 12 intervention group MD 2.37
large relative months) in the was 2.37 higher (1.68 higher
to undesira-
Probably yes (mg Fe/g dw)
control group was higher to 3.07 high- (1.68 higher -
evaluated by
-6.4-0.5 er), i.e. reduction in to 3.07
ble effects? Yes biopsy or
LIC was 2.37 lower higher)
SQUID - at
Varies 12 months
(3.07 lower to 1.68
lower), i.e. reduction
was higher in
deferoxamine group

Mean change The range for Change in serum MD 415.72


in serum change in serum ferritin (g/l) (at 8 higher
-
ferritin (g/l) ferritin (g/l) (at 8 and 12 months) in the (295.07
at 8 and 12 and 12 months) in intervention group higher to
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 26

months the control group was 415.72 higher 536.37


was -1277-211 (295.07 higher to higher)
536.37 higher), i.e.
reduction in serum
ferritin was 415.72
lower (536.37 lower
to 295.07 lower), i.e.
reduction was higher
in deferoxamine
group

13 fewer
Any serious
per 1000 RR 0.78
adverse 45 per 1000
58 per 1000 (from 22 (0.44 to
event-at 12 (25 to 80)
more to 32 1.38)
months
fewer)

Compliance (% of Compliance (% of
Compliance dose taken by dose taken by pa- MD 1.4
(% of dose patients) at 12 tients) at 12 months lower
taken by months in the in the intervention (3.75 lower -
patients) - at control group was group was 1.4 lower to 0.95
12 months 100.4 (3.75 lower to 0.95 higher)
higher)

No research evidence specific to KSA setting identified. No specific data on costs of defer-
No asirox or deferoxamine in KSA
Probably no setting found. A cost-utility analy-
sis of deferasirox for the treat-

Are the re- Uncertain ment of beta-thalassemia patients


with chronic iron overload esti-
Resource use sources re-
quired small?
Probably yes mates 23,179 pounds per year
treatment with deferasirox
Yes (Exjade) versus 8,025 pounds
per one-year treatment with ge-
Varies neric deferoxamine including
administration cost.53
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 27

Competitors provide a cheaper


alternative to Exjade in KSA.

No research evidence specific to KSA setting identified.


No
Probably no
Is the incre-
mental cost Uncertain
small relative
to the net
Probably yes
benefits? Yes
Varies

No research evidence specific to KSA setting identified. In government insured population


Increased of thalassemia patients, both
Probably in- treatment options are covered,
this is not the case for patients
creased not insured through a government
What would Uncertain plan. For these patients, no chela-
be the impact tion treatment is covered, so cost
Equity
on health Probably re- considerations will influence
inequities? duced choice of treatment.

Reduced
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 28

No research evidence specific to KSA setting identified. Most patients would likely prefer
One study (Taher 2010)26 was identified, including iron-overloaded thalassemia pa- oral application.
No tients from Saudi-Arabia, but also other patients from the Middle East, who had not
Probably no achieved successful iron chelation with DFO and/or deferiprone (n=237). Treated with
deferasirox for one year, 98.3% patients still received deferasirox (persistence). Over-
Is the option Uncertain all (mean (SD)) compliance was 98.4 (4.6) %. 86.1% received at least 95% of their
acceptable to scheduled doses. On a 5-point scale (ranging from "very satisfied" or "very conven-
Acceptability
key stake- Probably yes ient" to "very dissatisfied" or "very inconvenient") 90,7% of all patients reported being
holders? either "satisfied" or "very satisfied" with their iron chelation therapy versus 23.2% at
Yes baseline. 92.8% at end of study versus 21.5% at baseline considered their therapy to
be "convenient/very convenient". Time lost to therapy for daily activities was reduced
Varies (30.1 (44.2) (mean (SD) h/month) at baseline to (3.2 (8.6) h/month at end of study).

No research evidence specific to KSA setting identified. No obvious barriers to implemen-


No tation were identified.
Probably no
Is the option Uncertain
Feasibility feasible to
implement?
Probably yes
Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 29

Recommendation
Should deferasirox vs. deferoxamine be used for iron overload in thalassemia patients?
Desirable consequenc-
Undesirable consequences Undesirable consequences The balance between desir- Desirable consequences
es clearly outweigh
Balance of clearly outweigh desirable probably outweigh desirable able and undesirable conse- probably outweigh undesir-
undesirable conse-
consequences consequences in most set- consequences in most set- quences is closely balanced able consequences in most
quences in most set-
tings tings or uncertain settings
tings


Type of We recommend against offering this We suggest not offering this We suggest offering this
We recommend offering this option
recommendation option option option


For thalassemia patients with iron overload, the panel suggests treatment with deferasirox rather than treatment with deferoxamine (conditional
Recommendation
recommendation, low quality of evidence).

This recommendation is conditional mainly due to uncertain and assumed close balance based on low quality of evidence. Due to longer half-life
Justification of deferasirox suggesting better protection against free iron and probable better compliance due to oral administration, the panel suggests
treatment with deferasirox.

Deferoxamine should be considered as an alternative treatment in patients with adverse effects of deferasirox treatment or non-responsiveness
Subgroup considera- to deferasirox therapy.
tions In patients with severe iron overload and/or significant cardiac/endocrine impairment or non-responsiveness to monotherapy intensified chela-
tion therapy (e.g. combination therapy) needs to be considered.

Implementation
No specific considerations relevant for implementation of this recommendation.
considerations

Informed patient choice is of paramount importance.


Iron overload, compliance and side effects should be monitored in patients while on chelation therapy, for details see Regional consensus opin-
Monitoring and eval- ion (Qari et al)6.
uation Dose of iron chelation drug needs to be tailored according to iron overload.
For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured.
Patients need to be adequately educated and trained for deferoxamine administration.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 30

Ideally, further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conducted.
Research possibilities
Also, appropriate cost-effectiveness analyses in the KSA setting should be considered.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 31

Evidence Profile: Question 1: Should deferasirox versus deferoxamine be used for iron overload in thalassemia patients?

Quality assessment of patients Effect

Relative Quality Importance


of Study Risk of Other consid- Absolute
Inconsistency Indirectness Imprecision deferasirox deferoxamine (95%
studies design bias erations (95% CI)
CI)

Mortality at 48 weeks and 1 year


1 2
3 randomised serious not serious not serious serious none 2/440 4/404 (1.0%) RR 0.48 5 fewer per 1000 (from 9 fewer to 16 more) CRITICAL
trials (0.5%) (0.09 to LOW
2.63)

End-organ damage - Cardiac: Left ventricular ejection fraction (%) - at 12 months


3 4
1 randomised serious not serious not serious serious none 91 81 - MD 0.1 lower CRITICAL
trial (1.84 lower to 1.64 higher) LOW

Myocardial T2* (ms)-mean change from baseline - at 12 months


3 4
1 randomised serious not serious not serious serious none 91 81 "In the per-protocol population, Gmean (coefficient of CRITICAL
trial variance) myocardial T2* improved after 1 year of treat- LOW
ment with deferasirox by 12 % (11.2 [32.6] ms at base-
line to 12.6 [42.6] ms at EOS) and by 7% for DFO
(11.6[30.7] ms to 12.3 [34.7] ms). The ratio of the
Gmeans of deferasirox over DFO was 1.056 (repeated
95% CI 0.998, 1.133). Because the lower bound of the
95% CI was greater than prespecified margin of 0.9,
noninferiority of deferasirox compared with DFO for
myocardial iron removal was demonstrated. A trend for
superiority of deferasirox compared with DFO was ob-
served, although this did not reach statistical signifi-
cance. An analysis of the intention-to-treat population
showed similar results to the per-protocol population"
(Pennell 2014)

Mean change in liver iron concentration (mg Fe/g dw) evaluated by biopsy or SQUID - at 12 months
5 6 7
1 randomised serious serious not serious not serious dose response 268 273 - MD 2.37 higher CRITICAL
trial gradient (1.68 higher to 3.07 higher) MODERATE
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 32

Mean change in serum ferritin (g/l) at 8 and 12 months


8 9 10
3 randomised serious serious not serious not serious dose response 443 430 - MD 415.72 higher IMPORTANT
trials gradient (295.07 higher to 536.37 higher) MODERATE

Any serious adverse event - at 12 months


11 2
2 randomised serious not serious not serious serious none 18/392 22/381 (5.8%) RR 0.78 13 fewer per 1000 (from 22 more to 32 fewer) IMPORTANT
trials (4.6%) (0.44 to LOW
1.38)

Compliance (% of dose taken by patients) - at 12 months


3 4
1 randomised serious not serious not serious serious none 96 91 - MD 1.4 lower IMPORTANT
trial (3.75 lower to 0.95 higher) LOW

MD mean difference, RR relative risk, SD standard deviation

1. High risk of bias due to lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (3 studies), incomplete outcome data (1
study); Unclear: Random sequence generation (2 studies), allocation concealment (2 studies), incomplete outcome data (1 study), selective reporting (2 studies)
2. Very wide confidence interval including both clinically relevant benefit as well as harm
3. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment; Unclear: Random sequence generation
4. Only few patients were included in study
5. An additional study (Pennell 2014), including smaller study population, measured LIC (mg Fe/g dw) by MRI; a significant decrease with deferoxamine compared to
deferasirox was shown. Another study (Piga 2006) reported average decreases of similar magnitudes measured by SQUID; no SD mentioned
6. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment; Unclear: Random sequence generation, allocation
concealment, incomplete outcome data, selective reporting
7. I=91%, p<0.000001; Heterogeneity due to different ratio of drugs between subgroups
8. An additional study (Piga 2006) reported that "mean serum ferritin levels remained stable in the deferasirox 20 mg/kg/d and DFO groups, whereas there was a
tendency for ferritin values to increase modestly over time in patients randomised to deferasirox 10 mg/kg/day"
9. High risk of bias due to lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (3 studies), incomplete outcome data (1
study), selective reporting (1 study); Unclear: Random sequence generation (3 studies), allocation concealment (2 studies), incomplete outcome data (2 studies),
selective reporting (1 study)
10. I=84%, p<0.00001; heterogeneity due to different ratio of drugs between subgroups
11. High risk of bias due to lack of blinding of participants and personnel (2 studies), lack of blinding of outcome assessment (2 studies), incomplete outcome data (1
study); Unclear: Random sequence generation (2 studies), allocation concealment (1 study), incomplete outcome data (1 study), selective reporting (1 study)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 33

References
1. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood
2006;107:3455-62.
2. Piga A, Galanello R, Forni GL, 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;91:873-80.
3. Pennell DJ, Porter JB, Piga A, et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major
(CORDELIA). Blood 2014;123:1447-54.
4. Molavi MA DH, Nazemi A, Evazi R, Mansoori F. Comparison of therapeutic response and complications of oral Osveral and injection Desfereal chelating agent in
patient with thalassemia major. Asian Journal of Medical and Pharmaceutical Researches 2013;3:93-7.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 34

Guideline Question 2: Should deferoxamine versus deferiprone be used for iron overload in thalassemia patients?

Problem: Thalassemia patients with iron overload Background and Objective: Deferoxamine, the standard iron-chelating drug, is linked to poor compliance when
require treatment with iron chelators administered subcutaneously over 8-12 h/day by continuous infusions using a battery-operated portable pump.
Option: Deferoxamine Oral chelation therapy with deferiprone is suggested to be at least similarly effective, leading to increased patient
compliance due to the more convenient application.
Comparison: Deferiprone
Setting: KSA
Perspective: Clinical or health system
Criteria Judgements Research evidence Additional considerations

"The incidence of beta-thalassemia in Arabian Gulf countries is not exactly known due
No to lack of mandatory screening programs. 6
Probably no
In 2004, a 3.4% (307/8918) beta-thalassemia trait prevalence in premarital couples
Uncertain living in the Al-Hassa area was observed.2
Is there a
Problem problem prior- Probably A screening of 6750 healthy persons in Jeddah, western Saudi Arabia, showed that
ity? yes
316 (4.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait
Yes among neonates in the same area was 0.96% (8/834).1

Varies

The relative importance or values of the main outcomes of interest: Given the different modes of
No included application and the differing
What is the Certainty of the
studies Relative spectrum of possible adverse
Benefits & Outcome evidence
overall cer-
harms of the
tainty of this Very low importance
(GRADE)
effects, a variability of patients
values and preferences seems
options
evidence?
Low likely. Although, probably the
Mortality CRITICAL majority of patients would pre-
Moderate VERY LOW
fer oral application of iron che-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 35

lation, this might not be true for


High End organ damage - Cardiac: Left ventricular
all patients (e.g. small children,
ejection fraction: mean change from baseline CRITICAL
VERY LOW patients experiencing adverse
(%) - at 12 and 24 months
effects of deferiprone, etc.).
End organ damage - Liver: Liver fibrosis Ishak
Important score (ranging from 0-6; 0 indicating no fibro- CRITICAL

sis): mean at endpoint - at 12 months LOW
uncertainty or
variability
Liver iron concentration: mean change from
Possibly
baseline (mg/g dry weight) using SQUID - at CRITICAL
12 months VERY LOW
important
uncertainty or
Is there im- variability Serum ferritin concentration: mean change
IMPORTANT
portant uncer- from baseline (ng/ml) - at 6, 12 and 24 months VERY LOW
tainty about
Probably no
how much important Adverse events - Number of participants expe-
IMPORTANT
people value uncertainty of riencing an adverse event at 12 months LOW
the main out- variability
comes?

No im- Participant compliance (%) - at 12 months IMPORTANT

portant uncer- VERY LOW
tainty of vari-
ability Summary of findings: Deferoxamine compared to deferiprone for iron overload in
No known thalassemia patients

undesirable Relative
effect
With Difference
Outcome With deferoxamine (RR)
deferiprone (95% CI)
(95%
No CI)

Are the desir-


able antici- Probably no "Only one trial reported mortality as an outcome (Ha 2006). One
death occured in the deferiprone treatment arm after six months
pated effects
large?
Uncertain Mortality of treatment; this death was attributed to cardiac complications
and thought not to be related to deferiprone treatment" (Fisher
Probably 2013)
yes
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 36

Yes End organ dam- The range for Left ventricular ejec-
age - Cardiac: left ventricular tion fraction ( mean
Varies Left ventricular ejection fraction change from baseline
ejection frac- (mean change (%) at 12 and 24
MD 1.56
tion: mean from baseline months) in the inter-
lower
change from (%) at 12 and vention group was
(2.94 lower -
No baseline (%) - 24 months) in 1.56 lower (2.94 lower
to 0.17
at 12 and 24 the control to 0.17 lower), i.e.
lower)
Probably no months group was 0 - increase in left ven-
8.5 tricular ejection frac-
Are the unde- Uncertain tion was higher in
deferiprone group
sirable antici-
pated effects
Probably
yes End organ dam- Liver fibrosis Liver fibrosis Ishak
small?
age - Liver: Ishak score score (ranging from 0-
Yes Liver fibrosis (ranging from 6; 0 indicating no
MD 0.1
Ishak score 0-6; 0 indicat- fibrosis: mean at
Varies (ranging from 0 ing no fibrosis: endpoint at 12
higher
(0.78 lower -
6; 0 indicating mean at end- months) in the inter-
to 0.98
no fibrosis): point at 12 vention group was 0.1
higher)
mean at end- months) in the higher (0.78 lower to
point - at 12 control group 0.98 higher)
No months was 2.1

Probably no Liver iron con- Liver iron con- Liver iron concentra-
centration: centration ( tion (mean change
Are the desir- Uncertain mean change mean change from baseline (mg/g
able effects
from baseline from baseline dry weight) using
large relative Probably (mg/g dry (mg/g dry SQUID at 12 months)
MD 0.61
to undesirable lower
yes weight) using weight) using in the intervention
effects? (2.02 lower -
Yes SQUID - at 12
months
SQUID at 12
months) in the
group was 0.61 lower
(2.02 lower to 0.8
to 0.8
higher)
Varies control group higher), i.e. reduction
was -0.93 in LIC was 0.61 higher
(2.02 lower to 0.8
higher
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 37

Serum ferritin The range for Serum ferritin concen-


concentration: serum ferritin tration (mean change
mean change concentration ( from baseline (ng/ml)
from baseline mean change at 6, 12 and 24
MD 133.82
(ng/ml) - at 6, from baseline months) in the inter-
lower
12 and 24 (ng/ml) at 6, 12 vention group was
(313.12
months and 24 months) 133.82 lower (313.12 -
lower to
in the control lower to 45.49 high-
45.49 high-
group was - er), i.e. reduction in
er)
398.4-749.75 serum ferritin concen-
tration was 133.82
higher (45.49 lower to
313.12 higher)

Adverse events
186 fewer
- Number of
per 1000 RR 0.45
participants 152 per 1000
338 per 1000 (from 54 (0.24 to
experiencing an (81 to 284)
fewer to 0.84)
adverse event
257 fewer)
at 12 months

Participant Participant Participant compliance MD 1 low-


compliance (%) compliance (%) (%) at 12 months in er
- at 12 months at 12 months in the intervention group (4.88 lower -
the control was 1 lower (4.88 to 2.88
group was 94 lower to 2.88 higher) higher)

No research evidence specific to KSA setting identified. No specific data on costs of


No deferoxamine or deferiprone in

Are the re-


Probably no KSA setting available. A cost-
utility analysis of deferiprone
Resource use sources re- Uncertain for the treatment of beta-
quired small? thalassemia patients with
Probably chronic iron overload estimates
yes 5,519 pounds per year treat-
ment with deferiprone (Fer-
Yes riprox) versus 8,025 pounds
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 38

per one-year treatment with


Varies generic deferoxamine including
administration cost.53

In a study in Italy, total cost of


deferoxamine treatment was
estimated at 793 Euro per
month including administration
cost. Cost of treatment with
deferiprone was 480 Euro per
month.54

Comparing deferoxamine drug


cost including administration
cost to deferiprone drug cost,
the panel supposes that defer-
iprone might be cheaper. How-
ever, due to the need for close
monitoring of possible side
effects in deferiprone treat-
ment, combined resources
required for patients on defer-
iprone are likely higher.

No research evidence specific to KSA setting identified. Based on very low quality of
No evidence no clear benefits of
Probably no one option over the other sug-
gested. Due to testing and
Is the incre-
mental cost Uncertain monitoring of side effects in
patients treated with defer-
small relative
to the net
Probably iprone, incremental cost of
yes deferoxamine are smaller.
benefits?
Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 39

No research evidence specific to KSA setting identified. In government insured popula-


Increased tion of thalassemia patients,
Probably both treatment options are
covered, this is not the case for
increased
patients not insured through a
What would
be the impact Uncertain government plan. For these
Equity patients, no chelation treatment
on health
inequities?
Probably is covered, so the cheaper
reduced treatment option with deferox-
amine would likely be the pre-
Reduced ferred choice.

Varies

No research evidence specific to KSA setting identified. The panels judgement was that
No treatment with deferoxamine is
Probably no acceptable to government and
physicians, but many patients
Is the option Uncertain would likely prefer deferiprone
acceptable to due to its oral administration.
Acceptability
key stake- Probably
holders? yes

Yes
Varies

No research evidence specific to KSA setting identified. No obvious barriers to imple-


No mentation were identified.
Is the option Probably no
Feasibility feasible to
implement? Uncertain
Probably
yes
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 40

Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 41

Recommendation
Should deferoxamine vs. deferiprone be used for iron overload in thalassemia patients?
Undesirable consequences Undesirable consequences Desirable consequences Desirable consequences
The balance between desirable
Balance of clearly outweigh desirable probably outweigh desirable probably outweigh undesira- clearly outweigh undesirable
and undesirable consequences
consequences consequences in most set- consequences in most set- ble consequences in most consequences in most set-
is closely balanced or uncertain
tings tings settings tings


We recommend against offering this We suggest not offering this We suggest offering this We recommend offering this op-
Type of recommendation
option option option tion


For thalassemia patients with iron overload, the panel suggests treatment with deferoxamine rather than treatment with deferiprone (condi-
Recommendation
tional recommendation, very low quality of evidence).

This recommendation is conditional mainly due to the very limited evidence of very low quality. Due to lower cost, better safety profile and
Justification
less need for monitoring, the panel suggests treatment with deferoxamine.

Deferiprone should be considered as an alternative treatment in patients with severe cardiac iron overload, cardiac and/or endocrine impair-
ment, adverse effects of deferoxamine treatment or non-responsiveness to deferoxamine.
Subgroup considerations
In patients with severe iron overload and/or significant cardiac/endocrine impairment or non-responsiveness to monotherapy intensified chela-
tion therapy (e.g. combination therapy) needs to be considered.

Implementation consid-
No specific considerations relevant for implementation of this recommendation.
erations

Informed patient choice is of paramount importance.


Iron overload, compliance and side effect should be monitored in patients while on chelation therapy, for details see Regional consensus opin-
ion (Qari et al)6.
Monitoring and evalua-
Dose of iron chelation drug needs to be tailored according to iron overload.
tion
Patients need to be adequately educated and trained for deferoxamine administration.
For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured.
For patients treated with deferiprone: easy access to monitoring facilities (e.g. FBC), in particular in remote settings, needs to be ensured.

Ideally, further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conduct-
Research possibilities
ed. Also, appropriate cost-effectiveness analyses in the KSA setting should be considered.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 42

Evidence Profile: Question 2: Should deferoxamine versus deferiprone be used for iron overload in thalassemia patients?

Quality assessment of patients Effect

Relative Quality Importance


of Study Risk of Other consid- Absolute
Inconsistency Indirectness Imprecision deferoxamine deferiprone (95%
studies design bias erations (95% CI)
CI)

Mortality
1
1 randomised serious not serious not serious very seri- none 0/7 (0.0%) 1/6 (16.7%) "Only one trial reported mortality as an outcome (Ha CRITICAL
trial ous 2 2006). One death occured in the deferiprone treatment VERY LOW
arm after six months of treatment; this death was at-
tributed to cardiac complications and thought not to be
related to deferiprone treatment" (Fisher 2013)

End organ damage - Cardiac: Left ventricular ejection fraction: mean change from baseline (%) - at 12 and 24 months
3 4 5 6
3 randomised serious serious not serious serious none 114 113 - MD 1.56 lower CRITICAL
7
trials (2.94 lower to 0.17 lower) VERY LOW

End organ damage - Liver: Liver fibrosis Ishak score (ranging from 0-6; 0 indicating no fibrosis): mean at endpoint - at 12 months

1 randomised not not serious not serious very seri- none 15 21 - MD 0.1 higher CRITICAL
trial serious ous 2 (0.78 lower to 0.98 higher) LOW

Liver iron concentration: mean change from baseline (mg/g dry weight) using SQUID - at 12 months
89 10
1 randomised serious not serious not serious very seri- none 30 27 - MD 0.61 lower CRITICAL
trial ous 2 (2.02 lower to 0.8 higher) VERY LOW

Serum ferritin concentration: mean change from baseline (ng/ml) - at 6, 12 and 24 months
11 12 13 6
5 randomised serious serious not serious serious none 155 152 - MD 133.82 lower IMPORTANT
trials (313.12 lower to 45.49 higher) VERY LOW

Adverse events - Number of participants experiencing an adverse event at 12 months


14 6
1 randomised serious not serious not serious serious none 11/73 (15.1%) 24/71 RR 0.45 186 fewer per 1000 (from 54 fewer to 257 IMPORTANT
trial (33.8%) (0.24 to fewer) LOW
0.84)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 43

Participant compliance (%) - at 12 months


15 16
1 randomised serious not serious not serious very seri- none 32 29 - MD 1 lower IMPORTANT
trial ous 2 (4.88 lower to 2.88 higher) VERY LOW

MD mean difference, RR relative risk, SD standard deviation

1. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment, selective reporting, other bias (trial was stopped early due to
an unexpected sudden death); Unclear: Allocation concealment
2. Only very few patients were included in study/studies
3. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" between treatment arms; no specific values were reported
4. High risk of bias due to lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (2 studies), incomplete outcome data (1 study), se-
lective reporting (1 study); Unclear: Random sequence generation (2 studies), allocation concealment (2 studies), other bias (1 study)
5. Point estimates differ substantially, high I-value (77%), p=0.01; No clear clinical differences between the trials were identified which could account for this heterogeneity
6. Only few patients were included in study/studies
7. Using random-effects model, MD was not significant anymore
8. Four additional trials reported change from baseline in liver iron concentration (El-Beshlawy 2008, Ha 2006, Maggio 2002, Olivieri 1997), using different methods of meas-
urement; liver iron concentration decreased from baseline to the end of the trial in both treatment groups in two additional trials; the greatest decrease was observed in
the DFO group in El-Beshlawy 2008 and in the deferiprone group in Maggio 2002. Two other trials reported increase at the end of the trial in both treatment groups, the
increase was greatest in the deferiprone treated group in both trials, favouring DFO (Ha 2006, Olivieri 1997)
9. Three trials which reported liver iron concentrations at end of trial were analysed on a log scale due to apparent skewing data in one trial (Maggio 2002); El-Beshlawy: val-
ues of liver iron concentration in DFO treated patients were 1.5 times higher than in patients treated with deferiprone, result statistically significant; In Olivieri 1997, mean
liver iron concentration for DFO was 0.51 times that for deferiprone, result statistically significant; in a third trial (Maggio 2002), liver iron concentration in patients who re-
ceived deferiprone was 1.45 times that in patients with DFO, but result was not statistically significant
10. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment , selective reporting; Unclear: Random sequence generation,
allocation concealment
11. An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentration in both groups, with a greater decrease in the deferiprone group; no SD
mentioned
12. High risk of bias due to lack of blinding of participants and personnel (5 studies), lack of blinding of outcome assessment (4 studies), incomplete outcome data (2 studies),
selective reporting (3 studies), other bias (1 study); Unclear: Random sequence generation (3 studies), allocation concealment (4 studies), other bias (1 study)
13. Point estimates vary, I=67%, p=0.02
14. High risk of bias due to lack of blinding of participants and personnel
15. An older study (Olivieri 1997) showed a significant better compliance in deferiprone patients after 3 years
16. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment, selective reporting; Unclear: Random sequence generation,
allocation concealment
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 44

References
1. Aydinok Y, Evans P, Terzi A, Cetiner N, Porter JB. Randomised Prospective Evaluation of Iron Balance, Chelation Efficiency, Urine Excretion and NTBI Progression
with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. ASH Annual Meeting Abstracts 2005;106:2698-.
2. El-Beshlawy A, Manz C, Naja M, et al. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol 2008;87:545-50.
3. Gomber S, Saxena R, Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr
2004;41:21-7.
4. Ha SY, Chik KW, Ling SC, et al. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong
Kong. Hemoglobin 2006;30:263-74.
5. Maggio A, D'Amico G, Morabito A, et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis
2002;28:196-208.
6. Olivieri NF, Koren G, Hermann C, et al. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Lancet 1990;336:1275-9.
7. Olivieri NF BG. Final results of the randomized trial of deferiprone (L1) and deferoxamine (DFO) [abstract]. Blood 1997;90:264a.
8. Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic
myocardial siderosis. Blood 2006;107:3738-44.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 45

Guideline Question 3: Should deferoxamine alone versus deferoxamine in combination with deferiprone be used for iron overload in tha-
lassemia patients

Problem: Thalassemia patients with iron overload Background and Objective: Deferoxamine, the standard iron chelating drug is suggested to be more effective in
require treatment with iron chelators combination with deferiprone than alone.
Option: Deferoxamine alone
Comparison: Deferoxamine + Deferiprone
Setting: KSA
Perspective: Clinical or health system
Criteria Judgements Research evidence Additional considerations

"The incidence of beta-thalassemia in Arabian Gulf countries is not exactly known due to
No lack of mandatory screening programs."6

Probably no
In 2004, a 3.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living
Uncertain in the Al-Hassa area was observed.2
Is there a prob-
Problem
lem priority? Probably A screening of 6750 healthy persons in Jeddah, western Saudi Arabia, showed that 316
yes (4.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait among neo-

Yes nates in the same area was 0.96% (8/834).1

Varies

The relative importance or values of the main outcomes of interest: No data specific to thalassemia
No included patients in KSA identified.
Benefits & What is the
studies
harms of overall certainty Relative Certainty of the
the options of this evidence? Very low Outcome
importance evidence (GRADE)
The panels judgement was that
many patients would likely pre-
Low fer monotherapy
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 46

Moderate Mortality CRITICAL



VERY LOW
High
End-organ damage: Left ventricular ejection
CRITICAL
fraction: mean at endpoint (%) - at 12 months VERY LOW

Important
uncertainty or End-organ damage: Liver CRITICAL No data available
variability

Possibly Myocardial iron concentration: myocardial T2*


CRITICAL
important (ms) at 12 months VERY LOW
uncertainty or
Is there im- variability
Liver iron concentration: mean change from
portant uncer- Probably no baseline - SQUID at 12 months (mg/g wet CRITICAL

tainty about how VERY LOW
important weight)
much people
uncertainty of
value the main
variability
outcomes?
No im- Serum ferritin concentration: mean change
IMPORTANT
from baseline (ng/ml) - at 6 and 12 months VERY LOW
portant uncer-
tainty of varia-
bility
Adverse events - Number of participants expe-
IMPORTANT
No known riencing an adverse event - at 12 months LOW
undesirable
Summary of findings: Deferoxamine alone compared to deferoxamine + deferiprone for
iron overload in thalassemia patients

Are the desirable No With Relative


With Deferoxamine Difference
anticipated ef-
fects large?
Probably no Outcome Deferoxamine
and Deferiprone
alone (95% CI)
effect
(RR)
Uncertain (95%
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 47

Probably CI)
yes

Yes Mortality
"One patient in the combination arm died within a year of coming off
the study, while still on DFP" (Porter 2013)
Varies
End-organ dam- The range for left Left ventricular ejec-
age: Left ven- ventricular ejec- tion fraction (mean at
No tricular ejection tion fraction ( endpoint (%) - at 12
MD 6.22
lower
Probably no fraction: mean
at endpoint (%)
mean at endpoint
(%) - at 12
months) in the inter-
vention group was
(8.12 lower -
to 4.32
Are the undesir- Uncertain - at 12 months months) in the 6.22 lower (8.12 lower
lower)
control group was to 4.32 lower)
able anticipated
effects small?
Probably 68.4-78.04
yes

Yes End-organ
No data available
damage: Liver
Varies
Two trials reported myocardial T2* as an outcome measure at 12
months. Tanner 2007: "The between group difference in geometric
Myocardial iron
means of myocardial T2* was reported as significantly in favour of
No concentration:
the combined treatment group, with an estimate of a 10% increase
myocardial T2*
Probably no (ms) at 12
compared with the deferoxamine group (95% CI 2% to 19%,
p=0.02); Porter 2013: " At 12 months, the mean change in myocar-
months
Are the desirable Uncertain dial T2* was nearly identical in the two groups" (DFO + Deferiprone:
1.9 (1.6) ms; DFO: 1.9 (1.4) ms
effects large
relative to unde-
Probably
sirable effects? yes
Liver iron con- Liver iron concen- Liver iron concentra-
MD 0.17
Yes centration: tration: mean tion: mean change
lower
mean change change from base- from baseline - SQUID
Varies from baseline - line - SQUID at 12 at 12 months (mg/g
(0.45 lower -
to 0.11
SQUID at 12 months (mg/g wet wet weight) in the
higher)
months (mg/g weight) in the intervention group was
control group was 0.17 lower (0.45 lower
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 48

wet weight) -0.07 to 0.11 higher), i.e.


reduction in LIC was
0.17 higher (0.11
lower to 0.45 higher)

Serum ferritin The range for Serum ferritin concen-


concentration: serum ferritin tration (mean change
mean change concentration from baseline (ng/ml)
from baseline (mean change at 6 and 12 months) in MD 136.86
(ng/ml) - at 6 from baseline the intervention group lower
and 12 months (ng/ml) at 6 and was 136.86 lower (469.61
-
12 months) in the (469.61 lower to lower to
control group was 195.89 higher), i.e. 195.89
-987-28.79 reduction in serum higher)
ferritin was 136.86
higher (195.89 lower
to 469.61 higher)

Adverse events 254 per 1000 84 per 1000


170 fewer
- Number of (33 to 214)
per 1000 RR 0.33
participants
(from 41 (0.13 to
experiencing an
fewer to 0.84)
adverse event -
221 fewer)
at 12 months

No research evidence specific to KSA setting identified. No specific data on costs of


No deferoxamine alone or of com-
bination therapy in KSA setting
Resource
Are the re- Probably no available. A cost-utility analysis
sources required
for the treatment of beta-
use
small? Uncertain thalassemia patients with chron-
Probably ic iron overload estimates 8,025
pounds for treatment with ge-
yes
neric deferoxamine versus
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 49

Yes 11,939 pounds in combination


with deferiprone (Ferriprox)
Varies per one-year treatment includ-
ing administration cost in both
treatments.53

In a study in Italy, total cost of


deferoxamine treatment in
combination with deferiprone
was estimated at 963 Euro per
month including administration
cost. Cost of treatment with
deferoxamine alone was 793
Euro per month including ad-
ministration.54

The panel supposes that a com-


bination therapy requires more
resources than a monotherapy.

No research evidence specific to KSA setting identified. Based on very low quality of
No evidence no clear benefits of
Probably no one option over the other sug-
gested. However, incremental
Is the incremen- Uncertain costs of combination therapy
tal cost small are higher than for therapy with
relative to the Probably deferoxamine alone.
net benefits? yes

Yes
Varies

No research evidence specific to KSA setting identified. In government insured popula-


Equity
What would be Increased tion of thalassemia patients,
the impact on
health inequi- Probably monotherapy and combination
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 50

ties? increased are covered, this is not the case


for patients not insured through
Uncertain a government plan. For these
Probably patients, no chelation treatment
is covered, so the cheaper
reduced treatment option with deferox-
Reduced amine alone would likely be the
preferred choice.
Varies

No research evidence specific to KSA setting identified. The panels judgement was that
No many patients would likely pre-
Probably no fer monotherapy. Additionally,
combination therapy requires
Is the option Uncertain more resources.
acceptable to
Acceptability
key stakehold- Probably
ers? yes

Yes
Varies

No research evidence specific to KSA setting identified. No obvious barriers to imple-


No mentation were identified.
Probably no
Is the option Uncertain
Feasibility feasible to im-
plement?
Probably
yes

Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 51

Recommendation
Should deferoxamine alone vs. deferoxamine + deferiprone be used for iron overload in thalassemia patients?
Undesirable consequences Undesirable consequences Desirable consequences Desirable consequences
The balance between desirable
Balance of clearly outweigh desirable probably outweigh desirable probably outweigh undesira- clearly outweigh undesira-
and undesirable consequences is
consequences consequences in most set- consequences in most set- ble consequences in most ble consequences in most
closely balanced or uncertain
tings tings settings settings


Type of recommenda- We recommend against offering this We suggest not offering this We suggest offering this
We recommend offering this option
tion option option option


For thalassemia patients with iron overload, the panel suggests treatment with deferoxamine alone rather than treatment with deferoxamine in
Recommendation
combination with deferiprone (conditional recommendation, very low quality of evidence).

This recommendation is conditional mainly due to the very limited evidence of very low quality. Due to lower cost and assumed lower acceptabil-
Justification ity of combination therapy and possibly higher compliance and better safety profile with deferoxamine monotherapy, the panel suggests treat-
ment with deferoxamine alone.

Subgroup considera- Combination therapy should be considered as an alternative treatment in patients with severe cardiac iron overload, cardiac and /or endocrine
tions impairment or non-responsiveness to monotherapy.

Implementation con-
No specific considerations relevant for implementation of this recommendation.
siderations

Informed patient choice is of paramount importance.


Iron overload, compliance and side effects should be monitored in patients while on chelation therapy, for details see Regional consensus opin-
ion (Qari et al)6.
Monitoring and evalu-
Dose of iron chelation drug needs to be tailored according to iron overload.
ation
Patients need to be adequately educated and trained for deferoxamine administration.
For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured.
For patients treated with deferiprone: easy access to monitoring facilities (e.g. FBC), in particular in remote settings, needs to be ensured.

Ideally, further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conducted.
Research possibilities
Also, appropriate cost-effectiveness analyses in the KSA setting should be considered.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 52

Evidence Profile: Question 3: Should deferoxamine alone versus deferoxamine in combination with deferiprone be used for iron overload in thalas-
semia patients?

Quality assessment of patients Effect


Quality Importance
of Study Risk of Other consid- deferoxamine deferoxamine Relative Absolute
Inconsistency Indirectness Imprecision
studies design bias erations alone + deferiprone (95% CI) (95% CI)

Mortality
1
1 randomised serious not serious not serious very seri- none 9 11 "One patient in the combination arm died within CRITICAL
trial ous 2 a year of coming off the study, while still on DFP" VERY LOW
(Porter 2013)

End-organ damage: Left ventricular ejection fraction: mean at endpoint (%) - at 12 months
3 4 5 6
2 randomised serious serious not serious serious none 60 58 - MD 6.22 lower CRITICAL
7
trials (8.12 lower to 4.32 lower) VERY LOW

End-organ damage: Liver - not measured

- - - - - - - - not estimable - CRITICAL

Myocardial iron concentration: myocardial T2* (ms) at 12 months


8 9 11 11
2 randomised serious not serious not serious very seri- none 0/4 (0.0%) 0/7 (0.0%) Two trials reported myocardial T2* as an out- CRITICAL
trials ous 10 come measure at 12 months. Tanner 2007: "The VERY LOW
between group difference in geometric means of
myocardial T2* was reported as significantly in
favour of the combined treatment group, with an
estimate of a 10% increase compared with the
deferoxamine group (95% CI 2% to 19%, p=0.02);
Porter 2013: " At 12 months, the mean change in
myocardial T2* was nearly identical in the two
groups" (DFO + Deferiprone: 1.9 (1.6) ms; DFO:
1.9 (1.4) ms

Liver iron concentration: mean change from baseline - SQUID at 12 months (mg/g wet weight)
12 13
1 randomised serious not serious not serious very seri- none 30 29 - MD 0.17 lower CRITICAL
trial ous 10 (0.45 lower to 0.11 higher) VERY LOW
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 53

Serum ferritin concentration: mean change from baseline (ng/ml) - at 6 and 12 months
14 15 16 6
3 randomised serious serious not serious serious none 51 56 - MD 136.86 lower IMPORTANT
trials (469.61 lower to 195.89 VERY LOW
higher)

Adverse events - Number of participants experiencing an adverse event - at 12 months


17 18
2 randomised serious not serious not serious serious none 5/60 (8.3%) 15/59 (25.4%) RR 0.33 170 fewer per 1000 (from 41 IMPORTANT
trials (0.13 to 0.84) fewer to 221 fewer) LOW

MD mean difference, RR relative risk, SD standard deviation

1. Risk of bias: Unclear: Blinding of outcome assessment, incomplete outcome data (study was terminated due to slow patients accrual; only 11 of 20 patients completed close to 12 months of treatment)
2. Only very few cases
3. An additional trial reported "no significant difference in cardiac function" (El-Beshlawy 2008); another trial (Porter 2013) reported, that LVEF increased from 49.9% to 58.3% in combination group and
from 52.8% to 56.9% in DFO group at 12 months, SD not stated
4. High risk of bias due to lack of blinding of participants and personnel (1 study), lack of blinding of outcome assessment (1 study), selective reporting (1 study); Unclear: Random sequence generation (2
studies), allocation concealment (1 study), blinding of outcome assessment (1 study), incomplete outcome data (1 study)
5. Point estimates differ, I=89%, p=0.002; no clear clinical differences between these two trials were identified which could account for this heterogeneity
6. Only few patients included in study/studies
7. Differences remained significant under random-effects model
8. Unclear risk of bias: Random sequence generation (1 study), blinding of outcome assessment (2 studies), incomplete outcome data (2 studies)
9. Data not pooled, therefore difficult to assess. However, from narrative information no obvious inconsistency present
10. Only very few patients were included in studies
11. In one study (Tanner 2007), number of patients included in each outcome assessment was not clear, therefore no numbers could be included; 65 patients were randomised at beginning
12. An additional trial (Ha 2006) using AAS reported liver iron concentration as mean change (mg/g dry weight) at 6 months; no significant difference was measured between the treatment arms: MD=-0.13
(95%CI-8.67 to 8.41); Another study (Tanner 2007) using CMR reported a between-group difference in geometric means of 39% (95%CI 20% to 61%) in favour of combined treatment; a third trial (Porter
2013) using different methods reported a reduction from 16.1 (4.67) to 9.27 (3.61) mg/g dry wt with combination, and a reduction with DFO therapy from 5.62 (2.2) to 5.08 (3.18); a fourth trial (El-
Beshlawy 2008) reported change in liver iron concentration graphically; LIC decreased in both groups, but the difference in change between groups was not statistically significant
13. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment, selective reporting; Unclear: Random sequence generation, allocation concealment
14. Five additional trials reported reduction in serum ferritin in both treatment arms; at 12 months (Abdelrazik 2007, Mourad 2003, Tamaddoni 2010) on a log scale as ratio of geometric means due to skewed
data in Mourad 2003, pooled results showed significant difference favouring deferiprone combined with DFO; an additional trial (El-Beshlawy 2008) reported reduction in serum ferritin concentration for
both treatment arms at 12 months, no data to calculate SD was available; Tanner 2007 reported at 12 months "the between-group difference was significantly in favour of the combined treatment group
(-40%; 95% CI, -48% to -28%; P< 0.001), analysing geometric means; another trial (Porter 2013) reported serum ferritin concentrations at 12 months, serum ferritin declined from 3601 838 to 2132 646
g/L (n=7) in combination arm, in DFO monotherapy arm, serum ferritin increased from 1613 537 to 2018 898 g/L (n=4)
15. High risk of bias due to lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (3 studies), incomplete outcome data (1 study), selective reporting (3 studies),
other bias (1 study); Unclear: Random sequence generation (2 studies), allocation concealment (3 studies)
16. I=80%, p=0.008
17. High risk of bias due to lack of blinding of participants and personnel (2 studies), lack of blinding of outcome assessment (2 studies), selective reporting (2 studies); Unclear: Random sequence generation
(2 studies), allocation concealment (2 studies)
18. Only few cases
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 54

References
1. Aydinok Y, Evans P, Terzi A, Cetiner N, Porter JB. Randomised Prospective Evaluation of Iron Balance, Chelation Efficiency, Urine Excretion and NTBI Progression
with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. ASH Annual Meeting Abstracts 2005;106:2698-.
2. El-Beshlawy A, Manz C, Naja M, et al. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol 2008;87:545-50.
3. Gomber S, Saxena R, Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr
2004;41:21-7.
4. Ha SY, Chik KW, Ling SC, et al. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong
Kong. Hemoglobin 2006;30:263-74.
5. Abdelrazik N. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Hematology
2007;12:577-85.
6. Galanello R, Kattamis A, Piga A, 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;91:1241-3.
7. Mourad FH, Hoffbrand AV, Sheikh-Taha M, Koussa S, Khoriaty AI, Taher A. Comparison between desferrioxamine and combined therapy with desferrioxamine and
deferiprone in iron overloaded thalassaemia patients. Br J Haematol 2003;121:187-9.
8. Tamaddoni A RM. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. Iranian
Red Crescent Medical Journal 2010;12:655-9.
9. Tanner MA, Galanello R, Dessi C, 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;115:1876-84.
10. Porter JB, Wood J, Olivieri N, et al. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without
deferiprone. J Cardiovasc Magn Reson 2013;15:38.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 55

Guideline Question 4: Should deferoxamine in combination with deferiprone versus deferiprone alone be used for iron overload in tha-
lassemia patients?

Problem: Thalassemia patients with iron overload Background and Objective: Deferoxamine, the standard iron-chelating drug is suggested to be more effective in
require treatment with iron chelators combination with deferiprone than deferiprone alone.
Option: Deferoxamine + Deferiprone
Comparison: Deferiprone alone
Setting: KSA
Perspective: Clinical or health system
Criteria Judgements Research evidence Additional considerations

"The incidence of beta-thalassemia in Arabian Gulf countries is not exactly known due
No to lack of mandatory screening programs. 6
Probably
no In 2004, a 3.4% (307/8918) beta-thalassemia trait prevalence in premarital couples
living in the Al-Hassa area was observed.2
Is there a Uncertain
Problem problem pri-
ority?
Probably A screening of 6750 healthy persons in Jeddah, western Saudi Arabia, showed that
316 (4.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait
yes among neonates in the same area was 0.96% (8/834).1
Yes
Varies

What is the The relative importance or values of the main outcomes of interest: "Mean compliance with defer-
Benefits &
overall cer- No included iprone was reported as over
harms of the
tainty of this studies 90% in both treatment arms,
options Outcome Certainty of
Relative
evidence?
Very low the evidence whereas mean compliance with
DFO was 70.6%.42
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 56

The panels judgement was that


Low importance (GRADE)
many patients would likely pre-
Moderate fer monotherapy.

High Mortality - at 12 months and 5 years CRITICAL
VERY LOW

End organ damage - Cardiac: Left ventricular



Important ejection fraction: mean at endpoint (%) - at 12 CRITICAL
VERY LOW
months
uncertainty or
variability

Possibly End organ damage - Liver: Liver fibrosis Ishak



score (ranging from 0 to 6; 0 indicating no fibro- CRITICAL
important VERY LOW
sis) - at 12 months
Is there im- uncertainty or
portant un- variability
certainty Probably Liver iron concentration: mean at endpoint
CRITICAL

about how (mg/g dry weight) - at 12 months VERY LOW
no important
much people
uncertainty of
value the
variability
main out- Myocardial iron concentration: Myocardial T2*:
comes? No im- mean at endpoint (ms): DFO + DFP: at further
CRITICAL

portant uncer- (16(5) months; DFP: at further 14 (6) months VERY LOW
tainty of vari- (mean(SD))
ability

No known Serum ferritin concentration: mean at endpoint


IMPORTANT
undesirable (ng/ml) - at 6 and 12 months VERY LOW

Adverse Events - Risk of leucopenia, neutropenia


Are the desir- IMPORTANT
able antici- No and/or agranulocytosis VERY LOW
pated effects
large?
Probably
no
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 57

Summary of findings: Deferoxamine + deferiprone compared to deferiprone for iron


Uncertain overload in thalassemia patients
Probably
yes Relative
With effect
Yes Outcome
With
Deferiprone
Deferoxamine +
Difference
(95% CI)
(RR)
Deferiprone (95%
Varies CI)

"Mortality was reported in two trials (Aydinok 2007; Maggio


No 2009). In the first trial, one individual who was randomised to
receive deferiprone and DFO in combination, died at the start
Probably of the trial due to arrhythmia-induced congestive heart failure
no Mortality - at 12 (Aydinok 2007). One death due to arrhythmia whilst receiving
months and 5 deferiprone and DFO in combination was also reported in the
Are the unde- Uncertain years second trial (Maggio 2009). In this latter trial, a further five
sirable antici- deaths were reported in patients in whom the randomised
pated effects Probably treatment was withdrawn and treatment changed to DFO alone
small? yes due to adverse events; mortality occurred 11 to 60 months
after withdrawal of the randomised treatment." (Fisher 2013)
Yes
Varies End organ damage Left ventricular Left ventricular
- Cardiac: Left ejection fraction ejection fraction (
MD 5.2
ventricular ejec- (mean at end- mean at endpoint
higher
tion fraction: point (%) at 12 (%) at 12 months)
No mean at endpoint months) in the in the intervention
(1.99 lower
to 12.39
-

(%) - at 12 control group group was 5.2


Are the desir- Probably months was 67.4 higher (1.99 lower
higher)

able effects no to 12.39 higher)


large relative
to undesira-
Uncertain
ble effects?
Probably End organ damage
- Liver: Liver fibro-
"One trial reported liver fibrosis as an outcome, scored accord-
ing to the Ishak scoring system (Aydinok 2007). In this trial,
yes sis Ishak score results were presented graphically; the trial authors reported
Yes (ranging from 0 to that the fibrosis score "did not change significantly after one
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 58

Varies 6; 0 indicating no year in patients in any of the treatment arms" (Fisher 2013)
fibrosis) - at 12
months

Liver iron concen- Liver iron con- Liver iron concen-


tration: mean at centration tration (mean at
endpoint (mg/g (mean at end- endpoint (mg/g
MD 1 lower
dry weight) - at 12 point (mg/g dry dry weight) - at 12
(3.42 lower
months weight) at 12 months) in the -
to 1.42
months) in the intervention group
higher)
control group was 1 lower (3.42
was 7.5 lower to 1.42 high-
er)

Myocardial iron "Maggio 2009: Myocardial iron concentration was measured by


concentration: T2* MRI in a subset of patients with a mean (SD) duration
Myocardial T2*: from entry into the trial until the final MRI scan of further 16
mean at endpoint (5) months in the combined deferiprone and DFO group and
(ms): DFO + DFP: further 14 (6) months in patients receiving deferiprone alone.
at further (16(5) The difference in duration of follow up across this subset of
months; DFP: at patients prohibited calculation of the mean change in myocar-
further 14 (6) dial iron concentration; however the trial reported no signifi-
months cant differences in the T2* signals of the heart between the
(mean(SD)) two treatment groups" (Fisher 2013)

Serum ferritin The range for Serum ferritin


concentration: serum ferritin concentration MD 219.25
mean at endpoint concentration (mean at endpoint lower
(ng/ml) - at 6 and (mean at end- (ng/ml) at 6 and (468.87
-
12 months point (ng/ml) at 12 months in the lower to
6 and 12 intervention group) 30.36 high-
months) in the was 219.25 lower er)
control group (468.87 lower to
was 1633-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 59

3422.7 30.36 higher)

Adverse Events - 54 more


Risk of leucopenia, per 1000 RR 1.41
186 per 1000
neutropenia 132 per 1000 (from 32 (0.76 to
(100 to 345)
and/or agranulocy- fewer to 2.61)
tosis 213 more)

No research evidence specific to KSA setting identified. No specific data on costs of


deferiprone alone or of combina-
tion with deferoxamine in KSA
setting found. A cost-utility
analysis of deferiprone for the
treatment of beta-thalassemia

No patients with chronic iron over-


load estimates 5,519 pounds per
Probably year treatment with deferiprone
(Ferriprox) versus 11,939
no
pounds per one-year treatment
Are the re- Uncertain with generic deferoxamine in-
Resource use sources re- cluding administration cost in
quired small?
Probably combination with deferiprone
yes (Ferriprox).53

Yes In a study in Italy, total cost of


Varies deferoxamine treatment in com-
bination with deferiprone was
estimated at 963 Euro per
month including administration
cost. Cost of treatment with
deferiprone was 480 Euro per
month.54

The panel supposes that a com-


Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 60

bination therapy requires more


resources than a monotherapy.

No No research evidence specific to KSA setting identified. Based on very low quality of
evidence no clear benefits of
Probably one option over the other sug-
gested. However, incremental
no costs of combination therapy are
Is the incre-
mental cost Uncertain higher than for therapy with
deferiprone alone.
small relative
to the net
Probably
benefits? yes

Yes
Varies

No research evidence specific to KSA setting identified. In government insured popula-


Increased tion of thalassemia patients,
Probably monotherapy and combination
are covered. This is not the case
increased for patients not insured through
What would Uncertain a government plan. For these
be the impact patients, no chelation treatment
Equity
on health Probably is covered, so the cheaper
inequities? reduced treatment option with defer-
iprone alone would likely be the
Reduced preferred choice.

Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 61

No research evidence specific to KSA setting identified. The panels judgement was that
No many patients would likely pre-
Probably no fer monotherapy. Additionally,
combination therapy requires
Is the option Uncertain more resources.
acceptable to
Acceptability
key stake-
Probably
holders? yes

Yes
Varies

No research evidence specific to KSA setting identified. No obvious barriers to imple-


No mentation were identified.
Probably
no

Is the option Uncertain


Feasibility feasible to
implement?
Probably
yes

Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 62

Recommendation
Should deferoxamine in combination with deferiprone versus deferiprone alone be used for iron overload in tha-
lassemia patients?
Undesirable consequences Undesirable consequences Desirable consequences Desirable consequences
The balance between desirable
Balance of clearly outweigh desirable probably outweigh desirable probably outweigh undesira- clearly outweigh undesirable
and undesirable consequences
consequences consequences in most set- consequences in most set- ble consequences in most consequences in most set-
is closely balanced or uncertain
tings tings settings tings


Type of recommenda- We recommend against offering this We suggest not offering this We suggest offering this
We recommend offering this option
tion option option option


For thalassemia patients with iron overload, the panel suggests against treatment with deferoxamine in combination with deferiprone rather than
Recommendation
treatment with deferiprone alone (conditional recommendation against, very low quality of evidence).

This recommendation is conditional mainly due to the very limited evidence of very low quality. Due to higher cost and assumed lower acceptability
Justification of combination therapy and possibly higher compliance and better safety profile with deferiprone monotherapy, the panel suggests against treat-
ment with deferoxamine in combination with deferiprone.

Subgroup considera- Combination therapy should be considered as an alternative treatment in patients with severe cardiac iron overload, cardiac and/or endocrine im-
tions pairment or non-responsiveness to monotherapy.

Implementation con-
For this recommendation against a combination therapy, implementation considerations are not considered to be relevant by the panel members.
siderations

Informed patient choice is of paramount importance.


Iron overload, compliance and side effects should be monitored in patients while on chelation therapy, for details see Regional consensus opinion
(Qari et al)6.
Monitoring and evalu-
Dose of iron chelation drug needs to be tailored according to iron overload.
ation
For patients treated with deferiprone: easy access to monitoring facilities (e.g. FBC), in particular in remote settings, needs to be ensured.
For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured.
Patients need to be adequately educated and trained for deferoxamine administration.

Ideally, further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conducted.
Research possibilities
Also, appropriate cost-effectiveness analyses in the KSA setting should be considered.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 63

Evidence Profile: Question 4: Should deferoxamine in combination with deferiprone versus deferiprone alone be used for iron overload in thalasse-
mia patients?

Quality assessment of patients Effect

Relative Quality Importance


of Study Risk of Other consid- deferoxamine Absolute
Inconsistency Indirectness Imprecision deferiprone (95%
studies design bias erations + deferiprone (95% CI)
CI)

Mortality - at 12 months and 5 years


1 2
2 randomised serious not serious not serious very seri- none 117 120 "Mortality was reported in two trials (Aydinok 2007; CRITICAL
trials ous 3 Maggio 2009). In the first trial, one individual who was VERY LOW
randomised to receive deferiprone and DFO in combi-
nation, died at the start of the trial due to arrhythmia-
induced congestive heart failure (Aydinok 2007). One
death due to arrhythmia whilst receiving deferiprone
and DFO in combination was also reported in the
second trial (Maggio 2009). In this latter trial, a further
five deaths were reported in patients in whom the
randomised treatment was withdrawn and treatment
changed to DFO alone due to adverse events; mortali-
ty occurred 11 to 60 months after withdrawal of the
randomised treatment." (Fisher 2013)

End organ damage - Cardiac: Left ventricular ejection fraction: mean at endpoint (%) - at 12 months
4 5
1 randomised serious not serious not serious very seri- none 8 12 - MD 5.2 higher CRITICAL
trial ous 6 (1.99 lower to 12.39 higher) VERY LOW

End organ damage - Liver: Liver fibrosis Ishak score (ranging from 0 to 6; 0 indicating no fibrosis) - at 12 months
5
1 randomised serious not serious not serious very seri- none 8 12 "One trial reported liver fibrosis as an outcome, scored CRITICAL
trial ous 6 according to the Ishak scoring system (Aydinok 2007). VERY LOW
In this trial, results were presented graphically; the
trial authors reported that the fibrosis score "did not
change significantly after one year in patients in any of
the treatment arms" (Fisher 2013)

Liver iron concentration: mean at endpoint (mg/g dry weight) - at 12 months


789 10
1 randomised serious not serious not serious very seri- none 16 17 - MD 1 lower CRITICAL
trial ous 6 (3.42 lower to 1.42 higher) VERY LOW
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 64

Myocardial iron concentration: Myocardial T2*: mean at endpoint (ms): DFO + DFP: at further (16(5) months; DFP: at further 14 (6) months (mean(SD))
11
1 randomised serious not serious not serious very seri- none 34 20 "Maggio 2009: Myocardial iron concentration was CRITICAL
trial ous 6 measured by T2* MRI in a subset of patients with a VERY LOW
mean (SD) duration from entry into the trial until the
final MRI scan of further 16 (5) months in the com-
bined deferiprone and DFO group and further 14 (6)
months in patients receiving deferiprne alone. The
difference in duration of follow up across this subset
of patients prohibited calculation of the mean change
in myocardial iron concentration; however the trial
reported no significant differences in the T2* signals of
the heart between the two treatment groups" (Fisher
2013)

Serum ferritin concentration: mean at endpoint (ng/ml) - at 6 and 12 months


12 13 14
3 randomised serious not serious not serious very seri- none 100 93 - MD 219.25 lower IMPORTANT
trials ous 15 (468.87 lower to 30.36 higher) VERY LOW

Adverse Events - Risk of leucopenia, neutropenia and/or agranulocytosis


16
3 randomised serious not serious not serious very seri- none 17/96 (17.7%) 16/121 RR 1.41 54 more per 1000 (from 32 fewer to 213 IMPORTANT
trials ous 3 (13.2%) (0.76 to more) VERY LOW
2.61)

MD mean difference, RR relative risk, SD standard deviation


1. High risk of bias due to lack of allocation concealment (1 study), lack of blinding of participants and personnel (2 studies), lack of blinding of outcome assessment (1 study), incom-
plete outcome data (2 studies), selective reporting (Mortality was not pre-specified in one study), other bias (1 study); Unclear: Allocation concealment (1 study)
2. Data not pooled, therefore difficult to assess. However, from narrative information no obvious inconsistency present
3. Only very few cases
4. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function"
5. High risk of bias due to lack of allocation concealment, lack of blinding of participants and personnel, lack of blinding of outcome assessment, incomplete outcome data, selective
reporting
6. Only very few patients included in study/studies
7. Another trial (Maggio 2009) reported liver iron concentration by liver T2*; a reduction was only observed in the deferiprone group compared with an increase in combination group;
due to differences in follow up time, calculation of mean change is not possible; however the trial reported no signficant differences
8. In an additional trial liver iron concentration was measured by atomic emission spectrophotometry (Aydinok 2007); the mean LIC value did not change significantly in patients treat-
ed with DFP, but decreased significantly in patients receiving combination therapy; no SD for change reported; end of study values were not significant
9. Method used is not stated in this trial
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 65

10. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment, incomplete outcome data; Unclear: Allocation concealment, random
sequence generation
11. High risk of bias due to lack of blinding of participants and personnel, incomplete outcome data (differences in duration of follow up regarding myocardial iron concentration), other
bias; Unclear: Allocation concealment
12. An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentrations in both groups; no standard deviations are mentioned
13. Mean change in serum ferritin from baseline can be calculated from data in two trials (Gomber 2004, Maggio 2009). No statistically significant difference was observed in Gomber
2004; A reduction in serum ferritin concentration was maintained across five years of follow up in the combined treatment arm in Maggio 2009; in patients receiving deferiprone
only a reduction in mean serum ferritin concentration from baseline values was observed at two and five years; a significant difference in mean change of serum ferritin concentra-
tion in patients with combination therapy was maintained over four years of follow up; at five years, there was no significant difference in mean change of serum ferritin concentra-
tion between the two treatment arms, although number of patients was considerably reduced due to early termination of the trial
14. High risk of bias due to lack of allocation concealment (1 study), lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (2 studies), incom-
plete outcome data (3 studies), selective reporting (2 studies), other bias (1 study); Unclear: Random sequence generation (1 study), allocation concealment (2 studies),
15. Small study population and wide confindence interval
16. High risk of bias due to lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (3 studies), incomplete outcome data (3 studies), selective
reporting (1 study), other bias (1 study); Unclear: Random sequence generation (1 study), allocation concealment (2 studies)

References
1. Aydinok Y, Evans P, Terzi A, Cetiner N, Porter JB. Randomised Prospective Evaluation of Iron Balance, Chelation Efficiency, Urine Excretion and NTBI Progression
with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. ASH Annual Meeting Abstracts 2005;106:2698-.
2. El-Beshlawy A, Manz C, Naja M, et al. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol 2008;87:545-50.
3. Gomber S, Saxena R, Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr
2004;41:21-7.
4. Aydinok Y, Ulger Z, Nart D, et al. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone
monotherapy in patients with thalassemia major. Haematologica 2007;92:1599-606.
5. Maggio A, Vitrano A, Capra M, et al. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clin-
ical trial. Br J Haematol 2009;145:245-54.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 66

Guideline Question 5: Should bisphosphonates versus no bisphosphonates be used for management of thalassemia-associated osteo-
porosis?

Problem: Thalassemia patients often suffer from osteo- Background and Objective: Thalassemia patients are at higher risk to suffer from osteoporosis.
porosis Bisphosphonates are suggested to increase bone mineral density and prevent fractures in these patients.
Option: Treatment with bisphosphonates
Comparison: No treatment with bisphosphonates
Setting: KSA
Perspective: Clinical or health system

Additional
Criteria Judgements Research evidence
considerations

No "The incidence of beta-thalassemia in Arabian Gulf countries is not exactly known due to
lack of mandatory screening programs.6
Probably no
In 2004,a 3.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in
Uncertain the Al-Hassa area was observed.2

Problem
Is there a prob-
lem priority?
Probably A screening of 6750 healthy persons in Jeddah, western Saudi Arabia, showed that 316
yes (4.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait among neo-
nates in the same area was 0.96% (8/834).1
Yes
Varies

What is the The relative importance or values of the main outcomes of interest: No data specific to thalas-
Benefits &
overall certainty
No included semia patients in KSA
harms of
of this evi- studies identified.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 67

Additional
Criteria Judgements Research evidence
considerations

the options dence?


Very low Outcome
Relative Certainty of the
Panel members assumed
some variability in values
importance evidence (GRADE)
Low within the KSA thalasse-
mia population with re-
Moderate Number of participants experiencing at least gard to the considered
CRITICAL outcomes.
one vertebral fracture - at 12 and 24 months
High VERY LOW

Number of participants experiencing at least



one non-vertebral fracture - at 12 and 24 CRITICAL
Important months VERY LOW

uncertainty or
variability
Back or bone pain - at 12 months CRITICAL

LOW
Possibly
important
Is there im- uncertainty or Adverse events - Fever after first infusion
CRITICAL

portant uncer- variability zoledronic acid 4 mg LOW
tainty about
how much peo- Probably no
ple value the important Adverse events - Flu-like symptoms after first
CRITICAL
main outcomes? uncertainty of infusion neridronate 100 mg LOW
variability

No im-
portant uncer-
Lumbar spine BMD [g/cm] (DXA): mean at
IMPORTANT
endpoint - at 12 and 24 months LOW
tainty of vari-
ability

No known
undesirable
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 68

Additional
Criteria Judgements Research evidence
considerations

Femoral neck BMD [g/cm] (DXA): mean at


IMPORTANT
endpoint - at 12 and 24 months LOW

No
Summary of findings: Bisphosphonates compared to no bisphosphonates for thalassemia-
Probably no associated osteoporosis

Uncertain
Are the desira- Relative
ble anticipated Probably Without With Difference
effect
effects large? yes Outcome (RR)
bisphosphonates bisphosphonates (95% CI)
(95%
Yes CI)

Varies
Number of
participants
7 fewer per
experiencing RR 0.31
3 per 1000 1000 (from
No at least one
vertebral frac-
10 per 1000
(0 to 71) 10 fewer to
(0.01 to
6.85)
60 more)
Probably no ture - at 12
and 24 months
Uncertain
Are the undesir-
able anticipated Probably Number of
effects small? yes participants
experiencing 7 fewer per
Yes at least one
10 per 1000
3 per 1000 1000 (from
RR 0.31
(0.01 to
non-vertebral (0 to 71) 10 fewer to
Varies fracture - at 60 more)
6.85)

12 and 24
months

Are the desira-


ble effects large
No
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 69

Additional
Criteria Judgements Research evidence
considerations

relative to un-
desirable ef-
Probably no Voskaridou 2006:" At baseline patients hat mild to moderate pain ac-
cording to the pain scoring system used. There were no differences in
fects?
Uncertain pain score among the three studied groups. Patients in [intervention
group 1 and 2] had dramatic reductions of pain score after 6 and 12
Probably Back or bone months of zoledronic acid treatment. In contrast, [control group] patients
yes pain - at 12 had no change in bone pain during the study period." Forni 2012: "The
months mean back pain scale value was significantly higher (more favourable) in
Yes [intervention group] compared with [control group] [...] at 12 months
Varies (P=0.002%). A concomitant significant reduction (over 50%[intervention
group], 30% [control group]) in the use of analgesic drugs was noted
starting from the third month"

Control event rate: Experimental event No absolute


Adverse
0% (0/33) rate: 26.8% (15/26) effect esti-
events - Fever RR
mate given
after first 10.72
due to 0
infusion (1.49 to
events in
zoledronic acid 76.96)
control
4 mg
group

Adverse Control event rate: Experimental event No absolute


events - Flu- 0% (0/64) rate: 5.6% (3/54) effect esti-
like symptoms mate given RR 8.27
after first due to 0 (0.44 to
infusion neri- events in 156.70)
dronate 100 control
mg group

Lumbar spine Lumbar spine BMD Lumbar spine BMD MD 0.03 -


BMD [g/cm] ([g/cm] (DXA): ([g/cm] (DXA): mean higher
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 70

Additional
Criteria Judgements Research evidence
considerations

(DXA): mean mean at endpoint at at endpoint at 12 and (0.02 higher


at endpoint - 12 and 24 months) in 24 months) in the to 0.05
at 12 and 24 the control group was intervention group was higher)
months 0.723-0.9 0.03 higher (0.02
higher to 0.05 higher)

Femoral neck Femoral neck BMD Femoral neck BMD


BMD [g/cm] ([g/cm] (DXA): ([g/cm] (DXA): mean MD 0.05
(DXA): mean mean at endpoint at at endpoint at 12 and higher
at endpoint - 12 and 24 months) in 24 months) in the (0.02 higher -
at 12 and 24 the control group was intervention group was to 0.08
months 0.636-0.79 0.05 higher (0.02 higher)
higher to 0.08 higher)

No No research evidence specific to KSA setting identified. We found no economic


evaluation addressing the
Probably no use of bisphosphonates
versus no bisphospho-
Uncertain nates in the KSA setting.
Are the re- Specific cost data for
sources re- Probably various bisphosphonates
quired small? yes drugs and respective
Resource
doses were not available
use
Yes at the meeting, but were
judged to be moderate.
Varies

Is the incremen- No research evidence specific to KSA setting identified. Unclear, because signifi-
tal cost small No cant benefit was only
relative to the seen in surrogate out-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 71

Additional
Criteria Judgements Research evidence
considerations

net benefits?
Probably no comes. Benefits in pain
and fracture risk remain
Uncertain unclear. Observed ad-
verse events remained
Probably moderate, however no
long-term studies were
yes
identified.
Yes
Varies

Increased No research evidence specific to KSA setting identified. Treatment with bisphos-
phonates is covered in
Probably government insured tha-
lassemia patients with
increased osteoporosis. This is not
What would be Uncertain the case for patients not
the impact on insured through a gov-
Equity
health inequi- Probably ernment plan; therefore
ties? reduced health inequities might be
increased.
Reduced
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 72

Additional
Criteria Judgements Research evidence
considerations

No research evidence specific to KSA setting identified. For more severely affect-
No ed thalassemia patients
Probably no (e.g. pain, fractures)
acceptability seems likely.
Is the option Uncertain As prophylactic measure,
given the adverse effects
acceptable to
Acceptability
key stakehold-
Probably and potential costs for
ers? yes non-government insured
people, acceptability will
Yes likely vary.

Varies

No research evidence specific to KSA setting identified. No obvious barriers to


No implementation were
Probably no identified.

Is the option Uncertain


Feasibility feasible to im-
plement?
Probably yes
Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 73

Recommendation
Should bisphosphonates vs. no bisphosphonates be used for thalassemia-associated osteoporosis?
Undesirable consequences Undesirable consequences Desirable consequences Desirable consequences
The balance between desirable
Balance of clearly outweigh desirable probably outweigh desirable probably outweigh undesira- clearly outweigh undesirable
and undesirable consequences
consequences consequences in most set- consequences in most set- ble consequences in most consequences in most set-
is closely balanced or uncertain
tings tings settings tings


Type of We recommend against offering this We suggest not offering this We suggest offering this
We recommend offering this option
recommendation option option option


For patients with thalassemia-associated osteoporosis, the panel suggests against treatment with bisphosphonates (conditional recommendation
Recommendation
against, very low quality of evidence).

This recommendation against is based on very low quality of evidence. However, due to risk of side effects, additional cost, burden of administra-
Justification tion and unclear health benefits, the panel suggests no treatment with bisphosphonates in patients with thalassemia-associated osteoporosis. Pre-
vention and first line treatment of thalassemia-associated osteoporosis should be based on vitamin D and calcium supplementation

Subgroup Patients with a history of fractures and/or proven severe osteoporosis should be referred to an endocrinologist; jointly, a decision about treatment
considerations with bisphosphonates in selected patients should be made.

Implementation con- Standardized criteria for the use of bisphosphonates in high-risk patients should be established and its application monitored.
siderations Monitoring of benefits and adverse effects in patients treated with bisphosphonates should be established.

Monitoring and evalu-


Vitamin D, calcium and bone density should be monitored in patients with thalassemia.
ation

Ideally, further RCTs evaluating the benefits and harms of the alternatives and of bisphosphonates compared to exercises or Vitamin D + calcium
Research
including longer-term patient relevant outcomes should be conducted. Also, appropriate cost-effectiveness analyses in the KSA setting should be
possibilitiess
considered.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 74

Evidence Profile: Question 5: Should bisphosphonates versus no bisphosphonates be used for management of thalassemia-associated osteoporo-
sis?

Quality assessment of patients Effect

Relative Quality Importance


of Study Risk of Other consid- no bisphospho- Absolute
Inconsistency Indirectness Imprecision bisphosphonates (95%
studies design bias erations nates (95% CI)
CI)

Number of participants experiencing at least one vertebral fracture - at 12 and 24 months


12 3
3 randomised serious not serious not serious very seri- none 0/110 (0.0%) 1/97 (1.0%) RR 0.31 7 fewer per 1000 (from 10 fewer to 60 CRITICAL
trials ous 4 (0.01 to more)
6.85) VERY
LOW

Number of participants experiencing at least one non-vertebral fracture - at 12 and 24 months


12 3
3 randomised serious not serious not serious very seri- none 0/110 (0.0%) 1/97 (1.0%) RR 0.31 7 fewer per 1000 (from 10 fewer to 60 CRITICAL
trials ous 4 (0.01 to more)
6.85) VERY
LOW

Back or bone pain - at 12 months


5 6 7
2 randomised serious not serious not serious serious none 98 86 Voskaridou 2006:" At baseline patients hat mild to CRITICAL
trials moderate pain according to the pain scoring system
used. There were no differences in pain score LOW
among the three studied groups. Patients in [inter-
vention group 1 and 2] had dramatic reductions of
pain score after 6 and 12 months of zoledronic acid
treatment. In contrast, [control group] patients had
no change in bone pain during the study period."
Forni 2012: "The mean back pain scale value was
significantly higher (more favourable) in [interven-
tion group] compared with [control group] [...] at 12
months (P=0.002%). A concomitant significant
reduction (over 50%[intervention group], 30%
[control group]) in the use of analgesic drugs was
noted starting from the third month"
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 75

Adverse events - Fever after first infusion zoledronic acid 4 mg


8 9
2 randomised serious not serious not serious serious none 15/56 (26.8%) 0/33 (0.0%) RR No absolute effect estimate given due to CRITICAL
trials 10.72 0 events in control group
(1.49 to LOW
76.96)

Adverse events - Flu-like symptoms after first infusion neridronate 100 mg


10 9
1 randomised serious not serious not serious serious none 3/54 (5.6%) 0/64 (0.0%) RR 8.27 No absolute effect estimate given due to CRITICAL
trial (0.44 to 0 events in control group
156.70) LOW

Lumbar spine BMD [g/cm] (DXA): mean at endpoint - at 12 and 24 months


11 12 13 14 15
3 randomised serious not serious not serious serious none 105 86 - MD 0.03 higher IMPORTANT
trials (0.02 higher to 0.05 higher)
LOW

Femoral neck BMD [g/cm] (DXA): mean at endpoint - at 12 and 24 months


12 16 17 14 15
3 randomised serious not serious not serious serious none 105 86 - MD 0.05 higher IMPORTANT
trials (0.02 higher to 0.08 higher)
LOW

MD mean difference, RR relative risk, SD standard deviation


1. All included studies don't differentiate between vertebral and non-vertebral fractures
2. One study (Forni 2012) reported that "no fractures were observed during the study period except for the patient [intervention group], who discontinued the trial at 6 months after a
road traffic accident". We didn't count fractures as events due to unclear causation
3. High risk of bias due to lack of blinding of participants and personnel (2 studies), lack of blinding of outcome assessment (3 studies); Unclear: Random sequence generation (2 study),
allocation concealment (2 studies)
4. Only very few cases
5. High risk of bias due to lack of blinding of participants and personnel (2 studies), lack of blinding of outcome assessment (2 studies); Unclear: Random sequence generation (1 study),
allocation concealment (2 studies)
6. Data not pooled, therefore difficult to assess. However, from narrative information, no obvious inconsistency present
7. Only few patients were included in studies
8. High risk of bias due to lack of blinding of participants and personnel (1 study), lack of blinding of outcome assessment (2 studies); Unclear: Random sequence generation (1 study),
allocation concealment (1 study)
9. Only few patients were included in study/studies
10. High risk of bias due to lack of blinding of participants and personnel, lack of blinding of outcome assessment; Unclear: Allocation concealment
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 76

11. An additional study (Pennisi 2003) reported a decreased T-score from -2.71 (SD: 0.82) to -3.16 (SD: 0.88) in the control group (p< 0.01); in the intervention group BMD at lumbar
spine didn't change significantly at 12 months (p=0.65), but the difference between intervention and control group was significant at 12 months (p < 0.01); for the intervention
group, no specific values were reported
12. Two studies included two intervention groups; in Morabito 2002, both groups (clodronate 100 mg i.m., alendronate 10 mg p.o.) were included separately in our analysis; in Vos-
karidou 2006 both groups (zoledronic acid 4 mg i.v. every 3 months, zoledronic acid 4 mg i.v. every 6 months) were combined in one group (zoledronic acid 4 mg i.v. every 3 or 6
months)
13. An additional study (Gilfillan 2006) reported absolute change from baseline at 2 years; in placebo group, absolute change from baseline was 0.01; absolute change was 0.082 in pa-
tients treated with zoledronic acid; p comparing both groups was 0.008; no SD were mentioned
14. High risk of bias due to lack of blinding of participants and personnel (3 studies), lack of blinding of outcome assessment (3 studies); Unclear: Random sequence generation (2 stud-
ies), allocation concealment (3 studies)
15. Only few patients included in studies
16. An additional study (Pennisi 2003) reported a decreased T-score from -1.92 (SD: 0.74) to -2.44 (SD: 0.93) in the control group (p<0.01); in the intervention group, BMD at femoral
neck didn't change significantly at 12 months (p=0.13) but the difference between intervention group and control group was significant (p<0.01); for the intervention group, no spe-
cific values were reported
17. An additional study (Gilfillan 2006) reported absolute change in femoral neck BMD at 2 years; in placebo group, absolute change was -0.034; absolute change was 0.042 in patients
treated with zoledronic acid; p comparing both groups was <0.001; no SD were mentioned

References
1. Forni GL, Perrotta S, Giusti A, et al. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results
from a phase 2, randomized, parallel-arm, open-label study. Br J Haematol 2012;158:274-82.
2. Gilfillan CP, Strauss BJ, Rodda CP, et al. A randomized, double-blind, placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-
associated osteopenia. Calcif Tissue Int 2006;79:138-44.
3. Morabito N, Lasco A, Gaudio A, et al. Bisphosphonates in the treatment of thalassemia-induced osteoporosis. Osteoporos Int 2002;13:644-9.
4. Pennisi P, Pizzarelli G, Spina M, Riccobene S, Fiore CE. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. J Bone Miner
Metab 2003;21:402-8.
5. Voskaridou E, Anagnostopoulos A, Konstantopoulos K, et al. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a
single-center, randomized, placebo-controlled trial. Haematologica 2006;91:1193-202.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 77

Guideline Question 6: Should zinc supplements versus no zinc supplements be used in children and adolescents with beta thalassemia
major?

Problem: Thalassemia patients often suffer from Background and Objective: Beta-thalassemia major patients often suffer from growth retardation due to the underly-
growth retardation. Iron chelation therapy may cause ing anemia and different endocrinopathies. Zinc is required for the synthesis of somatomedins and it is therefore hy-
zinc deficiency. pothesized that supplementation supports growth in thalassemic children and adolescents. Besides, treatment with
iron chelators may cause zinc deficiency.
Option: Zinc supplements
Comparison: No zinc supplements
Setting: KSA
Perspective: Clinical or health system
Additional
Criteria Judgements Research evidence
considerations

"The incidence of beta-thalassemia in Arabian Gulf countries is not clearly known due to
lack of mandatory screening programs.6
No
Probably no In 2004, a 3,4% (307/8918) beta-thalassemia trait prevalence in premarital couples
living in the Al-Hassa area was observed.2
Uncertain
Is there a problem A screening of 6750 healthy persons in Jeddah, western Saudi Arabia, showed that 316
Problem
priority? Probably yes (4.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait among
neonates in the same area was 0.96% (8/834).1
Yes
No prevalence studies were identified describing growth retardation or zinc deficiency in
Varies thalassaemic patients in KSA.

Treatment with iron chelators may cause zinc deficiency in thalassemia patients.7

Benefits & What is the overall The relative importance or values of the main outcomes of interest: Panel members assumed
harms of the certainty of this
No included some variability in values
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 78

options evidence? studies within the KSA thalasse-


Certainty of the
Relative
Very low Outcome
importance
evidence
mia population with regard
to the considered out-
(GRADE)
Low comes, in particular given
the prophylactic nature of
Moderate Height - absolute value [cm] or z-score at end-

this intervention.
point - at 1-7 years 22.5-90 mg zinc, 9 months CRITICAL
High 30 mg zincsulfate and 18 months 25 mg zinc VERY LOW

Body mass index - mean [kg/m] at endpoint -


CRITICAL
Important at 3 months 220 mg zincsulfate LOW
uncertainty or
variability Weight - absolute value [kg] or z-score at end-

Possibly point - at 9 months 30 mg zincsulfate and 18 CRITICAL
LOW
months 25 mg zinc
important uncer-
tainty or varia-
bility Adverse events - at 1-7 years 22.5-90 mg zinc,
Is there important
uncertainty about Probably no 18 months 25 mg zinc and 9 months 30 mg
zincsulfate
CRITICAL
VERY LOW
how much people important uncer-
value the main tainty of variabil-
outcomes? ity Serum zinc [g/dl] - mean at endpoint - at 9
IMPORTANT
No important months 30 mg and 3 months 220 mg zincsulfate LOW
uncertainty of
variability
Haemoglobin level IMPORTANT No data available
No known
undesirable Summary of findings: Zinc supplements compared to no zinc supplements in children
and adolescents with beta thalassemia major

Outcome Relative
Without zinc With zinc Difference
Are the desirable effect
anticipated effects
No
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 79

large?
Probably no supplements supplements (95% CI) (RR)
(95%
Uncertain CI)

Probably yes
Height - abso- Height (absolute Height (absolute
Yes lute value [cm] value [cm] or z- value [cm] or z-
or z-score at score at endpoint at score at endpoint
Varies endpoint - at 1- 1-7 years 22.5-90 at 1-7 years 22.5-
7 years 22.5-90 mg zinc, 9 months 90 mg zinc, 9
SMD 0.11
mg zinc, 9 30 mg zincsulfate months 30 mg
lower
months 30 mg and 18 months 25 zincsulfate and 18
(0.47 lower -
No zincsulfate and mg zinc) in the months 25 mg
to 0.25
18 months 25 control group was zinc) in the inter-
Probably no mg zinc 125.3-143.4 (range vention group was
higher)

for absolute values) 0.11 standard


Are the undesirable Uncertain and -1.33 (z-score) deviations lower
anticipated effects
small?
Probably yes (0.47 lower to 0.25
higher)
Yes
Varies Body mass Body mass index ( Body mass index (
index - mean mean [kg/m] at mean [kg/m] at
[kg/m] at endpoint at 3 endpoint at 3 MD 0.6
endpoint - at 3 months 220 mg months 220 mg higher
months 220 mg zincsulfate) in the zincsulfate) in the (0.65 lower -
No zincsulfate control group was intervention group to 1.85
19.5 was 0.6 higher higher)

Are the desirable


Probably no (0.65 lower to 1.85
higher)
effects large rela- Uncertain
tive to undesirable
effects? Probably yes Weight - abso- Weight (absolute Weight (absolute
SMD 0.22
lute value [kg] value [kg] or z- value [kg] or z-
Yes or z-score at score at endpoint score at endpoint
higher -
(0.19 lower
Varies endpoint - at 9
months 30 mg
at 9 months 30 mg
zincsulfate and 18
at 9 months 30 mg
zincsulfate and 18
to 0.63
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 80

zincsulfate and months 25 mg zinc) months 25 mg higher)


18 months 25 in the control group zinc) in the inter-
mg zinc was was -35.2 (ab- vention group was
solute value) 1.37 0.22 standard
(z-score) deviations higher
(0.19 lower to 0.63
higher)

One study didn't observe significant differences in adverse events


Adverse events when presented as percentage of all subject visits between placebo
- at 1-7 years and zinc groups including diarrhea, stomach upset and nausea (18
22.5-90 mg months 25 mg zinc, Fung 2013); "No visible side effects have been
zinc, 18 months observed at the doses used in the study" (22.5-90 mg zinc at 1-7
25 mg zinc and years, Arasoy 1987); "The most common reported side effect in the
9 months 30 mg study population was gastrointestinal disturbances which were seen
zincsulfate in only 1-8% of subjects" (at 9 months 30 mg zincsulfate, Ghah-
ramanlu 2014)

Serum zinc
[g/dl] - mean 220 mg zincsulfate (Rashidi 2011) led to a significant higher serum
at endpoint - at zinc (MD 47.30, 95% CI: 16.16 to 78.44) compared to no treat-
9 months 30 mg ment with zinc supplements (60 patients), while dispensing 30 mg
and 3 months zincsulfate (Gharhamanlu 2014) showed no difference (60 patients,
220 mg zincsul- MD 0.60, 95% CI: -12.83 to 14.03)
fate

Haemoglobin
No data available
level

No research evidence specific to KSA setting identified. No specific data on costs


Resource use
Are the resources No of zinc supplements in KSA
required small?
setting found. Costs are
Probably no likely to be low. Monitoring
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 81

zinc uptake is not available


Uncertain at all medical centers in
Probably yes KSA, therefore additional
resources in these cases
Yes are required.

Varies

No research evidence specific to KSA setting identified. Uncertain, since no obvi-


No ous, significant health
benefits.
Probably no
Is the incremental Uncertain
cost small relative
to the net benefits? Probably yes
Yes
Varies

No research evidence specific to KSA setting identified. Cost of zinc supplements


Increased are likely low, but limited
Probably access to measurement
and monitoring of zinc
increased levels might increase
What would be the Uncertain health inequities.
Equity impact on health
inequities? Probably
reduced

Reduced
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 82

No research evidence specific to KSA setting identified. Treatment with zinc sup-
No plements was assumed to
be acceptable for govern-
Probably no ment and physicians due
to no/little side effects and
Is the option ac- Uncertain low cost. However, it
Acceptability ceptable to key
stakeholders? Probably yes might well be that some
patient subgroups in the
Yes KSA setting will deem this
prophylactic intervention
Varies rather unacceptable given
the unclear benefits.

No research evidence specific to KSA setting identified. No obvious barriers to


No implementation identified.
Probably no
Uncertain
Is the option feasi-
Feasibility
ble to implement? Probably yes
Yes
Varies
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 83

Recommendation
Should zinc supplements vs. no zinc supplements be used in children and adolescents with thalassemia?
Undesirable consequences Undesirable consequences Desirable consequences Desirable consequences
The balance between desirable
Balance of clearly outweigh desirable probably outweigh desirable probably outweigh undesira- clearly outweigh undesirable
and undesirable consequences
consequences consequences in most set- consequences in most set- ble consequences in most consequences in most set-
is closely balanced or uncertain
tings tings settings tings


Type of recommenda- We recommend against offering this We suggest not offering this We suggest offering this
We recommend offering this option
tion option option option


For children and adolescents with thalassemia major, the panel suggests zinc supplementation rather than no zinc supplementation. (conditional
Recommendation recommendation, very low quality of evidence)

Due to very low quality of evidence for benefits of zinc supplementation, relevance of health benefits is somewhat uncertain. However, due to no
Justification relevant side effects, feasible implementation, moderate to small resource use and prevention of zinc deficiency, the panel suggests offering this
option in children and adolescents with thalassemia major.

Subgroup considera-
Patients with proven zinc deficiency should receive zinc supplementation.
tions

Implementation con-
No specific considerations relevant for implementation of this recommendation.
siderations

Monitoring and eval- Practically all patients with thalassemia major are receiving (or will receive) iron chelation therapy which can interact with zinc metabolism, so
uation serum zinc levels should be monitored in patients with iron chelation therapy.

Ideally, further RCTs evaluating the benefits and harms of zinc supplementation stratified by baseline zinc levels including longer-term patient
Research possibilities relevant outcomes and research of prevalence in zinc deficiency should be conducted. Also, appropriate cost-effectiveness analyses in the KSA
setting should be considered.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 84

Evidence Profile: Question 6: Should zinc supplements versus no zinc supplements be used in children and adolescents with beta thalassemia ma-
jor?

Quality assessment of patients Effect


Quality Importance
of Study Risk of Other consid- zinc sup- no zinc Relative Absolute
Inconsistency Indirectness Imprecision
studies design bias erations plements supplements (95% CI) (95% CI)

Height - absolute value [cm] or z-score at endpoint - at 1-7 years 22.5-90 mg zinc, 9 months 30 mg zincsulfate and 18 months 25 mg zinc
1 2
3 randomised serious not serious not serious very seri- none 69 55 - SMD 0.11 lower CRITICAL
trials ous 3 (0.47 lower to 0.25 higher) 4
VERY LOW

Body mass index - mean [kg/m] at endpoint - at 3 months 220 mg zincsulfate


5
1 randomised not not serious not serious very seri- none 30 30 - MD 0.6 higher CRITICAL
trial serious ous 3 (0.65 lower to 1.85 higher) LOW

Weight - absolute value [kg] or z-score at endpoint - at 9 months 30 mg zincsulfate and 18 months 25 mg zinc
6
2 randomised not not serious not serious very seri- none 48 44 - SMD 0.22 higher CRITICAL
trials serious ous 3 (0.19 lower to 0.63 higher) 7
LOW

Adverse events - at 1-7 years 22.5-90 mg zinc, 18 months 25 mg zinc and 9 months 30 mg zincsulfate
2 8
3 randomised serious not serious not serious very seri- none 77 61 One study didn't observe significant differences in CRITICAL
trials ous 9 adverse events when presented as percentage of all VERY LOW
subject visits between placebo and zinc groups includ-
ing diarrhea, somach upset and nausea (18 months 25
mg zinc, Fung 2013); "No visible side effects have been
observed at the doses used in the study" (22.5-90 mg
zinc at 1-7 years, Arasoy 1987); "The most common
reported side effect in the study population was gastro-
intestinal disturbances which were seen in only 1-8% of
subjects" (at 9 months 30 mg zincsulfate, Ghahramanlu
2014)

Serum zinc [g/dl] - mean at endpoint - at 9 months 30 mg and 3 months 220 mg zincsulfate
10 11
2 randomised not not serious not serious very seri- none 60 60 220 mg zincsulfate (Rashidi 2011) led to a significant IMPORTANT
trials serious ous 3 higher serum zinc (MD 47.30, 95% CI: 16.16 to 78.44) LOW
compared to no treatment with zinc supplements (60
patients), while dispensing 30 mg zincsulfate (Ghar-
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 85

hamanlu 2014) showed no difference (60 patients, MD


0.60, 95% CI: -12.83 to 14.03)

Haemoglobin level - not measured

- - - - - - - - not - IMPORTANT
estimable

MD mean difference, RR relative risk, SD standard deviation

1. Absolute value from two studies and z-score from one study were included
2. High risk due to lack of random sequence generation (1 study), lack of blinding of participants and personnel (1 study), lack of blinding of outcome assessment (1 study); Unclear: Al-
location concealment (3 studies), blinding of participants and personnel (1 study), blinding of outcome assessment (1 study)
3. Only very few patients included in study/studies
4. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of -1.70 cm; back-transformation using SD of both baseline values in
Arcasoy 1987 yields an effect size of -2.18 cm
5. An additional trial (Fung 2013) reported BMI z-scores; in the intervention group, BMI z-score increased from - 0.16 (95% CI: - 0.51 to 0.19) to -0.14 (95%CI: -0.56; 0.28); in placebo
group, BMI z-score increased from -0.71 (95%CI: -1.06 to -0.37) to -0.66 (95% CI: -0.95 to -0.36). Study was not included in meta-analysis due to significant baseline difference
(p=0.025)
6. Absolute value from one study and z-score from one study were included
7. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of 2,4 kg
8. Data not pooled, therefore difficult to assess. However, from narrative information no obvious inconsistency present
9. Only very few cases
10. An additional study (Arcasoy 1987) reported that "patients receiving zinc therapy showed an increase in mean plasma and erythrocyte zinc content in comparison with values ob-
tained before zinc supplementation"; no specific values were reported; another study (Fung 2013) reported that "Plasma zinc increased by 14.7% and 15.2% respectively, at 3 and 6
months in the zinc group, although it did not change with time in the placebo group"; no additional values were reported
11. Data not pooled because of different doses; if pooled meta-analysis showed high I=86% and p = 0.007; however differences are likely related to doses

References
1. Arcasoy A, Cavdar A, Cin S, et al. Effects of zinc supplementation on linear growth in beta-thalassemia (a new approach). Am J Hematol 1987;24:127-36.
2. Rashidi M, Aboomardani M, Rafraf M, Arefhosseini SR, Keshtkar A, Joshaghani H. Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalasse-
mia major Patients. Iran J Pediatr 2011;21:8-14.
3. Fung EB, Kwiatkowski JL, Huang JN, Gildengorin G, King JC, Vichinsky EP. Zinc supplementation improves bone density in patients with thalassemia: a double-blind,
randomized, placebo-controlled trial. Am J Clin Nutr 2013;98:960-71.
4. Ghahramanlu E, Banihashem A, Mirhossini NZ, et al. Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia
major. Hematology 2014;19:113-9.
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 86

Appendix 2: Search Strategies and Results

1.) Interventions (deferoxamine, deferiprone, deferasirox) for iron overload in thalassemia pa-
tients

Database: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE 1946
to Present
Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (19716)
2 (thalassemi* or thalassaemi*).tw. (17291)
3 (cooley* and (anemi* or anaemi*)).tw. (400)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1585)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (162)
6 or/1-5 (24197)
7 exp Iron Overload/ (11956)
8 (iron adj3 overload*).tw. (7420)
9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (9136)
10 or/1-9 (39162)
11 exp Iron Chelating Agents/ (19063)
12 Chelation Therapy/ (1152)
13 (deferoxamine* or deferoximine* or deferrioxamine* or desferioximine* or desferrioxamine* or desferrox-
amine* or desferal* or desferral* or desferin* or desferol* or DFO or dfom).mp. (8833)
14 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp).mp.
(45370)
15 (exjade* or deferasirox*).mp. [mp=title, abstract, original title, name of substance word, subject heading word,
keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique
identifier] (662)
16 (icl adj 670*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword
heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
(4)
17 (cgp adj "72670").mp. [mp=title, abstract, original title, name of substance word, subject heading word, key-
word heading word, protocol supplementary concept word, rare disease supplementary concept word, unique iden-
tifier] (0)
18 or/11-17 (66801)
19 10 and 18 (3265)
20 limit 19 to yr="2013 -Current" (268)
21 limit 19 to ed=20130301-20141003 (248)
22 20 or 21 (299)
23 limit 22 to "therapy (maximizes sensitivity)" (193)

Records Retrieved 193

Data base: Embase <1974 to 2014 October 07>


Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (25389)
2 (thalassemi* or thalassaemi*).tw. (21563)
3 (cooley* and (anemi* or anaemi*)).tw. (435)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1864)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (146)
6 or/1-5 (28859)
7 exp Iron Overload/ (10091)
8 (iron adj3 overload*).tw. (9979)
9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (10968)
10 or/1-9 (46063)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 87

11 (deferoxamine* or deferoximine* or deferrioxamine* or desferioximine* or desferrioxamine* or desferrox-


amine* or desferal* or desferral* or desferin* or desferol* or DFO or dfom).mp. (13924)
12 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp).mp.
(49133)
13 (exjade* or deferasirox*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
title, device manufacturer, drug manufacturer, device trade name, keyword] (1970)
14 (icl adj 670*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer, device trade name, keyword] (187)
15 (cgp adj "72670").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,
device manufacturer, drug manufacturer, device trade name, keyword] (7)
16 iron chelation/ (4597)
17 iron chelating agent/ (2758)
18 chelation therapy/ (2788)
19 deferoxamine/ (11125)
20 deferoxamine mesylate/ (2080)
21 deferasirox/ (1920)
22 deferiprone/ (2173)
23 (iron adj5 (chelat* or reduc*)).tw. (17654)
24 or/11-23 (77850)
25 10 and 24 (7220)
26 limit 25 to yr="2013 -Current" (876)
27 limit 26 to "therapy (maximizes sensitivity)" (208)

Records Retrieved 208

Data base: CENTRAL


Search strategy: Date of search: 10/2014
#1 MeSH descriptor: [Thalassemia] explode all trees 234
#2 thalassemi* or thalassaemi* 560
#3 cooley* anemia or cooley* anaemia 13
#4 hemoglobin near disease or haemoglobin near disease 518
#5 mediterranean anemia* or mediterranean anaemia* 59
#6 erythroblastic anemia* or erythroblastic anaemia* 5
#7 MeSH descriptor: [Iron Overload] explode all trees 142
#8 iron near overload* 293
#9 hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis 182
#10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 1307
#11 MeSH descriptor: [Iron Chelating Agents] explode all trees 169
#12 MeSH descriptor: [Chelation Therapy] this term only 78
#13 deferiprone or L1* or kelfer* or DMHP* or ferriprox* or cp20 or dmohpo or hdmpp next cpd or hdpp
974
#14 exjade* or deferasirox* or (icl next 670) or icl670* or (cgp next 72670) or cgp72670 152
#15 deferoxamine* or deferoximine* or deferrioxamine* or desferioximine* or desferrioxamine* or desferrox-
amine* or desferal* or desferral* or DFO or desferin* or desferol* or dfom 296
#16 (iron near/5 (chelat* or reduc*)) 681
#17 #11 or #12 or #13 or #14 or #15 or #16 1755
#18 #10 and #17 Publication Year from 2013 to 2014, in Trials 33

Records Retrieved 33
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 88

Summary of Searches:

Total No. Retrieved: 434


MEDLINE 193
Embase 208
CENTRAL 33
Duplicates: 119
No. Total without 315
duplicates
Screening (Title and Abstract Review)
No. Excluded: 308
Included for Full Text 7
review:
Selection (Full Text Review)
No. Excluded: 4
Reasons for exclusions:
1. Comment
2. Observational study
3. No control group
4. Broken randomisation

2.) Bisphosphonates for thalassemia

Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE 1946
to Present
Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (19716)
2 (thalassemi* or thalassaemi*).tw. (17291)
3 (cooley* and (anemi* or anaemi*)).tw. (400)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1585)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (162)
6 or/1-5 (24197)
7 exp Diphosphonates/ (21267)
8 bisphosphonate*.mp. (12141)
9 exp Bone Density Conservation Agents/ (101021)
10 or/7-9 (107598)
11 6 and 10 (105)
12 limit 11 to yr="2012 -Current" (17)

Records Retrieved 17

Data base: Embase <1974 to 2014 October 07>


Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (25389)
2 (thalassemi* or thalassaemi*).tw. (21563)
3 (cooley* and (anemi* or anaemi*)).tw. (435)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1864)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (146)
6 or/1-5 (28859)
7 exp bisphosphonic acid derivative/ (46599)
8 bisphosphonate*.mp. (17815)
9 7 or 8 (47829)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 89

10 6 and 9 (146)
11 limit 10 to yr="2012 -Current" (45)

Records Retrieved 45

Data base: CENTRAL


Search strategy: Date of search:10/2014
#1 MeSH descriptor: [Thalassemia] explode all trees 234
#2 thalassemi* or thalassaemi* 560
#3 cooley* anemia or cooley* anaemia 13
#4 hemoglobin near disease or haemoglobin near disease 518
#5 mediterranean anemia* or mediterranean anaemia* 59
#6 erythroblastic anemia* or erythroblastic anaemia* 5
#7 MeSH descriptor: [Iron Overload] explode all trees 142
#8 iron near overload* 293
#9 hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis 182
#10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 1307
#11 MeSH descriptor: [Diphosphonates] explode all trees 1933
#12 MeSH descriptor: [Bone Density Conservation Agents] explode all trees 1225
#13 bisphosphonate* 1145
#14 #11 or #12 or #13 2752
#15 #10 and #14 Publication Year from 2012 to 2014, inTrials 2

Records Retrieved 2

Summary of Searches:

Total No. Retrieved: 64


MEDLINE 17
Embase 45
CENTRAL 2
Duplicates: 17
No. Total 47
without duplicates:
Screening (Title and Abstract Review)
No. Excluded: 42
Included for Full Text 3
review:
Selection (Full Text Review)
No. Excluded: 3
Reasons for exclusions:
1. Observational study (n=2)
2. Already included in systematic review

3.) Zinc for thalassemia

Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE 1946
to Present
Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (19716)
2 (thalassemi* or thalassaemi*).tw. (17291)
3 (cooley* and (anemi* or anaemi*)).tw. (400)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 90

4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1585)


5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (162)
6 or/1-5 (24197)
7 Zinc/ or zinc.mp. (109880)
8 6 and 7 (185)
9 limit 8 to yr="2013 -Current" (11)

Records Retrieved 11

Data base: Embase <1974 to 2014 October 07>


Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (25389)
2 (thalassemi* or thalassaemi*).tw. (21563)
3 (cooley* and (anemi* or anaemi*)).tw. (435)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1864)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (146)
6 or/1-5 (28859)
7 zinc.mp. or zinc/ (169814)
8 6 and 7 (393)
9 limit 8 to yr="2013 -Current" (52)
10 limit 9 to "therapy (maximizes sensitivity)" (16)

Records Retrieved 16

Data base: CENTRAL


Search strategy: Date of search: 10/2014
#1 MeSH descriptor: [Thalassemia] explode all trees 234
#2 thalassemi* or thalassaemi* 560
#3 cooley* anemia or cooley* anaemia 13
#4 hemoglobin near disease or haemoglobin near disease 518
#5 mediterranean anemia* or mediterranean anaemia* 59
#6 erythroblastic anemia* or erythroblastic anaemia* 5
#7 MeSH descriptor: [Iron Overload] explode all trees 142
#8 iron near overload* 293
#9 hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis 182
#10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 1307
#11 MeSH descriptor: [Zinc] explode all trees 1196
#12 zinc 3391
#13 #11 or #12 3391
#14 #10 and #13 Publication Year from 2013 to 2014, in Trials 4

Records Retrieved 4

Summary of Searches:

Total No. Re- 31


trieved:
Medline 11
Embase 16
CENTRAL 4
Duplicates: 7
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 91

No. Total 24
without duplicates:
Screening (Title and Abstract Review)
No. Excluded: 22
Included for Full 2
Text review:
Selection (Full Text Review)
No. Excluded: 0

Patients Values and Preferences Searches:

Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE 1946
to Present
Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (19711)
2 (thalassemi* or thalassaemi*).tw. (17271)
3 (cooley* and (anemi* or anaemi*)).tw. (399)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1582)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (162)
6 or/1-5 (24174)
7 exp Iron Overload/ (11956)
8 (iron adj3 overload*).tw. (7416)
9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (9133)
10 or/1-9 (39133)
11 patient$ participation.mp. or exp patient participation/ (19647)
12 patient$ satisfaction.mp. or exp patient satisfaction/ (74926)
13 attitude to health.mp. or exp Attitude to health/ (377915)
14 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or
patient$ view$ or patient$ value$).mp. (25059)
15 (patient$ utilit$ or health utilit$).mp. (1416)
16 health related quality of life.mp. or exp "quality of life"/ (128400)
17 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. or exp Health Status Indicators/
(204864)
18 11 or 12 or 13 or 14 or 15 or 16 or 17 (686777)
19 10 and 18 (847)
20 Saudi Arab$.mp,in. or Saudi Arabia/ (30920)
21 Riyadh.mp,in. (16216)
22 Jeddah.mp,in. (3718)
23 Kh*bar.mp,in. (759)
24 Dammam.mp,in. (1349)
25 20 or 21 or 22 or 23 or 24 (31341)
26 Kuwait$.mp,in. or Kuwait/ (6933)
27 United Arab Emirates.mp,in. or United Arab Emirates/ (4471)
28 Qatar$.mp,in. or Qatar/ (2460)
29 Oman$.mp,in. or Oman/ (3876)
30 Yemen$.mp,in. or Yemen/ (1915)
31 Bahr*in$.mp,in. or Bahrain/ (1250)
32 26 or 27 or 28 or 29 or 30 or 31 (20062)
33 Middle East$.mp,in. or Middle East/ (11866)
34 Jordan$.mp,in. or Jordan/ (10272)
35 Libya$.mp,in. or Libya/ (1843)
36 Egypt$.mp,in. or Egypt/ (38709)
37 Syria$.mp,in. or Syria/ (10739)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 92

38 Iraq$/ or Iraq.mp,in. (8084)


39 Morocc$.mp,in. or Morocco/ (8642)
40 Tunisia$.mp,in. or Tunisia/ (12790)
41 Leban$.mp,in. or Lebanon/ (14812)
42 West Bank.mp,in. (763)
43 Iran$.mp,in. or Iran/ (65729)
44 Turkey/ or (Turkey or Turkish).mp,in. (153093)
45 Algeria$.mp,in. or Algeria/ (4301)
46 Arab$.mp,in. or Arabs/ (122834)
47 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 (331078)
48 46 or 47 (445204)
49 25 or 32 or 48 (457645)
50 19 and 49 (94)

Records Retrieved 94

Data base: Embase <1974 to 2014 October 02>


Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (25374)
2 (thalassemi* or thalassaemi*).tw. (21547)
3 (cooley* and (anemi* or anaemi*)).tw. (435)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1864)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (146)
6 or/1-5 (28843)
7 exp Iron Overload/ (10086)
8 (iron adj3 overload*).tw. (9971)
9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (10967)
10 or/1-9 (46040)
11 patient$ participation.mp. or exp patient participation/ (18705)
12 patient$ satisfaction.mp. or exp patient satisfaction/ (94477)
13 attitude to health.mp. or exp Attitude to health/ (80874)
14 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or
patient$ view$ or patient$ value$).mp. (38280)
15 (patient$ utilit$ or health utilit$).mp. (1980)
16 health related quality of life.mp. or exp "quality of life"/ (279285)
17 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. or exp Health Status Indicators/
(8220)
18 11 or 12 or 13 or 14 or 15 or 16 or 17 (485079)
19 10 and 18 (745)
20 Saudi Arab$.mp,in. or Saudi Arabia/ (48722)
21 Riyadh.mp,in. (26446)
22 Jeddah.mp,in. (6792)
23 Kh*bar.mp,in. (1255)
24 Dammam.mp,in. (1960)
25 20 or 21 or 22 or 23 or 24 (49018)
26 Kuwait$.mp,in. or Kuwait/ (11067)
27 United Arab Emirates.mp,in. or United Arab Emirates/ (9883)
28 Qatar$.mp,in. or Qatar/ (4798)
29 Oman$.mp,in. or Oman/ (5605)
30 Yemen$.mp,in. or Yemen/ (2585)
31 Bahr*in$.mp,in. or Bahrain/ (3086)
32 26 or 27 or 28 or 29 or 30 or 31 (34963)
33 Middle East$.mp,in. or Middle East/ (15249)
34 Jordan$.mp,in. or Jordan/ (30681)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 93

35 Libya$.mp,in. or Libya/ (3001)


36 Egypt$.mp,in. or Egypt/ (69210)
37 Syria$.mp,in. or Syria/ (16149)
38 Iraq$/ or Iraq.mp,in. (10462)
39 Morocc$.mp,in. or Morocco/ (18553)
40 Tunisia$.mp,in. or Tunisia/ (25085)
41 Leban$.mp,in. or Lebanon/ (27069)
42 West Bank.mp,in. (1105)
43 Iran$.mp,in. or Iran/ (111023)
44 Turkey/ or (Turkey or Turkish).mp,in. (254818)
45 Algeria$.mp,in. or Algeria/ (7980)
46 Arab$.mp,in. or Arabs/ (157020)
47 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 (572180)
48 46 or 47 (707715)
49 25 or 32 or 48 (726932)
50 19 and 49 (93)
Records Retrieved 93

Data base: PsycINFO <1987 to October Week 1 2014


Search strategy: Date of search: 10/2014
1 (thalassemi* or thalassaemi*).tw. (160)
2 (cooley* and (anemi* or anaemi*)).tw. (1)
3 ((hemoglobin or haemoglobin) adj3 disease).tw. (19)
4 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (0)
5 iron overload.mp. (64)
6 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (77)
7 or/1-6 (294)
8 client$ participation.mp. or exp client participation/ (1533)
9 client$ satisfaction.mp. or exp client satisfaction/ (5022)
10 exp Health Attitudes/ (7993)
11 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or
patient$ view$ or patient$ value$ or patient$ attitude$).mp. (8296)
12 (patient$ utilit$ or health utilit$).mp. (527)
13 health related quality of life.mp. or exp "quality of life"/ (29337)
14 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. (142)
15 (standard gambl$ or time trade off or willingness to pay or visual analog scale or (VAS or "visual analog$ adj 2
scal$")).mp. (4704)
16 or/8-15 (54515)
17 7 and 16 (17)

Records Retrieved 17

Summary of Searches:

Total No. Re- 204


trieved
MEDLINE 94
Embase 93
PsycInfo 17
Duplicates: 24
No. Total 180
without duplicates
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 94

Screening (Title and Abstract Review)


No. Excluded: 179
Included for Full 1
Text review:
Selection (Full Text Review)
No. Excluded: 0

Cost-Effectiveness Search:

Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE 1946
to Present
Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (19711)
2 (thalassemi* or thalassaemi*).tw. (17271)
3 (cooley* and (anemi* or anaemi*)).tw. (399)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1582)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (162)
6 or/1-5 (24174)
7 exp Iron Overload/ (11956)
8 (iron adj3 overload*).tw. (7416)
9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (9133)
10 or/1-9 (39133)
11 economics/ or exp economics, hospital/ or exp economics, medical/ or economics, nursing/ or economics,
pharmaceutical/ (66169)
12 exp "Costs and Cost Analysis"/ (185622)
13 Value-Based Purchasing/ (210)
14 exp "Fees and Charges"/ (27373)
15 budget$.mp. or Budgets/ (25521)
16 (low adj cost).mp. (26833)
17 (high adj cost).mp. (8495)
18 (health?care adj cost$).mp. (4933)
19 (cost adj estimate$).mp. (1505)
20 (cost adj variable$).mp. (110)
21 (unit adj cost$).mp. (1667)
22 (fiscal or funding or financial or finance).tw. (87888)
23 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (185340)
24 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 (497461)
25 10 and 24 (495)
26 Saudi Arab$.mp,in. or Saudi Arabia/ (30920)
27 Riyadh.mp,in. (16216)
28 Jeddah.mp,in. (3718)
29 Kh*bar.mp,in. (759)
30 Dammam.mp,in. (1349)
31 26 or 27 or 28 or 29 or 30 (31341)
32 Kuwait$.mp,in. or Kuwait/ (6933)
33 United Arab Emirates.mp,in. or United Arab Emirates/ (4471)
34 Qatar$.mp,in. or Qatar/ (2460)
35 Oman$.mp,in. or Oman/ (3876)
36 Yemen$.mp,in. or Yemen/ (1915)
37 Bahr*in$.mp,in. or Bahrain/ (1250)
38 32 or 33 or 34 or 35 or 36 or 37 (20062)
39 Middle East$.mp,in. or Middle East/ (11866)
40 Jordan$.mp,in. or Jordan/ (10272)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 95

41 Libya$.mp,in. or Libya/ (1843)


42 Egypt$.mp,in. or Egypt/ (38709)
43 Syria$.mp,in. or Syria/ (10739)
44 Iraq$/ or Iraq.mp,in. (8084)
45 Morocc$.mp,in. or Morocco/ (8642)
46 Tunisia$.mp,in. or Tunisia/ (12790)
47 Leban$.mp,in. or Lebanon/ (14812)
48 West Bank.mp,in. (763)
49 Iran$.mp,in. or Iran/ (65729)
50 Turkey/ or (Turkey or Turkish).mp,in. (153093)
51 Algeria$.mp,in. or Algeria/ (4301)
52 Arab$.mp,in. or Arabs/ (122834)
53 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 (331078)
54 52 or 53 (445204)
55 31 or 38 or 54 (457645)
56 25 and 55 (62)

Records Retrieved 62

Data base: Embase <1974 to 2014 October 02>


Search strategy: Date of search: 10/2014
1 exp Thalassemia/ (25374)
2 (thalassemi* or thalassaemi*).tw. (21547)
3 (cooley* and (anemi* or anaemi*)).tw. (435)
4 ((hemoglobin or haemoglobin) adj3 disease).tw. (1864)
5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).tw. (146)
6 or/1-5 (28843)
7 exp Iron Overload/ (10086)
8 (iron adj3 overload*).tw. (9971)
9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. (10967)
10 or/1-9 (46040)
11 economic evaluation$.mp. or exp economic evaluation/ (217926)
12 fee$.mp. or exp fee/ (603340)
13 health care cost$.mp. or exp "health care cost"/ (213142)
14 hospital cost$.mp. or exp "hospital cost"/ (29327)
15 pharmacoeconomics.mp. or exp pharmacoeconomics/ (170837)
16 health economics.mp. or health economics/ (35972)
17 budget$.mp. or budget/ (36219)
18 socioeconomics.mp. or socioeconomics/ (110656)
19 11 or 12 or 13 or 14 or 15 or 16 (1073744)
20 17 or 19 (1096280)
21 18 or 20 (1189909)
22 (low adj cost).mp. (30329)
23 (high adj cost).mp. (9673)
24 (health?care adj cost$).mp. (13883)
25 (cost adj estimate$).mp. (2060)
26 (cost adj variable$).mp. (164)
27 (unit adj cost$).mp. (2516)
28 (fiscal or funding or financial or finance).tw. (108400)
29 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (233512)
30 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 (375661)
31 21 or 30 (1425432)
32 20 or 30 (1349591)
Management of Thalassemia Iron chela-
tion therapy, Bisphosphonates and Zinc
supplementation 96

33 19 or 30 (1331392)
34 10 and 33 (1585)
35 Saudi Arab$.mp,in. or Saudi Arabia/ (48722)
36 Riyadh.mp,in. (26446)
37 Jeddah.mp,in. (6792)
38 Kh*bar.mp,in. (1255)
39 Dammam.mp,in. (1960)
40 35 or 36 or 37 or 38 or 39 (49018)
41 Kuwait$.mp,in. or Kuwait/ (11067)
42 United Arab Emirates.mp,in. or United Arab Emirates/ (9883)
43 Qatar$.mp,in. or Qatar/ (4798)
44 Oman$.mp,in. or Oman/ (5605)
45 Yemen$.mp,in. or Yemen/ (2585)
46 Bahr*in$.mp,in. or Bahrain/ (3086)
47 41 or 42 or 43 or 44 or 45 or 46 (34963)
48 Middle East$.mp,in. or Middle East/ (15249)
49 Jordan$.mp,in. or Jordan/ (30681)
50 Libya$.mp,in. or Libya/ (3001)
51 Egypt$.mp,in. or Egypt/ (69210)
52 Syria$.mp,in. or Syria/ (16149)
53 Iraq$/ or Iraq.mp,in. (10462)
54 Morocc$.mp,in. or Morocco/ (18553)
55 Tunisia$.mp,in. or Tunisia/ (25085)
56 Leban$.mp,in. or Lebanon/ (27069)
57 West Bank.mp,in. (1105)
58 Iran$.mp,in. or Iran/ (111023)
59 Turkey/ or (Turkey or Turkish).mp,in. (254818)
60 Algeria$.mp,in. or Algeria/ (7980)
61 Arab$.mp,in. or Arabs/ (157020)
62 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 (572180)
63 61 or 62 (707715)
64 40 or 47 or 63 (726932)
65 34 and 64 (149)

Records Retrieved 149

Summary of Searches:

Total No. Retrieved: 211


MEDLINE: 62
Embase: 149
Duplicates: 46
No. Total 165
without duplicates:
Screening (Title and Abstract Review)
No. Excluded: 165
Included for Full Text 0
review: