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Management of Thalassemia – Iron chela

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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 Brożek, MD PhD, and
Holger J Schünemann, 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-
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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-
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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,
patient’s 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

The guideline panel met in Riyadh on March 17 & 18. requires lifelong frequent red blood cell ies included in the existing systematic reviews (RBC) transfusions. and costs and resource use spe- cific to the Saudi context. Accordingly. Em- for the synthesis of evidence consisted of up. ate. Marked variable frequencies of beta- thalassemia have been reported in different Methodology areas and populations of the Kingdom of Saudi Arabia (KSA). several co. base and CENTRAL. a group of inherited blood dis.7 Zinc full guidelines for the KSA. KSA from 2004-2009. information to prepare GRADE evidence-to- tients. Based on the sys- While life expectancy can be increased tematic reviews we prepared summaries of through improved transfusion programs com. 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). we only regarded randomised controlled trials Beta-thalassemia major. based decision-making on management of eases.4 cal practice across the Kingdom. genes. The Saudi expert guideline panel selected the bisphosphonates and zinc supplementation in topic of this guideline and all healthcare ques- thalassemia patients. 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. Assessment. (RCT). The guideline has this focused tematic reviews on management of thalasse- scope as the chosen methodological approach mia patients8-13 by searching MEDLINE. iron chela.0 for carriers and 0.14 We used this use has been suggested in thalassemia pa.5 for cases per ers and reduce unnecessary variation in clini- 1000 examined persons. Risk of bias assessment of primary stud- type. zation process. iron chela. This document focuses on iron chelation. is caused by mutations in hemoglobin thalassemia patients.Management of Thalassemia – Iron chela- tion therapy. For all selected questions we morbidities other than thalassemia-associated updated the literature search of existing sys- osteoporosis. may cause zinc deficiency. 2015 and formulated all recommen- . Bisphosphonates and Zinc supplementation 1 Given the importance of this topic. bisphosphonates and Evaluation) approach. including searches has an important influence on growth and the for information about patients’ values and immune system. with thalassemia living in Saudi Arabia. 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. However.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. for information that was required to develop tors. According to the inclusion dating existing systematic reviews.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. Development sis may occur. criteria of underlying systematic reviews. As a result of the additional was double-checked and adopted if appropri- iron load caused by transfusions. Recommendations. mendation following the GRADE (Grading of morbidities such as osteopenia or osteoporo. the more severe sub. preferences. The guideline does not tions addressed herein using a formal prioriti- address patients with thalassemia and co. in turn. available evidence supporting each recom- bined with iron chelation therapy. We also conducted systematic searches tion therapy is essential.

Management of Thalassemia – Iron chela-
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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
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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-
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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

the panel suggests zinc supple- mentation rather than no zinc supplementa- tion. 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 . (conditional recommendation. a decision about treat- ment with bisphosphonates in se- lected patients should be made. the panel suggests against treatment with bisphosphonates. 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.Management of Thalassemia – Iron chela- tion therapy. jointly. very low quality of evidence) Remarks:  Vitamin D. Bisphosphonates and Zinc supplementation 5 Recommendation 5: For patients with thalassemia-associated osteoporosis. (condition- al recommendation against. Recommendation 6: For children and adolescents with thalasse- mia major.

dominal swelling. 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. thalassemia living in Saudi Arabia.6 In morbidities such as osteopenia or osteoporosis 2004.2 Additionally. are pallor. a group of inherited blood dis. the more severe sub- Health of Saudi Arabia to establish a program type. a 3. symptomatic thalassemia is about 0.000 newborns per year19. is caused by mutations in hemoglobin within the first years of life. may cause zinc defi- 1000 births18 summing up to more than ciency. a screening of 6750 healthy persons in Jeddah. Other health care professionals and policy This document focuses on iron chelation.5 tion.140) for cases per 1000 examined includes both paediatric and adult haematolo. irritability.4% (307/8918) beta-thalassemia may occur.69%) had beta-thalassemia trait. ab- mate goal being to provide guidance for clini. bisphosphonates and zinc supplementation in lines. Transfusion therapy has to be commenced eases. The objective of this document is to provide western Saudi Arabia. bisphosphonates use trait prevalence in premarital couples living in has been suggested in thalassemia patients.4 gists in the Kingdom of Saudi Arabia (KSA). due to bined with iron chelation therapy. Given the .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. and reduce unnecessary variability in clinical practice across the Kingdom.Management of Thalassemia – Iron chela- tion therapy. (28. makers may also benefit from these guide. A therapy with regular red blood cell transfu- sions is required to reach sufficiently high he- Introduction moglobin levels for adequate growth and de- velopment in children with thalassemia major and has a beneficial effect on life expectancy. 2009. persons. positive for beta-thalassemia was 18. hepatosplenomegaly and cians and other healthcare decision makers jaundice. This practice guideline is a part of the larger initiative of the Ministry of Beta-thalassemia major. But as a result of genes. several co- a lack of a mandatory screening program. 6 months and one year. bisphosphonates and zinc supplementa. frequencies of beta-thalassemia have been reported in different areas and populations of While life expectancy can be increased the Kingdom of Saudi-Arabia. the additional iron load caused by transfusions The worldwide birth rate for children with iron chelation therapy is essential. The preva. Observable symptoms ment of guidelines in the Kingdom. Marked variable growth and the immune system. sion-making. is usually diagnosed in children between of rigorous adaptation and de novo develop.96% (8/834).572. the Minis. thalassemia patients. morbidities other than thalassemia-associated try of Health (MoH) of Saudi Arabia with the osteoporosis.7 Zinc has an important influence on 40.140) for carriers and 0. in turn. Bisphosphonates and Zinc supplementation 6 lence of beta-thalassemia trait among neo- Scope and purpose nates in the same area was 0. Accordingly.235/1. sisted of updating existing systematic reviews.44 per iron chelators. The guideline does not address patients with thalassemia and co- Given the importance of this topic.1-5 The preva. growth retardation. Thalassemia. the ulti. through improved transfusion programs com- lence in the KSA is not precisely known. the mean prevalence of couples testing mia patients focusing on iron chelation thera.0 py. the Al-Hassa area was observed. showed that 316 guidance for the management of patients with (4.572. The target audience of this guideline (771/1. However.

or “very low” based on was limited due to the paucity of existing sys. Where mate of the effect. 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. 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. dence profile and an evidence-to-decision (EtD) table following the GRADE (Grading of Grading of the strength of recommendations Recommendations. “low”. ferent from the estimate of effect.Management of Thalassemia – Iron chela- tion therapy. dence in the effect estimate: The true effect is likely to be substantially dif- Next. guidelines to assist health care providers in We used the GRADE evidence-to-decision evidence-based decision-making on manage. tion. According to the GRADE approach. the Ministry of lished evidence was lacking. decisions about methodological characteris- tematic reviews evaluating management op.16 We assessed the quality of evidence tions addressed herein using a formal prioriti. 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. frameworks to follow a structured consensus ment of thalassemia patients. 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. identify new randomised controlled trials. 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. 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). University working group produced practice 2015 to formulate the final recommendations. the . timate of the effect.14. Assessment. we developed for each question an evi. particularly when pub. effects. The definition of each questions we updated the existing systematic category is as follows: reviews on iron chelation therapy.20 which we can be confident that desirable ef- The guideline panel was invited to provide fects of an intervention outweigh undesirable additional information. 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. Potential con- flicts of interests of all panel members were Methodology managed according to the World Health Or- ganization (WHO) rules. the meta-analyses were updated. tics of the available evidence for a specific tions in thalassemia patients. Bisphosphonates and Zinc supplementation 7 importance of this topic. using the GRADE approach. including searches for be substantially different from the es- information about patients’ values and pref. Embase and CENTRAL to timate of the effect. sibility that it is substantially different. process and transparently document all deci- sions made during the meeting. scope and choice of questions to be addressed “moderate”.15 To facilitate the interpretation of these guide- lines. zation process. the Quality of evidence is classified as “high”. effect is likely to be close to the esti- checked and adopted if appropriate. erences. For the chosen health care problem. In the case of this guideline on management of patients with thalassemia. and costs and resource use specific  Very low: We have very little confi- to the Saudi context (see Appendix 2). but there is a pos- possible.

(see Table 1) The following is a list of the clinical questions As a quality measure for any practice guide. thalassemia patients? vide clinicians and their patients with a basis 4. Should deferasirox versus deferox- this guideline development. 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. The guideline panel did not specify doses for medications in its recom. institutional review com. feasibility. selected by the Saudi expert panel and ad- line prior to publication. Should deferoxamine versus defer- How to use these guide. As described in other guidelines fol. patients. Should deferoxamine in combination for rational decisions about the treatment with deferiprone versus deferiprone with iron chelators. or the courts bisphosphonates be used in manage- should never view these recommendations as ment of thalassemia-associated oste- dictates. the final report have dressed in this guideline. iprone be used for iron overload in thalassemia patients? lines 3. been externally peer reviewed by a methodo- logical expert who has not been involved in 1. no guideline or 6. Should bisphosphonates versus no mittees. no mia major? one charged with evaluating clinicians’ actions should attempt to apply the recommenda. are its integral parts and serve to facilitate an accurate interpretation. bisphosphonates and zinc alone be used for iron overload in tha- in thalassemia patients. amine be used for iron overload in thalassemia patients? 2. deferoxamine be used for iron overload in . 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. to the KSA setting and it is not addressed in marks accompanying each recommendation this guideline. While initially identified during the prioritiza- tions from these guidelines by rote or in a tion process as potentially relevant. oporosis? lowing the GRADE approach. was determined by the panel to be irrelevant acceptability as well as other qualifying re.17 Understanding adjustments. equity. other stakeholders. and adolescents with beta thalasse- vidual clinical circumstances. 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. Therefore. 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. 5. Question 1: Should deferasirox versus mendations as they may differ by product. resources. Clinicians. lassemia patients? third-party payers. Recommendations ommendation. 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.Management of Thalassemia – Iron chela- tion therapy. 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.

84 to ferasirox.07.6 and of these trials23.1. absolute effect: 13 In government insured population of thalas- serious adverse events fewer per 1000.g. moderate quality of evidence). probably the majority of pa- 1. 541 patients. 95% CI: 0. . At a ratio of less than 1:2.72.64.75 to 0. low quality of evidence). The same trial tients would prefer oral application of iron demonstrated non-inferiority of deferasirox in chelation. was patients from the Middle-East. published in Chinese lan. while deferox- trolled trials21. RR Given the different modes of application and 0. no chelation treatment is covered. 187 patients.63. both treatment options are CI: from 22 more to 32 fewer. low. different (1 trial. absolute effect: 5 the differing spectrum of possible adverse fewer patients per 1000. the latter was statistically more conducted in the Middle East.37. 1:5.4. Mortality at 48 weeks and 1 year was report- ed to be not significantly different between Values and Preferences: treatment groups (3 trials. The search strategy for values and pref. events at 12 months (2 trials. Compliance (% of dose taken by insured through a government plan.Management of Thalassemia – Iron chela- tion therapy.22. including two randomised con. Data preferences seems likely. The evidence showed no deferoxamine and/or deferiprone (n=237) significant difference between treatment before. effective.68 to 3. MD 2. Although this might from one trial (172 patients) were unclear not be true for all patients (e.37. 844 patients. 95% CI: -1. The overall 536. RR 0. this is not the case for patients not evidence).24 in the updated literature search. low quality of covered. Bisphosphonates and Zinc supplementation 9 thalassemia patients? 95% CI: 1. 873 patients. equal efficacy was achieved only in the highly iron-overloaded subgroup at a Benefits & Harms of the Option: mean ratio of 1:1. Data from this trial reflect the dose- Summary of Findings: response and ratio effect: at a ratio of 1:1. small children. treatment. low quality of evidence). One three subgroups at ratios of 1:2.78.2.44 to 1. highly iron overloaded people.2 of deferasirox to erences led to the inclusion of one study26 deferoxamine. For these patients) at 12 months was not significantly patients. An additional trial25 was identified as part higher in the deferoxamine group (3 trials. MD 415. of an updated version of the Cochrane sys.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. etc. 95% CI: 295. has not been considered in this analysis tin (µg/l) at 8 and 12 months was significantly yet. the reduction in serum ferri- guage.07 to tematic review by Meerpohl10. moderate quality of evi- dence). In addition. 95% CI: from 9 fewer effects. at 12 months (1 trial.5. 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.38. a variability of patient’s values and to 16 more. Treatment with deferasirox for one groups in the number of serious adverse year led to high compliance and satisfaction. 1:3. MD -1. with regard to left ventricular ejection fraction patients experiencing adverse effects of de- (%) at 12 months (MD -0. This assumption is supported by a myocardial iron removal (myocardial T2*) and study26 including iron-overloaded thalassemia a trend for superiority which. 773 patients. We found two additional amine showed higher efficacy in the other trials23. low quality of evidence). Data quality of evidence for our prioritised patient.8.09 to 2.). however.95. 95% so cost considerations will influence choice of CI: -3. 95% CI: 0. 95% semia patients. who had not not statistically significant at 12 months (low achieved successful iron chelation with quality of evidence). from one trial (563 patients) showed a clear important critical outcomes was judged as dose-response effect for serum ferritin levels.48.

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. further RCTs evaluating the benefits better compliance due to oral administration. lassemia patients? amine. conducted. Bisphosphonates and Zinc supplementation 10 Feasibility: amine: regular ophthalmologic ex- No obvious barriers to implementation were amination and audiometry needs to identified.g. For thalassemia patients with iron overload. very low quality of evidence) showed administration no superiority of deferoxamine compared to  For patients treated with deferox.78 to 0. (conditional recommendation. not thought to be related to the deferiprone tients with adverse effects of defer. 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. deferiprone be used for iron overload in tha- asirox rather than treatment with deferox. Research Priorities: ter protection against free iron and probable Ideally. low quality of evidence) Summary of Findings: The summary of evidence is based on two Remarks: Cochrane systematic reviews by Fisher8. Only one trial (13 patients) reported data on load mortality. deferiprone for change in liver iron concentra- tion (mg/g dry weight) using SQUID at 12 . treatment (very low quality of evidence). cluding eight randomised controlled trials 27-34. Question 2: Should deferoxamine versus the panel suggests treatment with defer.Management of Thalassemia – Iron chela- tion therapy. quality of evidence). and harms of the alternatives including long- the panel suggests treatment with defer. Due to longer half-life of deferasirox suggesting bet. dence based on our prioritized patient- tients while on chelation therapy. sirable and undesirable consequences.98. appropriate cost- effectiveness analyses in the KSA setting Recommendation 1: should be considered. for important critical outcomes was judged as details see “Regional consensus very low.1. One death occurred after 6 months  Deferoxamine should be considered in the deferiprone group which. therapy (e. Also. The overall quality of evi- effects should be monitored in pa. opinion” (Qari et al)6  Dose of iron chelation drug needs to Benefits & Harms of the Option: be tailored according to iron over. Data from one trial (57 cated and trained for deferoxamine patients. was as an alternative treatment in pa. Data asirox treatment or non. from one trial (36 patients) were unclear with responsiveness to deferasirox thera. compliance and side literature search. however. low  Patients need to be adequately edu. in-  Informed patient choice is of para. er-term patient-relevant outcomes should be asirox. 95% CI: -0. regard to liver fibrosis (Ishak score) at 12 py months (MD 0.9. mount importance We found no additional trials in the updated  Iron overload.

For these  Iron overload. 95% CI: -2. probably the majority of patients would prefer oral For thalassemia patients with iron overload. opinion” (Qari et al)6  Dose of iron chelation drug needs to Acceptability: be tailored according to iron over- The panel’s judgement was that treatment load with deferoxamine is acceptable to govern. A meta-analysis of three trials (227 patients. Comparing deferoxamine absolute effect: 186 fewer participants per drug cost including administration cost to 1000. this is not the case for patients not mount importance insured through a government plan. at 12 months (MD -1. 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. for deferoxamine would likely be the preferred details see “Regional consensus choice. 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. but many patients would meta-analysis of five trials (307 patients. the panel supposes quality of evidence). low deferiprone drug cost. Data from one trial (61 that deferiprone might be cheaper.82. better safety profile and the lower overall 0. low quality of evidence) In the government insured population of tha.49) whether one No obvious barriers to implementation were drug is superior to the alternative with regard identified.24 to 0.61. very likely prefer deferiprone due to its oral admin- low quality of evidence) evaluated change in istration. pa. very low quality of evidence) suggests a signif.88). both treatment options are  Informed patient choice is of para- covered.84.56. very iprone. Bisphosphonates and Zinc supplementation 11 months (MD -0. this might not be the panel suggests treatment with deferox- true for all patients (e. patients. combined resources required for patients on deferiprone are likely higher.8). (conditional recommendation.17). compliance and side patients. serum ferritin concentration (ng/ml) at 6. 95% CI: -4. 95% CI -313. Feasibility: 133.g. 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.  Patients need to be adequately edu- . the differing spectrum of possible adverse effects. 95% CI: -2.Management of Thalassemia – Iron chela- tion therapy. the KSA setting. 95% CI: 0. to change of serum ferritin (ng/ml). no chelation treatment is covered. 12 and 24 months. Although. However.45. the benefit of a of deferiprone (MD -1. iprone. a variability of patient’s values and Recommendation 2: preferences seems likely. 95% CI: from 54 fewer to 257 fewer. It remains unclear (MD .12 to 45. application of iron chelation.). A ment and physicians. amine rather than treatment with defer- tients experiencing adverse effects of defer.88 to 2. effects should be monitored in pa- so the cheaper treatment option with tients while on chelation therapy. Remarks: lassemia patients.94 to . small children. 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.02 to 0. etc.

appropriate cost. 95% CI: -0. on deferiprone (1 trial.g. Also. 95% CI -8. 95% CI: 41 fewer to 221 fewer. adverse effects of deferox. A significantly effectiveness analyses in the KSA setting lower number of patients experiencing ad- should be considered. 119 patients. cluding nine randomised controlled trials27. very low quality of evidence). (number of patients at end of study was not cardiac and/or endocrine impair.12 to -4.32. 95% CI 0. clear. We found one additional trial40 in the dence) when compared to the combination updated literature search. needs to be ensured quality evidence was available for myocardial  Deferiprone should be considered as T2* (ms) at 12 months (2 trials). One trial with severe cardiac iron overload. The overall quality therapy group at 12 months. MD – 0. 0. MD -136. Liver damage was not cilities (e. 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. very low quality of evi- 30.17. quality of evidence). Bisphosphonates and Zinc supplementation 12 cated and trained for deferoxamine important critical outcomes was judged as administration very low. 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. of evidence based on our prioritized patient- Values and Preferences: . very low quality of evidence). but 65 patients were randomised at the ment. 59 patients. 107 pa- er-term patient relevant outcomes should be tients. reported in any of the trials. absolute effect: 170 fewer participants sus deferoxamine in combination with defer. 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 Fisher8.45 to 0. 20 patients. Whereas. verse events at 12 months was reported in the group treated with deferoxamine alone (2 trials. per 1000.9.33.g. in.  For patients treated with deferox- amine: regular ophthalmologic ex. combination therapy) treatment groups. groups at 6 and 12 months (3 trials. low iprone be used for iron overload in thalasse. 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.35-39 . treated with deferoxamine alone(MD -6. There was Research Priorities: no significantly different change in serum Ideally. beginning) reported a significant benefit on amine treatment or non.Management of Thalassemia – Iron chela- tion therapy. trial.89. conducted. quality of evidence).22.11.13 to Question 3: Should deferoxamine alone ver. Only very low mote settings. FBC). very low iprone: easy access to monitoring fa. 95% CI -469. in particular in re. RR 0.84.86. There are an alternative treatment in patients unclear data for this outcome.61 to 195. further RCTs evaluating the benefits ferritin concentration (ng/ml) between both and harms of the alternatives including long. 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.

compliance and side Acceptability: effects should be monitored in pa- The panel’s judgement was that many pa. mia patients? the panel suggests treatment with deferox- . tients while on chelation therapy.  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. iprone. mount importance  Iron overload. this is not the case for pa. consequences in most settings. 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. FBC). no chelation treatment is covered. appropriate cost- effectiveness analyses in the KSA setting should be considered. amine alone rather than treatment with semia patients. the desirable overload. very tients not insured through a government plan. Addi. Bisphosphonates and Zinc supplementation 13 In government insured population of thalas. the panel  For patients treated with defer- supposes that combination therapy requires iprone: easy access to monitoring fa- more resources than monotherapy. cilities (e. to monotherapy ient application and possibly higher compli- ance using deferoxamine alone rather than Implementation Considerations: deferoxamine in combination with defer. be ensured iprone in the KSA setting. cardiac and/or endocrine consequences (i. Research Priorities: Ideally. However. combination therapy requires more opinion” (Qari et al)6 resources. deferoxamine in combination with defer- tion are covered. 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. There were no specific considerations relevant iprone) probably outweigh the undesirable for implementation of this recommendation. so the cheaper treatment option Remarks: with deferoxamine alone would likely be the  Informed patient choice is of para- preferred choice. low quality of evidence) For these patients.Management of Thalassemia – Iron chela- tion therapy. 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. (conditional recommendation. the lower overall resource impairment or non-responsiveness utilization. better safety profile. in particular in re- mote settings. details see “Regional consensus tionally. more conven.e. for tients would likely prefer monotherapy. further RCTs evaluating the benefits and harms of the alternatives including long- er-term patient-relevant outcomes should be conducted.g. Also. monotherapy and combina.

died at the beginning of the trial due to ar. Feasibility: tion (%) in the combination therapy group was No obvious barriers to implementation were not clearly evident when compared to mono. 20 patients. ably outweigh the desirable consequences in pared to deferiprone alone on serum ferritin most settings. no significant dif- cluding five randomised controlled trials27. therapy at 12 months (1 trial. supposes data). very low quality of Resource Use: evidence). very low quality of very low.Management of Thalassemia – Iron chela- tion therapy. tionally.87 to 30. 95% CI: 0. The same trial also re- ported five further deaths in patients who Acceptability: were relocated to treatment with deferox. so the cheaper treatment option The other trial reported one death in 5 years. Lastly. 193 patients. One trial semia patients. very low Cochrane systematic reviews by Fisher8. the burden of administra- mean change was not possible. We found no additional trials in the and/or agranulocytosis was found (3 trials. 95% CI: -468. evidence). possibly lower compliance. only graphic presentation of KSA setting.61. randomised to combination therapy. covered. .42. The panel. No clear feriprone rather than deferiprone alone prob- benefit or harm of combination therapy com. monotherapy and combina- (duration: 12 months) reported that one par. MD -1. A higher or lower left ventricular ejection frac. updated literature search. very low quali. Bisphosphonates and Zinc supplementation 14 concentration (ng/ml) at 6 and 12 months was Summary of Findings: evident in the data (3 trials. neutropenia 29. In government insured population of thalas- tients. RR 1. A benefit or harm of combination ther.41.39. however.99 to 12. The overall quality 217 patients.9. iron concentration (mg/g dry weight) at 12 months could not be demonstrated clearly (1 Balance between desirable and undesirable trial. very patients with iron overload. with deferiprone alone would likely be the due to arrhythmia in the group treated with preferred choice. but calculating the consequences (i. this is not the case for pa- ticipant.42 to 1. very low quality of evidence). 95% CI: -1. deferiprone versus deferiprone alone in the ty of evidence.41. MD The summary of evidence is based on two -219. However.2. consequences: very low quality of evidence). The panel’s judgement was that many pa- amine alone due to adverse events of the tients would likely prefer monotherapy. withdrawal of the randomised treatment. 20 patients. MD 5. tients not insured through a government plan. combination therapy.e.76 to 2. absolute effect: 54 more cases per 1000.25. the undesirable low quality of evidence). ference in risk for leucopenia. For these patients. identified. in. tion are covered. due to varia. 95% CI -3. 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. 95% important critical outcomes was judged as CI: 32 fewer to 213 more. Benefits & Harms of the Option: Values and Preferences: Mortality was reported in two trials (237 pa. 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. that a combination therapy requires more apy compared to deferiprone alone on liver resources than a monotherapy. Myocardial T2* The panel considered that for thalassemia was reported by one trial (54 patients. quality of evidence).36. Addi- treatment they were initially randomised to. 33 patients. no chelation treatment is rhythmia-induced congestive heart failure. tion. of evidence based on our prioritized patient. combination therapy requires more these patients died 11 to 60 months after resources.42 . higher re- ble durations of follow up.

12 including five random-  Iron overload. 95% CI: 0. 95% CI: 0. patients treated with bisphosphonates using er-term patient-relevant outcomes should be DXA at 12 and 24 months was reported (3 trials.44 to 156. In the  Combination therapy should be first trial. RR 0. Regarding flu-like symptoms Implementation Considerations: after a first infusion of neridronate 100mg. The summary of evidence is based on two mount importance systematic reviews11. The follow-up48 after effects should be monitored in pa. overload  For patients treated with defer. For thalassemia patients with iron overload. 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.g. 207 patients. patients treated with zoledronic acid considered as an alternative treat.02 to . cross-over of one trial47 was not considered. Question 5: Should bisphosphonates versus iprone rather than treatment with defer. 95% CI: 0. reported only narratively on back or bone pain amine administration at 12 months (low quality of evidence).27. amination and audiometry needs to absolute effect: 7 fewer patients per 1000. showed a high reduction of pain scores. We found no additional trial in the updated for details see “Regional consensus literature search. low Research Priorities: quality of evidence). Bisphosphonates and Zinc supplementation 15 conducted. A significantly higher Ideally. tients while on chelation therapy. quality of evidence). In the crine impairment or non. ment in patients with severe cardiac whereas patients in the control group showed iron overload. Benefits & Harms of the Option: iprone: easy access to monitoring Comparing bisphosphonates to no bisphos- facilities (e. no change during the study period. further RCTs evaluating the benefits lumbar spine bone mineral density (g/cm²) in and harms of the alternatives including long. RR 8. patients. no bisphosphonates be used for manage- iprone alone. appropriate cost- Recommendation 4: effectiveness analyses in the KSA setting should be considered. the evidence did not preclude a lower or tion therapy. and 24 months was very imprecise (3 trials. be ensured 95% CI: from 10 fewer to 60 more.31.03. (conditional recommendation ment of thalassemia-associated osteoporo- against. compliance and side ised controlled trials43-47.01 to 6. needs to be en. cardiac and/or endo. 191 patients MD 0.Management of Thalassemia – Iron chela- tion therapy. other trial. very low  Patients need to be adequately ed. 118 members. the panel suggests against treatment with deferoxamine in combination with defer. For this recommendation against a combina. implementation considerations higher incidence of symptoms compared to no are not considered to be relevant by the panel bisphosphonate treatment (one trial. FBC). number of participants experiencing at least sured one vertebral or non-vertebral fracture at 12  For patients treated with deferox. very low quality of evidence) sis? Remarks: Summary of Findings:  Informed patient choice is of para. in particular in phonates the estimate for the difference in remote settings. Also. amine: regular ophthalmologic ex.85.70. mean back pain scale score was responsiveness to monotherapy also significantly improved in patients treated with neridronate. Two trials (184 patients) ucated and trained for deferox.

ty should be monitored in patients tion with regard to the considered outcomes. tients treated with bisphosphonates should be established. Resource Use: We found no economic evaluation addressing Research Priorities: the use of bisphosphonates versus no Ideally. A significantly consequences (i. possible side-effects) (g/cm²) 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. and calcium supplementation therefore health inequities might be in. Remarks: er.  Patients with a history of fractures creased. treatment with bisphosphonates. 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. higher femoral neck bone mineral density resource utilization. Bisphosphonates and Zinc supplementation 16 0. relevant outcomes should be conducted.49 to osteoporosis. low quality of evidence). This is not the case for patients rosis should be based on vitamin D not insured through a government plan. fractures) acceptability seems selected patients should be made likely. appropriate cost-effectiveness analyses in the Balance between desirable and undesirable KSA setting should be considered. very low Values and Preferences: quality of evidence) No published evidence with regard to the considered outcomes was identified. but were judged to be moderate.96. calcium and bone densi- in values within the KSA thalassemia popula.e.Management of Thalassemia – Iron chela- tion therapy.g.05. with thalassemia Treatment with bisphosphonates is covered in  Prevention and first line treatment government insured thalassemia patients with of thalassemia-associated osteopo- osteoporosis. benefits. the undesirable Question 6: Should zinc supplements versus . low quality of evidence).05 . low quality of evidence). MD 0. 95% CI: 1.72. 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. 95% CI: 0.02 sirable consequences given unclear health to 0. Also. a decision about For more severely affected thalassemia pa. Implementation Considerations and Monitor- government insured people.08. (condi- tional recommendation against. treatment with bisphosphonates in tients (e. given the ad- verse effects and potential costs for non. consequences: The panel considered that for thalassemia patients with osteoporosis. jointly. Moni- No obvious barriers to implementation were toring of benefits and adverse effects in pa- identified. acceptability will ing: likely vary. 89 patients. and/or proven severe osteoporosis should be referred to an endocri- Acceptability: nologist. As prophylactic measure. RR 10. Howev. panel members assumed some variability  Vitamin D. the panel suggests against 76. pain. Standardized criteria for the use of bisphos- phonates in high-risk patients should be es- Feasibility: tablished and its application monitored. burden of administration. 191 patients. further RCTs evaluating the benefits bisphosphonates in the KSA setting.

the health benefits is somewhat uncertain. MD 0.6. and adolescents with thalassemia major. Cost of zinc supplements are likely low. but ing two randomised controlled trials49.Management of Thalassemia – Iron chela- tion therapy. feasible rum zinc at 3 months (MD 47. In one trial (60 patients). panel members assumed some variability adolescents with beta thalassemia major? in values within the KSA thalassemia popula- tion with regard to the considered outcomes. ever. tion. Bisphosphonates and Zinc supplementation 17 no zinc supplements be used in children and er. No trial reported haemoglobin Recommendation 6: levels. months. it might well be that some z-score) at 9 months.03) in the other trial at 9 months (low quality of evidence). the with zinc supplements. 60 patients.19 to 0. Three trials reported ting. 95% CI: implementation.44) compared to no treatment use and prevention of zinc deficiency.60. For children and adolescents with thalasse- Values and Preferences: mia major. includ. therefore additional resources in diarrhea. due to no relevant side effects.52 in the updated literature search. 95% CI: -12. MD 0. Cochrane systematic review by Swe13. The ties.11 .0.22. the panel suggests zinc supple- No published evidence with regard to the mentation rather than no zinc supplementa- considered outcomes was identified.85. SMD 0. stomach upset and nausea at 18 these cases are required. We limited access to measurement and monitor- found two additional randomised controlled ing of zinc levels might increase health inequi- trials51. How- use of 220 mg zincsulfate led to a higher se. However.63. very . SMD . moderate to small resource 16. One trial did not observe signifi. relevance of levels (µg/dl). overall quality of evidence based on our prior- itized patient-important critical outcomes was Acceptability: judged as very low. Howev. consequences: turbances in 1-8% of the study population at 9 Due to very low quality of evidence for bene- months.50. 95% ceptable given the unclear benefits. Summary of Findings: in particular given the prophylactic nature of The summary of evidence is based on a this intervention.16 to 78. adverse events (138 patients.25. low the use of zinc versus no zinc in the KSA set- quality of evidence). 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. Two studies reported serum zinc fits of zinc supplementation. Balance between desirable and undesirable The third trial mentioned gastrointestinal dis. Data from two trials were unclear with regard to bodyweight Resource Use: (kg or z-score) at 9 and 18 months (92 pa. very low quality of evidence). CI: -0.83 to 14.65 to fied.30. No significantly higher or lower body mass Feasibility: index (kg/m²) at 3 months was observed (1 No obvious barriers to implementation identi- trial. We found no economic evaluation addressing tients. 1. (conditional recommendation. very low quality Costs are likely to be low. The second trial reported that no visible side effects were observed at 1-7 years. low quality of evidence). 95% CI: -0. Monitoring zinc of evidence). tients.47 to 0. 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. 95%CI: -0. uptake is not available at all medical centers in cant differences in adverse events including the KSA. while dispensing 30 panel suggests offering this option in children mg zincsulfate showed no difference (60 pa.

by baseline zinc levels including longer-term olism patient-relevant outcomes and research of • Serum zinc levels should be moni.Management of Thalassemia – Iron chela- tion therapy. Remarks: • Practically all patients with thalas. Research Priorities: semia major are receiving (or will Ideally. Bisphosphonates and Zinc supplementation 18 low quality of evidence) There were no specific considerations relevant for implementation of this recommendation. Also. further RCTs evaluating the benefits receive) iron chelation therapy and harms of zinc supplementation stratified which can interact with zinc metab. prevalence in zinc deficiency should be con- tored in patients with iron chelation ducted. 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: .

Guyatt G. Alhamdan NA. 9. 18.5:1147-53.27:109-11. Modell B. western Saudi Arabia. Helfand M. Chowdhury O. Schunemann HJ. Darlison M. Swe KM. Osteoporos Int 2010. 17. A phase 3 study of deferasirox (ICL670). Genet Med 2007. Roberts DJ. WHO Handbook for Guideline Development. Global epidemiology of haemoglobin disorders and derived service indicators. Premarital screening for thalassemia and sickle cell disease in Saudi Arabia. Global epidemiology of hemoglobin disorders. Mamtani M. in patients with beta-thalassemia. Erdogan E. Oral deferiprone for iron chelation in people with thalassaemia. Oxman AD. Oxman AD. Nair NS. Saeedi MY.9:372-7. Guyatt G. 3. Blood 2006. Alswaidi FM. Fisher SA. Al Jaouni S. Orphanet J Rare Dis 2013. 15.107:3455-62. Deferasirox for managing iron overload in people with thalassaemia. Choudhry AJ.int/iris/bitstream/10665/75146/1/9789241548441_eng. Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials. 8. Andrews J. Bulletin of the World Health Organization 2008. et al.64:383-94. Prevalence of thalassemia disorders and hemoglobinopathies in Jeddah. 7. The effects of chelators on zinc levels in patients with thalassemia major. Albagshi MH. Cochrane Database Syst Rev 2013. et al. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 2013. 6. J Clin Epidemiol 2011. Cochrane Database Syst Rev 2013. J Epidemiol Glob Health 2011. et al. J Clin Epidemiol 2011. 5. Annals of the New York Academy of Sciences 1998. GRADE guidelines: 1. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. Brunskill SJ. Angastiniotis M. Giusti A.1:61-8. Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia.who. Guyatt GH. 12. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Vist GE. 2. East Mediterr Health J 1999. Cochrane Database Syst Rev 2012.32:606-15.336:924-6. Bhardwaj A.8:Cd004450. Prevalence of beta-thalassemia trait in premarital screening in Al-Hassa. Meerpohl JJ. et al. (Accessed February 7. World Health Organization. 20.64:401-6. Al-Suliman A. 4. Going from evidence to recommendations: the significance and presentation of recommendations. Introduction-GRADE evidence profiles and summary of findings tables.1:43-6. Qari MH. Vural H. Barua A. Antes G. Modell B. Journal of Applied Hematology 2010. Cappellini MD. Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area. 2012. Ann Saudi Med 2006. J Bone Miner Metab 2014. Abas AB. Owaidah TM. 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. Cochrane Database Syst Rev 2013.66:719-25. Fisher SA. Memish ZA. Aylak F. Saudi Arabia. Warsy AS. Doree C. Gooding S. GRADE guidelines: 3. Roberts DJ. Kulkarni H.Management of Thalassemia – Iron chela- tion therapy. .8:Cd004839. et al. Balshem H. Chowdhury O. a once-daily oral iron chelator. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review. 19. Almazrou YY.2:Cd007476. 11. Akl EA. BMJ 2008. Rating the quality of evidence. Gooding S. El-Hazmi MA. 10. Brunskill SJ. 2014. Wali Y.86:480-7.850:251-69. Doree C.26:14-6.8:143. Piga A. Bisphosphonates and Zinc supplementation 19 References 1. Rucker G.21:183-7. 13. Cohen A. et al. 21.) 16. Zinc supplements for treating thalassaemia and sickle cell disease. Oxman AD. at http://apps. J Clin Epidemiol 2013. GRADE guidelines: 14.pdf. et al. Ormeci AR. 14.6:Cd009415. Canatan D.

23. Abdelrazik N. et al. et al. D'Amico G. et al.30:263-74. Br J Haematol 2003. Forni GL. Kattamis A. in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Morabito A.3:93-7. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. Chik KW. et al. 36. Aydinok Y. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). Molavi MA DH. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Galanello R. Pennell DJ. Bisphosphonates and Zinc supplementation 20 22. Berdoukas V. 31. Final results of the randomized trial of deferiprone (L1) and deferoxamine (DFO) [abstract]. Terzi A.336:1275-9. Saxena R. Blood Cells Mol Dis 2002. Evazi R.106:2698-. et al. double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Hermann C. Comparison of deferasirox and deferoxamine treatment in iron-overloaded patients: Liver iron concentration determined by quantitative MRI-R2*. et al. Sheikh-Taha M. placebo-controlled. Tanner MA. [Chinese]. . 35. Hemoglobin 2006. Evans P. a once-daily. Taher A. 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. Ling SC.12:577-85. Ha SY. Peng P. Haematologica 2006. Naja M. Koussa S. Tamaddoni A RM. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. ASH Annual Meeting Abstracts 2005.12:655-9. Khoriaty AI. Piga A. Long LL. Gomber S. deferiprone and in combination on iron chelation in thalassemic children. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Circulation 2007. Comparison of therapeutic response and complications of oral Osveral and injection Desfereal chelating agent in patient with thalassemia major. Taher A. Al Jefri A. 39. Porter JB. A randomized. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 1997. Porter JB. Indian Pediatr 2004. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Huang ZK.87:545-50. 33. Karagiorga M. Comparative efficacy of desferrioxamine. Iranian Red Crescent Medical Journal 2010. Acta haematologica 2010. Haematologica 2006. Piga A. Maggio A. Galanello R. Manz C. Asian Journal of Medical and Pharmaceutical Researches 2013. 32.107:3738-44. Chinese Journal of Radiology (China)2013:55-9. et al. Madan N. Randomized phase II trial of deferasirox (Exjade. Blood 2006. 29. Ann Hematol 2008. Mansoori F. Chelation Efficiency.28:196-208. 25.90:264a. et al. et al. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong.123:220-5. Piga A. Olivieri NF BG. Nazemi A.91:873-80.121:187-9. 28. orally-administered iron chelator. Olivieri NF. Galanello R. 27. 34. 30. 24. Elalfy MS. et al. Pennell DJ.115:1876-84.Management of Thalassemia – Iron chela- tion therapy. Hoffbrand AV. ICL670). Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. Blood 2014. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Dessi C. Randomised Prospective Evaluation of Iron Balance.123:1447-54. Lancet 1990.91:1241-3. El-Beshlawy A. Hematology 2007. et al. Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial. Mourad FH. 37. Cetiner N.41:21-7. 38. Koren G. 26.

Nart D. Haematologica 2007. quality of life. King JC. Aydinok Y.24:127-36. 45. Gildengorin G. parallel-arm.158:274-82.21:402-8. Strauss BJ. Morabito N. Konstantopoulos K.19:113-9. Capra M. et al. Cavdar A. et al. Krol M.145:245-54. Voskaridou E. Voskaridou E. et al. Pennisi P. Cost-utility analysis of deferiprone for the treatment of beta-thalassaemia patients with chronic iron overload: a UK perspective. et al. Ulger Z. Osteoporos Int 2002. Rodda CP. Bisphosphonates and Zinc supplementation 21 40. Tricta F. Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia major.21:8-14. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center. open-label study. J Cardiovasc Magn Reson 2013. Hematology 2014. Mantovani LG.24:1905-17. Fung EB. 53. 46. 54. Lasco A. Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalassemia major Patients.79:138-44.15:38. Br J Haematol 2009. et al. Arcasoy A. Anagnostopoulos A. Vitrano A. Joshaghani H. Am J Hematol 1987. Pharmacoeconomics 2013. Vichinsky EP. Calcif Tissue Int 2006.98:960-71. 43. Banihashem A. 49. Gillard S. Riccobene S.91:1193-202. Effects of zinc supplementation on linear growth in beta- thalassemia (a new approach). Kwiatkowski JL. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2. Arefhosseini SR. randomized. Bentley A. 52. treatment satisfaction and compliance in patients with beta-thalassemia major undergoing iron chelation therapy: the ITHACA study. placebo-controlled trial. Connelly J. Haematologica 2006. Huang JN. 42.93:1588-90. Pizzarelli G. Br J Haematol 2012. Alexakos P. Haematologica 2008. Zinc supplementation improves bone density in patients with thalassemia: a double-blind. . Wood J.31:807-22. Terpos E. placebo-controlled trial. Fiore CE. 48. Gilfillan CP. 41. Christoulas D. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. 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. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. Tsiftsakis E. placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia. Spino M. Giusti A. et al. Gaudio A. Rafraf M. Current medical research and opinion 2008. J Bone Miner Metab 2003. Scalone L. double-blind. Cin S. Am J Clin Nutr 2013. randomized. 44. et al. Costs. Rashidi M. Aboomardani M. Forni GL. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial. Spina M. et al. et al.Management of Thalassemia – Iron chela- tion therapy.13:644-9. Konstantinidou M. 50. et al. Mirhossini NZ. Maggio A. 51. Porter JB. randomized. 47. Keshtkar A.92:1599-606. Olivieri N. Bisphosphonates in the treatment of thalassemia- induced osteoporosis. placebo-controlled trial. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. Perrotta S. Ghahramanlu E. Iran J Pediatr 2011. A randomized.

Management of Thalassemia – Iron chela- tion therapy. Appendix 2: Search Strategies and Results . Appendix 1: Evidence-to-Decision Tables 2. Bisphosphonates and Zinc supplementation 22 Appendices 1.

Relative Certainty of the What is the studies Outcome Given the different modes of ap- Benefits & importance evidence (GRADE) harms of the overall cer. .4% (307/8918) beta-thalassemia trait prevalence in premarital couples Is there a ○ Uncertain living in the Al-Hassa area was observed. Alt- hough this might not be true for ○ Moderate all patients (e. 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. The prevalence of beta-thalassemia trait ● Yes among neonates in the same area was 0. small children.1 ○ Varies The relative importance or values of the main outcomes of interest: Long term experience with defer- ○ No included asirox is limited.Management of Thalassemia – Iron chela- tion therapy. leading to increased patient compliance due to the more convenient application. western Saudi Arabia. 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. ○ Very low plication and the differing spec- trum of possible adverse effects. Background and Objective: Deferoxamine.g. the standard iron chelating drug. a tainty of this ⨁⨁◯◯ options evidence? ● Low Mortality at 48 weeks and 1 year CRITICAL LOW variability of patient’s values and preferences seems likely. showed that 316 (4.69%) had beta-thalassemia trait. Oral chelation Option: Deferasirox therapy with deferasirox is suggested to be at least similarly effective.2 Problem problem pri- ority? ○ Probably yes A screening of 6750 healthy persons in Jeddah."6 ○ Probably no In 2004.96% (8/834). a 3. 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.

Treatment with deferasirox Is there im. etc.1 ○ Varies damage . (mg Fe/g dw) evaluated by biopsy or CRITICAL ⨁⨁⨁◯ chelation with deferoxamine MODERATE and/or deferiprone (n=237) be- portant uncer. ity comes? ○ No important Compliance (% of dose taken by pa- IMPORTANT ⨁⨁◯◯ uncertainty of tients) . Any serious adverse event . ○ Uncertain Mortality at 5 fewer per RR 0. for one year led to high compli- portant un.at 12 months LOW iron-overloaded thalassemia pa- variability tients from the Middle-East.at 12 CRITICAL ably the majority of patients months LOW would prefer oral application of iron chelation.mean change from ⨁⨁◯◯ supported by a study26 including CRITICAL uncertainty or baseline .). tainty or variabil.Cardiac: Left ven- ⨁⨁◯◯ effects of deferasirox. certainty IMPORTANT about how ○ Probably no 8 and 12 months MODERATE much people important uncer- ⨁⨁◯◯ value the tainty of variabil.09 to 2. SQUID . This assumption is ● Important Myocardial T2* (ms) .at 12 months fore.Management of Thalassemia – Iron chela- tion therapy. ity Mean change in serum ferritin (µg/l) .63) large? 16 more) ○ Yes End-organ Left ventricular Left ventricular ejec. ejection fraction tion fraction (%) at lower - . MD 0.at ⨁⨁⨁◯ ance and satisfaction.48 able antici.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. prob- tricular ejection fraction (%) .at 12 months IMPORTANT LOW main out. Bisphosphonates and Zinc supplementation 24 patients experiencing adverse ○ High End-organ damage . 5 per 1000 1000 (from pated effects ○ Probably yes 48 weeks and 10 per 1000 1 year (1 to 26) 9 fewer to (0. who Mean change in liver iron concentration had not achieved successful iron ○ Possibly im.

07 ble effects? ○ Yes biopsy or LIC was 2.37 large relative months) in the was 2.133). 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.07 lower to 1. i. by biopsy or SQUID at Are the desir.at ○ Varies 12 months (3.68 lower).6] ms at EOS) and ○ Varies Myocardial T2* (ms)- by 7% for DFO (11.at lower to 1.056 (repeated 95% CI 0.e.64 ○ Probably no ejection frac.7] ms).4-0.07 at 8 and 12 and 12 months) in intervention group higher to . The ratio of the Gmeans of deferasirox over DFO was 1. reduction was higher in deferoxamine group Mean change The range for Change in serum MD 415. A trend for months superiority of deferasirox compared with DFO was observed.4 was 0.84 higher) tion (%) .3 [34.68 higher - evaluated by -6. Gmean (coefficient of variance) small? myocardial T2* improved after 1 year of treatment with deferasirox ○ Yes by 12 % (11.6 [42.Management of Thalassemia – Iron chela- tion therapy.37 lower higher) SQUID .68 higher to undesira- ○ Probably yes (mg Fe/g dw) control group was higher to 3.998. reduction in to 3. group was 66.7] ms to 12. Because the lower bound of the 95% CI was greater than from baseline prespecified margin of 0. noninferiority of deferasirox compared .e. i.9. 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 1.2 [32.07 high. ed by biopsy or 12 months) in the able effects ● Uncertain in liver iron concentration SQUID at 12 intervention group MD 2. ● Uncertain 12 months sirable antici- pated effects ○ Probably yes "In the per-protocol population.6] ms at baseline to 12.1 lower (1. mean change 1. (1.6 [30.64 higher) Are the unde.72 in serum change in serum ferritin (µg/l) (at 8 higher - ferritin (µg/l) ferritin (µg/l) (at 8 and 12 months) in the (295.5 er).at 12 with DFO for myocardial iron removal was demonstrated. alt- hough this did not reach statistical significance.37 higher (1.

95 12 months 100.75 lower to 0.37 higher). i.37 lower to 295.Management of Thalassemia – Iron chela- tion therapy.53 . No specific data on costs of defer- ○ No asirox or deferoxamine in KSA ○ Probably no setting found.37 was -1277-211 (295.07 higher to higher) 536.4 lower to 0.44 to event-at 12 (25 to 80) more to 32 1.78 adverse 45 per 1000 58 per 1000 (from 22 (0.95 higher) higher) No research evidence specific to KSA setting identified.4 (3.e. ○ Uncertain ment of beta-thalassemia patients with chronic iron overload esti- Resource use sources re- quired small? ● Probably yes mates 23.at control group was group was 1. A cost-utility analy- sis of deferasirox for the treat- Are the re.025 pounds per one-year treatment with ge- ○ Varies neric deferoxamine including administration cost.72 lower (536.179 pounds per year treatment with deferasirox ○ Yes (Exjade®) versus 8.38) months fewer) Compliance (% of Compliance (% of Compliance dose taken by dose taken by pa. Bisphosphonates and Zinc supplementation 26 months the control group was 415.4 (% of dose patients) at 12 tients) at 12 months lower taken by months in the in the intervention (3. reduction was higher in deferoxamine group 13 fewer Any serious per 1000 RR 0. i. MD 1.e.75 lower - patients) . reduction in serum ferritin was 415.72 higher 536.07 lower).

Bisphosphonates and Zinc supplementation 27 Competitors provide a cheaper alternative to Exjade® in KSA. so cost Equity on health ○ Probably re. In government insured population ○ Increased of thalassemia patients. ○ 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. both ● Probably in. For these patients. no chela- be the impact tion treatment is covered. No research evidence specific to KSA setting identified. treatment options are covered. considerations will influence inequities? duced choice of treatment. ○ Reduced ○ Varies . this is not the case for patients creased not insured through a government What would ○ Uncertain plan.Management of Thalassemia – Iron chela- tion therapy.

Over- Is the option ○ Uncertain all (mean (SD)) compliance was 98. ○ No tients from Saudi-Arabia.8% at end of study versus 21.4 (4. ○ Probably no Is the option ○ Uncertain Feasibility feasible to implement? ○ Probably yes ● Yes ○ Varies . ○ Probably yes ient" to "very dissatisfied" or "very inconvenient") 90.3% patients still received deferasirox (persistence). 98. Most patients would likely prefer One study (Taher 2010)26 was identified.oral application.6) %. On a 5-point scale (ranging from "very satisfied" or "very conven- Acceptability key stake. including iron-overloaded thalassemia pa. Treated with deferasirox for one year. No research evidence specific to KSA setting identified.2% at ● Yes baseline.2 (8.6) h/month at end of study). 92.Management of Thalassemia – Iron chela- tion therapy.7% of all patients reported being holders? either "satisfied" or "very satisfied" with their iron chelation therapy versus 23. 86. Bisphosphonates and Zinc supplementation 28 No research evidence specific to KSA setting identified. Time lost to therapy for daily activities was reduced ○ Varies (30.2) (mean (SD) h/month) at baseline to (3. who had not ○ Probably no achieved successful iron chelation with DFO and/or deferiprone (n=237).1% received at least 95% of their acceptable to scheduled doses.1 (44.5% at baseline considered their therapy to be "convenient/very convenient". No obvious barriers to implemen- ○ No tation were identified. but also other patients from the Middle East.

Management of Thalassemia – Iron chela- tion therapy. compliance and side effects should be monitored in patients while on chelation therapy. For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured. the panel suggests treatment with deferasirox rather than treatment with deferoxamine (conditional Recommendation recommendation. for details see “Regional consensus opin- Monitoring and eval. Due to longer half-life Justification of deferasirox suggesting better protection against free iron and probable better compliance due to oral administration. 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. Desirable consequences es clearly outweigh Balance of clearly outweigh desirable probably outweigh desirable able and undesirable conse. uation Dose of iron chelation drug needs to be tailored according to iron overload. deferoxamine be used for iron overload in thalassemia patients? Desirable consequenc- Undesirable consequences Undesirable consequences The balance between desir. low quality of evidence).g. Patients need to be adequately educated and trained for deferoxamine administration. probably outweigh undesir- undesirable conse- consequences consequences in most set. Bisphosphonates and Zinc supplementation 29 Recommendation Should deferasirox vs. . Iron overload. considerations Informed patient choice is of paramount importance. combination therapy) needs to be considered. This recommendation is conditional mainly due to uncertain and assumed close balance based on low quality of evidence. Deferoxamine should be considered as an alternative treatment in patients with adverse effects of deferasirox treatment or non-responsiveness Subgroup considera. Implementation No specific considerations relevant for implementation of this recommendation. the panel suggests treatment with deferasirox. ion” (Qari et al)6. tions In patients with severe iron overload and/or significant cardiac/endocrine impairment or non-responsiveness to monotherapy intensified chela- tion therapy (e. consequences in most set. to deferasirox therapy.

appropriate cost-effectiveness analyses in the KSA setting should be considered.Management of Thalassemia – Iron chela- tion therapy. . Research possibilities Also. further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conducted. Bisphosphonates and Zinc supplementation 30 Ideally.

at 12 months 3 4 1 randomised serious not serious not serious serious none 91 81 . although this did not reach statistical signifi- cance.056 (repeated 95% CI 0.6 [42. 1.7] ms to 12.6] ms at base- line to 12.09 to LOW 2.6] ms at EOS) and by 7% for DFO (11. MD 0.63) End-organ damage .5%) (0.6[30.3 [34.84 lower to 1. Gmean (coefficient of ⨁⨁◯◯ CRITICAL trial variance) myocardial T2* improved after 1 year of treat. A trend for superiority of deferasirox compared with DFO was ob- served. MD 2.7] ms).68 higher to 3.Cardiac: Left ventricular ejection fraction (%) .64 higher) LOW Myocardial T2* (ms)-mean change from baseline .1 lower ⨁⨁◯◯ CRITICAL trial (1. 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 (1.48 5 fewer per 1000 (from 9 fewer to 16 more) ⨁⨁◯◯ CRITICAL trials (0.Management of Thalassemia – Iron chela- tion therapy.at 12 months 5 6 7 1 randomised serious serious not serious not serious dose response 268 273 .0%) RR 0.07 higher) MODERATE .37 higher ⨁⨁⨁◯ CRITICAL trial gradient (1. Because the lower bound of the 95% CI was greater than prespecified margin of 0.9. The ratio of the Gmeans of deferasirox over DFO was 1. noninferiority of deferasirox compared with DFO for myocardial iron removal was demonstrated. LOW ment with deferasirox by 12 % (11.at 12 months 3 4 1 randomised serious not serious not serious serious none 91 81 "In the per-protocol population. 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.133).998. 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 .2 [32.

selective reporting (2 studies) 2. heterogeneity due to different ratio of drugs between subgroups 11. MD 1. lack of blinding of outcome assessment (3 studies). including smaller study population. lack of blinding of outcome assessment.07 higher to 536. SD – standard deviation 1. Bisphosphonates and Zinc supplementation 32 Mean change in serum ferritin (µg/l) at 8 and 12 months 8 9 10 3 randomised serious serious not serious not serious dose response 443 430 .38) Compliance (% of dose taken by patients) . I²=84%.44 to LOW 1. incomplete outcome data (1 study). lack of blinding of outcome assessment (2 studies). lack of blinding of outcome assessment.4 lower ⨁⨁◯◯ IMPORTANT trial (3. Very wide confidence interval including both clinically relevant benefit as well as harm 3. Only few patients were included in study 5. no SD mentioned 6. High risk of bias due to lack of blinding of participants and personnel.at 12 months 3 4 1 randomised serious not serious not serious serious none 96 91 . measured LIC (mg Fe/g dw) by MRI. selective reporting (1 study). High risk of bias due to lack of blinding of participants and personnel (2 studies). Unclear: Random sequence generation (3 studies). lack of blinding of outcome assessment (3 studies). whereas there was a tendency for ferritin values to increase modestly over time in patients randomised to deferasirox 10 mg/kg/day" 9.8%) RR 0. incomplete outcome data (1 study). incomplete outcome data (2 studies).at 12 months 11 2 2 randomised serious not serious not serious serious none 18/392 22/381 (5.72 higher ⨁⨁⨁◯ IMPORTANT trials gradient (295. a significant decrease with deferoxamine compared to deferasirox was shown. MD 415. High risk of bias due to lack of blinding of participants and personnel.00001. incomplete outcome data. incomplete outcome data (1 study). An additional study (Piga 2006) reported that "mean serum ferritin levels remained stable in the deferasirox 20 mg/kg/d and DFO groups. incomplete outcome data (1 study). Unclear: Random sequence generation (2 studies). RR – relative risk. p<0. Unclear: Random sequence generation 4. Another study (Piga 2006) reported average decreases of similar magnitudes measured by SQUID.75 lower to 0. selective reporting (1 study) 10. p<0.6%) (0. I²=91%. Unclear: Random sequence generation (2 studies). High risk of bias due to lack of blinding of participants and personnel (3 studies). High risk of bias due to lack of blinding of participants and personnel (3 studies). selective reporting (1 study) . allocation concealment (2 studies). Heterogeneity due to different ratio of drugs between subgroups 8. incomplete outcome data (1 study). Unclear: Random sequence generation. allocation concealment (2 studies).78 13 fewer per 1000 (from 22 more to 32 fewer) ⨁⨁◯◯ IMPORTANT trials (4. An additional study (Pennell 2014).Management of Thalassemia – Iron chela- tion therapy. allocation concealment (1 study).37 higher) MODERATE Any serious adverse event . allocation concealment.95 higher) LOW MD – mean difference. selective reporting 7.000001.

123:1447-54. Asian Journal of Medical and Pharmaceutical Researches 2013. Pennell DJ. 3. Blood 2006. Piga A.91:873-80. Comparison of therapeutic response and complications of oral Osveral and injection Desfereal chelating agent in patient with thalassemia major. 2. in patients with beta-thalassemia. a once-daily. a once-daily oral iron chelator.Management of Thalassemia – Iron chela- tion therapy. Mansoori F. Evazi R. 4. Cohen A. Galanello R. Piga A. et al. Molavi MA DH. Bisphosphonates and Zinc supplementation 33 References 1. Forni GL. Piga A. Haematologica 2006. Nazemi A. et al. A phase 3 study of deferasirox (ICL670). . Blood 2014. ICL670). et al.3:93-7. orally-administered iron chelator. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). Randomized phase II trial of deferasirox (Exjade.107:3455-62. Porter JB. Cappellini MD. in comparison to deferoxamine in thalassemia patients with transfusional iron overload.

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. Although. 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.69%) had beta-thalassemia trait.96% (8/834). western Saudi Arabia.4% (307/8918) beta-thalassemia trait prevalence in premarital couples ○ Uncertain living in the Al-Hassa area was observed. probably the Mortality CRITICAL majority of patients would pre- ○ Moderate VERY LOW fer oral application of iron che- .2 Is there a Problem problem prior.” 6 ○ Probably no In 2004. ○ Probably A screening of 6750 healthy persons in Jeddah. Option: Deferoxamine Oral chelation therapy with deferiprone is suggested to be at least similarly effective. showed that ity? yes 316 (4. leading to increased patient compliance due to the more convenient application.Management of Thalassemia – Iron chela- tion therapy. a 3. 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. a variability of patient’s values and preferences seems options evidence? ○ Low ⨁◯◯◯ likely. the standard iron-chelating drug. The prevalence of beta-thalassemia trait ● Yes among neonates in the same area was 0.1 ○ 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.

at 6.at CRITICAL 12 months VERY LOW important uncertainty or Is there im. etc. One death occured in the deferiprone treatment arm after six months pated effects large? ○ Uncertain Mortality of treatment. 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. from baseline (ng/ml) .Liver: Liver fibrosis Ishak ●Important score (ranging from 0-6. ⨁⨁◯◯ IMPORTANT people value uncertainty of riencing an adverse event – at 12 months LOW the main out.Cardiac: Left ventricular ⨁◯◯◯ all patients (e.).Management of Thalassemia – Iron chela- tion therapy. ○ Probably no "Only one trial reported mortality as an outcome (Ha 2006). End organ damage . variability Serum ferritin concentration: mean change ⨁◯◯◯ IMPORTANT portant uncer. 0 indicating no fibro.variability comes? ○ No im. CRITICAL ⨁⨁◯◯ sis): mean at endpoint . small children.g. ejection fraction: mean change from baseline CRITICAL VERY LOW patients experiencing adverse (%) .Number of participants expe. this might not be true for ○ High End organ damage . this death was attributed to cardiac complications and thought not to be related to deferiprone treatment" (Fisher ● Probably 2013) yes .at 12 and 24 months effects of deferiprone. 12 and 24 months VERY LOW tainty about ○ Probably no how much important Adverse events .at 12 months LOW uncertainty or variability Liver iron concentration: mean change from ○ Possibly ⨁◯◯◯ baseline (mg/g dry weight) using SQUID . Participant compliance (%) . Bisphosphonates and Zinc supplementation 35 lation.at 12 months IMPORTANT ⨁◯◯◯ portant uncer.

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

Is the option ○ Probably no Feasibility feasible to implement? ○ Uncertain ○ Probably yes . No obvious barriers to imple- ○ No mentation were identified. but many patients Is the option ○ Uncertain would likely prefer deferiprone acceptable to due to its oral administration. In government insured popula- ○ Increased tion of thalassemia patients. ●Probably holders? yes ○ Yes ○ Varies No research evidence specific to KSA setting identified. For these Equity patients. ○ Varies No research evidence specific to KSA setting identified. so the cheaper reduced treatment option with deferox- amine would likely be the pre- ○ Reduced ferred choice.Management of Thalassemia – Iron chela- tion therapy. this is not the case for increased patients not insured through a What would be the impact ○ Uncertain government plan. Acceptability key stake. The panel’s judgement was that ○ No treatment with deferoxamine is ○ Probably no acceptable to government and physicians. ○ Probably both treatment options are covered. Bisphosphonates and Zinc supplementation 39 No research evidence specific to KSA setting identified. no chelation treatment on health inequities? ● Probably is covered.

Bisphosphonates and Zinc supplementation 40 ● Yes ○ Varies .Management of Thalassemia – Iron chela- tion therapy.

Iron overload.Management of Thalassemia – Iron chela- tion therapy. better safety profile and Justification less need for monitoring.g. appropriate cost-effectiveness analyses in the KSA setting should be considered. Deferiprone should be considered as an alternative treatment in patients with severe cardiac iron overload. further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conduct- Research possibilities ed. Bisphosphonates and Zinc supplementation 41 Recommendation Should deferoxamine vs. consequences in most set. . very low quality of evidence). cardiac and/or endocrine impair- ment. Ideally. needs to be ensured. combination therapy) needs to be considered. Due to lower cost. clearly outweigh undesirable and undesirable consequences consequences consequences in most set. for details see “Regional consensus opin- ion” (Qari et al)6. compliance and side effect should be monitored in patients while on chelation therapy. Implementation consid- No specific considerations relevant for implementation of this recommendation. tion Patients need to be adequately educated and trained for deferoxamine administration. the panel suggests treatment with deferoxamine rather than treatment with deferiprone (condi- Recommendation tional recommendation. erations Informed patient choice is of paramount importance. 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. This recommendation is conditional mainly due to the very limited evidence of very low quality. 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. adverse effects of deferoxamine treatment or non-responsiveness to deferoxamine. FBC). the panel suggests treatment with deferoxamine. 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. Also. Subgroup considerations In patients with severe iron overload and/or significant cardiac/endocrine impairment or non-responsiveness to monotherapy intensified chela- tion therapy (e. Monitoring and evalua- Dose of iron chelation drug needs to be tailored according to iron overload. in particular in remote settings.

at 6.61 lower ⨁◯◯◯ CRITICAL trial ous 2 (2.7%) "Only one trial reported mortality as an outcome (Ha ⨁◯◯◯ CRITICAL trial ous 2 2006).Number of participants experiencing an adverse event – at 12 months 14 6 1 randomised serious not serious not serious serious none 11/73 (15.8 higher) VERY LOW Serum ferritin concentration: mean change from baseline (ng/ml) .84) .at 12 months 89 10 1 randomised serious not serious not serious very seri. 12 and 24 months 11 12 13 6 5 randomised serious serious not serious serious none 155 152 .Management of Thalassemia – Iron chela- tion therapy. none 30 27 .17 lower) VERY LOW End organ damage . 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.at 12 and 24 months 3 4 5 6 3 randomised serious serious not serious serious none 114 113 .78 lower to 0.1%) 24/71 RR 0. this death was at- tributed to cardiac complications and thought not to be related to deferiprone treatment" (Fisher 2013) End organ damage .at 12 months 1 randomised not not serious not serious very seri. 0 indicating no fibrosis): mean at endpoint . One death occured in the deferiprone treatment VERY LOW arm after six months of treatment. none 15 21 .12 lower to 45.82 lower ⨁◯◯◯ IMPORTANT trials (313.45 186 fewer per 1000 (from 54 fewer to 257 ⨁⨁◯◯ IMPORTANT trial (33. MD 0.8%) (0.0%) 1/6 (16.56 lower ⨁◯◯◯ CRITICAL 7 trials (2. MD 1.02 lower to 0.98 higher) LOW Liver iron concentration: mean change from baseline (mg/g dry weight) using SQUID .94 lower to 0. MD 133.24 to fewer) LOW 0.49 higher) VERY LOW Adverse events .Cardiac: Left ventricular ejection fraction: mean change from baseline (%) .1 higher ⨁⨁◯◯ CRITICAL trial serious ous 2 (0.Liver: Liver fibrosis Ishak score (ranging from 0-6. MD 0. 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. none 0/7 (0.

MD 1 lower ⨁◯◯◯ IMPORTANT trial ous 2 (4. Unclear: Allocation concealment 2. High risk of bias due to lack of blinding of participants and personnel (3 studies).at 12 months 15 16 1 randomised serious not serious not serious very seri. lack of blinding of outcome assessment. lack of blinding of outcome assessment.01. lack of blinding of outcome assessment . lack of blinding of outcome assessment (2 studies).5 times higher than in patients treated with deferiprone. Point estimates vary. I²=67%. An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentration in both groups. but result was not statistically significant 10. other bias (1 study). selective reporting (3 studies). SD – standard deviation 1. other bias (1 study) 5. Olivieri 1997) 9. selective reporting. Only few patients were included in study/studies 7. liver iron concentration decreased from baseline to the end of the trial in both treatment groups in two additional trials. Maggio 2002. Olivieri 1997). result statistically significant. lack of blinding of outcome assessment (4 studies). MD was not significant anymore 8. incomplete outcome data (2 studies). Unclear: Random sequence generation. Two other trials reported increase at the end of the trial in both treatment groups. High risk of bias due to lack of blinding of participants and personnel 15. no SD mentioned 12.51 times that for deferiprone. other bias (trial was stopped early due to an unexpected sudden death). the greatest decrease was observed in the DFO group in El-Beshlawy 2008 and in the deferiprone group in Maggio 2002. other bias (1 study) 13. high I²-value (77%). allocation concealment . liver iron concentration in patients who re- ceived deferiprone was 1.Management of Thalassemia – Iron chela- tion therapy. none 32 29 . selective reporting. allocation concealment 11. Unclear: Random sequence generation. An older study (Olivieri 1997) showed a significant better compliance in deferiprone patients after 3 years 16. Bisphosphonates and Zinc supplementation 43 Participant compliance (%) . High risk of bias due to lack of blinding of participants and personnel. p=0. High risk of bias due to lack of blinding of participants and personnel. Unclear: Random sequence generation (3 studies). 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). No clear clinical differences between the trials were identified which could account for this heterogeneity 6.88 higher) VERY LOW MD – mean difference. In Olivieri 1997. p=0. Point estimates differ substantially. se- lective reporting (1 study). using different methods of meas- urement. allocation concealment (4 studies). favouring DFO (Ha 2006. Using random-effects model. allocation concealment (2 studies). High risk of bias due to lack of blinding of participants and personnel. result statistically significant. RR – relative risk. El-Beshlawy: val- ues of liver iron concentration in DFO treated patients were 1. High risk of bias due to lack of blinding of participants and personnel (5 studies). selective reporting.45 times that in patients with DFO. no specific values were reported 4. mean liver iron concentration for DFO was 0. in a third trial (Maggio 2002). the increase was greatest in the deferiprone treated group in both trials. with a greater decrease in the deferiprone group. Unclear: Random sequence generation (2 studies).88 lower to 2. incomplete outcome data (1 study). Ha 2006. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" between treatment arms.02 14. Only very few patients were included in study/studies 3. Four additional trials reported change from baseline in liver iron concentration (El-Beshlawy 2008.

Madan N. et al. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Evans P. Ling SC. 8. deferiprone and in combination on iron chelation in thalassemic children. 5. . Indian Pediatr 2004. Cetiner N. Terzi A. Saxena R. Porter JB. Ann Hematol 2008. Maggio A.107:3738-44. Blood 1997. Randomised Prospective Evaluation of Iron Balance. Olivieri NF BG. Morabito A. Naja M. Manz C. et al. Comparative efficacy of desferrioxamine. Chik KW.90:264a. et al. Gomber S. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong.336:1275-9. Hermann C. D'Amico G.28:196-208. Chelation Efficiency. ASH Annual Meeting Abstracts 2005. et al. Aydinok Y. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. Pennell DJ. Final results of the randomized trial of deferiprone (L1) and deferoxamine (DFO) [abstract].Management of Thalassemia – Iron chela- tion therapy. Lancet 1990. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Koren G. Hemoglobin 2006. Bisphosphonates and Zinc supplementation 44 References 1. Berdoukas V. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience.41:21-7. 2. Blood 2006. 4. El-Beshlawy A. Blood Cells Mol Dis 2002. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. 3. Karagiorga M.106:2698-. et al.30:263-74. Olivieri NF. Ha SY. 6.87:545-50. 7.

showed that 316 yes (4. The prevalence of beta-thalassemia trait among neo- ● Yes nates in the same area was 0.1 ○ Varies The relative importance or values of the main outcomes of interest: No data specific to thalassemia ○ No included patients in KSA identified. western Saudi Arabia.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.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living ○ Uncertain in the Al-Hassa area was observed. 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 panel’s judgement was that many patients would likely pre- ○Low fer monotherapy .2 Is there a prob- Problem lem priority? ○ Probably A screening of 6750 healthy persons in Jeddah.69%) had beta-thalassemia trait.96% (8/834). a 3."6 ○ Probably no In 2004. 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.

Number of participants expe.Management of Thalassemia – Iron chela- tion therapy.at 6 and 12 months VERY LOW portant uncer- tainty of varia- bility Adverse events . ⨁⨁◯◯ IMPORTANT ○ No known riencing an adverse event . Bisphosphonates and Zinc supplementation 46 ○ Moderate Mortality CRITICAL ⨁◯◯◯ VERY LOW ○ High End-organ damage: Left ventricular ejection ⨁◯◯◯ CRITICAL fraction: mean at endpoint (%) . Serum ferritin concentration: mean change ⨁◯◯◯ IMPORTANT from baseline (ng/ml) .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.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. variability Liver iron concentration: mean change from portant uncer.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% . ○ Probably no baseline .

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 0.6) ms.22 lower ○ Probably no fraction: mean at endpoint (%) mean at endpoint (%) . with an estimate of a 10% increase myocardial T2* ● Probably no (ms) – at 12 compared with the deferoxamine group (95% CI 2% to 19%.9 (1. Liver iron concentra- MD 0.at 12 months months) in the 6. from baseline .32 Are the undesir. Porter 2013: " At 12 months.12 lower lower) control group was to 4.45 lower - to 0.02).04 yes ○ Yes End-organ No data available damage: Liver ○ Varies Two trials reported myocardial T2* as an outcome measure at 12 months.Management of Thalassemia – Iron chela- tion therapy. while still on DFP" (Porter 2013) ○ Varies End-organ dam. tion fraction (mean at ○ No tricular ejection tion fraction ( endpoint (%) . ventricular ejec.at 12 MD 6. 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.SQUID ○ Varies from baseline .32 lower) able anticipated effects small? ● Probably 68.17 lower (0. DFO: 1. p=0.4) ms effects large relative to unde- ○ Probably sirable effects? yes Liver iron con. the mean change in myocar- months Are the desirable ○ Uncertain dial T2* was nearly identical in the two groups" (DFO + Deferiprone: 1.17 ○ Yes centration: tration: mean tion: mean change lower mean change change from base. ○ Uncertain . line . The range for left Left ventricular ejec- age: Left ven.9 (1. Liver iron concen.22 lower (8.SQUID at 12 at 12 months (mg/g (0.12 lower - to 4.45 lower . 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.4-78.at 12 months) in the inter- vention group was (8.

33 participants (from 41 (0.Number of (33 to 214) per 1000 RR 0. 195.89 -987-28. reduction in LIC was 0.79 reduction in serum higher) ferritin was 136. i. ○ Probably no available. i.07 to 0.86 lower (469.13 to experiencing an fewer 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 136.84) adverse event - 221 fewer) at 12 months No research evidence specific to KSA setting identified.at 6 from baseline the intervention group lower and 12 months (ng/ml) at 6 and was 136. No specific data on costs of ○ No deferoxamine alone or of com- bination therapy in KSA setting Resource Are the re.86 higher (195.025 pounds for treatment with ge- yes neric deferoxamine versus .61 higher) Adverse events 254 per 1000 84 per 1000 170 fewer .11 higher). Bisphosphonates and Zinc supplementation 48 wet weight) -0. A cost-utility analysis sources required for the treatment of beta- use small? ○ Uncertain thalassemia patients with chron- ○ Probably ic iron overload estimates 8.17 higher (0.Management of Thalassemia – Iron chela- tion therapy.86 (ng/ml) .61 lower to lower to control group was 195.e.89 higher).e.61 - 12 months) in the (469.89 lower to 469.11 lower to 0.

net benefits? yes ○ Yes ○ Varies No research evidence specific to KSA setting identified.54 The panel supposes that a com- bination therapy requires more resources than a monotherapy. In government insured popula- Equity What would be ○ Increased tion of thalassemia patients. However. ○ Probably monotherapy and combination . 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. Cost of treatment with deferoxamine alone was 793 Euro per month including ad- ministration. ●Uncertain costs of combination therapy tal cost small are higher than for therapy with relative to the ○ Probably deferoxamine alone. the impact on health inequi. total cost of deferoxamine treatment in combination with deferiprone was estimated at 963 Euro per month including administration cost. 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.53 In a study in Italy.Management of Thalassemia – Iron chela- tion therapy. incremental Is the incremen.

acceptable to Acceptability key stakehold. Additionally. No obvious barriers to imple- ○ No mentation were identified. For these ● Probably patients. no chelation treatment is covered. Bisphosphonates and Zinc supplementation 50 ties? increased are covered.Management of Thalassemia – Iron chela- tion therapy. ● Probably ers? yes ○ Yes ○ Varies No research evidence specific to KSA setting identified. The panel’s judgement was that ○ No many patients would likely pre- ○ Probably no fer monotherapy. ○ Varies No research evidence specific to KSA setting identified. ○ Probably no Is the option ○ Uncertain Feasibility feasible to im- plement? ● Probably yes ○ Yes ○ Varies . combination therapy requires Is the option ○ Uncertain more resources. this is not the case for patients not insured through ○ Uncertain a government plan. so the cheaper reduced treatment option with deferox- ○ Reduced amine alone would likely be the preferred choice.

cardiac and /or endocrine tions impairment or non-responsiveness to monotherapy. for details see “Regional consensus opin- ion” (Qari et al)6. This recommendation is conditional mainly due to the very limited evidence of very low quality. FBC). 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. siderations Informed patient choice is of paramount importance. very low quality of evidence). consequences in most set. ation Patients need to be adequately educated and trained for deferoxamine administration. ble consequences in most ble consequences in most closely balanced or uncertain tings tings settings settings ○ ○ ○ ● ○ Type of recommenda. . clearly outweigh undesira- and undesirable consequences is consequences consequences in most set. Bisphosphonates and Zinc supplementation 51 Recommendation Should deferoxamine alone vs. Research possibilities Also.g. Ideally.Management of Thalassemia – Iron chela- tion therapy. Iron overload. further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conducted. in particular in remote settings. Implementation con- No specific considerations relevant for implementation of this recommendation. 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. Subgroup considera. appropriate cost-effectiveness analyses in the KSA setting should be considered. needs to be ensured. Combination therapy should be considered as an alternative treatment in patients with severe cardiac iron overload. the panel suggests treatment with deferoxamine alone rather than treatment with deferoxamine in Recommendation combination with deferiprone (conditional recommendation. the panel suggests treat- ment with deferoxamine alone. compliance and side effects should be monitored in patients while on chelation therapy. Monitoring and evalu- Dose of iron chelation drug needs to be tailored according to iron overload. For patients treated with deferiprone: easy access to monitoring facilities (e. Due to lower cost and assumed lower acceptabil- Justification ity of combination therapy and possibly higher compliance and better safety profile with deferoxamine monotherapy. For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured.

. p=0.Management of Thalassemia – Iron chela- tion therapy.32 lower) VERY LOW End-organ damage: Liver .6) ms. none 0/4 (0. MD 0. Porter 2013: " At 12 months.at 12 months 3 4 5 6 2 randomised serious serious not serious serious none 60 58 . DFO: 1.12 lower to 4.9 (1. . .02). 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.0%) 0/7 (0. not estimable . . with an estimate of a 10% increase compared with the deferoxamine group (95% CI 2% to 19%.0%) Two trials reported myocardial T2* as an out.45 lower to 0. while still on DFP" VERY LOW (Porter 2013) End-organ damage: Left ventricular ejection fraction: mean at endpoint (%) . MD 6. .17 lower ⨁◯◯◯ CRITICAL trial ous 10 (0.SQUID at 12 months (mg/g wet weight) 12 13 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. 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. CRITICAL Myocardial iron concentration: myocardial T2* (ms) – at 12 months 8 9 11 11 2 randomised serious not serious not serious very seri.not measured .22 lower ⨁◯◯◯ CRITICAL 7 trials (8. the mean change in myocardial T2* was nearly identical in the two groups" (DFO + Deferiprone: 1.9 (1. .11 higher) VERY LOW . ⨁◯◯◯ CRITICAL trials ous 10 come measure at 12 months. 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. none 30 29 .4) ms Liver iron concentration: mean change from baseline . .

in DFO monotherapy arm.67) to 9.18).Management of Thalassemia – Iron chela- tion therapy. Bisphosphonates and Zinc supplementation 53 Serum ferritin concentration: mean change from baseline (ng/ml) .4%) RR 0. 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. Unclear: Random sequence generation (2 studies). Differences remained significant under random-effects model 8. -48% to -28%.Number of participants experiencing an adverse event .001). no data to calculate SD was available.61) mg/g dry wt with combination. pooled results showed significant difference favouring deferiprone combined with DFO. I²=80%. Only very few cases 3. selective reporting (3 studies). Data not pooled. an additional trial (El-Beshlawy 2008) reported reduction in serum ferritin concentration for both treatment arms at 12 months.86 lower ⨁◯◯◯ IMPORTANT trials (469. only 11 of 20 patients completed close to 12 months of treatment) 2. that LVEF increased from 49. selective reporting. High risk of bias due to lack of blinding of participants and personnel (1 study). analysing geometric means. p=0.1 (4. incomplete outcome data (1 study) 5. allocation concealment (3 studies) 16. lack of blinding of outcome assessment (3 studies).41). no significant difference was measured between the treatment arms: MD=-0. Unclear risk of bias: Random sequence generation (1 study). An additional trial reported "no significant difference in cardiac function" (El-Beshlawy 2008). Mourad 2003. Unclear: Random sequence generation. incomplete outcome data (2 studies) 9. blinding of outcome assessment (2 studies).33 170 fewer per 1000 (from 41 ⨁⨁◯◯ IMPORTANT trials (0. Only very few patients were included in studies 11.9% in DFO group at 12 months.62 (2. P< 0. RR – relative risk. no clear clinical differences between these two trials were identified which could account for this heterogeneity 6. High risk of bias due to lack of blinding of participants and personnel (2 studies).2) to 5. a fourth trial (El- Beshlawy 2008) reported change in liver iron concentration graphically.27 (3.13 (95%CI-8.08 (3.67 to 8. lack of blinding of outcome assessment. 65 patients were randomised at beginning 12. Tanner 2007 reported at 12 months "the between-group difference was significantly in favour of the combined treatment group (-40%. another trial (Porter 2013) reported serum ferritin concentrations at 12 months.8% to 56. from narrative information no obvious inconsistency present 10.9% to 58. Unclear: Random sequence generation (2 studies). MD 136. High risk of bias due to lack of blinding of participants and personnel (3 studies). Unclear: Random sequence generation (2 studies). Only few patients included in study/studies 7. However. therefore no numbers could be included.89 VERY LOW higher) Adverse events . at 12 months (Abdelrazik 2007. 95% CI. number of patients included in each outcome assessment was not clear.at 6 and 12 months 14 15 16 6 3 randomised serious serious not serious serious none 51 56 . I²=89%. serum ferritin increased from 1613 ± 537 to 2018 ± 898 μg/L (n=4) 15. Five additional trials reported reduction in serum ferritin in both treatment arms. Only few cases . blinding of outcome assessment (1 study). selective reporting (2 studies).3%) 15/59 (25. Point estimates differ. Tamaddoni 2010) on a log scale as ratio of geometric means due to skewed data in Mourad 2003. SD not stated 4. allocation concealment 14. lack of blinding of outcome assessment (1 study). and a reduction with DFO therapy from 5. serum ferritin declined from 3601± 838 to 2132 ± 646 μg/L (n=7) in combination arm. another trial (Porter 2013) reported. Risk of bias: Unclear: Blinding of outcome assessment. lack of blinding of outcome assessment (2 studies). therefore difficult to assess. incomplete outcome data (study was terminated due to slow patients accrual.3% in combination group and from 52. High risk of bias due to lack of blinding of participants and personnel. In one study (Tanner 2007). incomplete outcome data (1 study).61 lower to 195. An additional trial (Ha 2006) using AAS reported liver iron concentration as mean change (mg/g dry weight) at 6 months. SD – standard deviation 1.002. allocation concealment (2 studies) 18.84) fewer to 221 fewer) LOW MD – mean difference.at 12 months 17 18 2 randomised serious not serious not serious serious none 5/60 (8. allocation concealment (1 study). other bias (1 study). but the difference in change between groups was not statistically significant 13. selective reporting (1 study). LIC decreased in both groups. a third trial (Porter 2013) using different methods reported a reduction from 16.13 to 0. p=0.008 17.

Manz C. Naja M.121:187-9. Khoriaty AI. Mourad FH.115:1876-84. . et al. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. Porter JB. et al. et al. Ann Hematol 2008. Koussa S. Br J Haematol 2003.Management of Thalassemia – Iron chela- tion therapy.41:21-7. Ling SC. 9. Galanello R. Iranian Red Crescent Medical Journal 2010. Galanello R. Chik KW.12:655-9. Porter JB. Aydinok Y.12:577-85.30:263-74. Piga A. Evans P. 2. Ha SY. 6. et al. et al. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. 4. Tanner MA. 7. Saxena R. Bisphosphonates and Zinc supplementation 54 References 1. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Comparative efficacy of desferrioxamine. Dessi C. A randomized. El-Beshlawy A. 10. Madan N. Hoffbrand AV. deferiprone and in combination on iron chelation in thalassemic children. Tamaddoni A RM. Randomised Prospective Evaluation of Iron Balance.15:38.91:1241-3. 3. Haematologica 2006. Kattamis A. Abdelrazik N. Indian Pediatr 2004. Sheikh-Taha M. Wood J. 5. 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. 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.87:545-50. Circulation 2007. Hematology 2007. 8. J Cardiovasc Magn Reson 2013. Cetiner N. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Terzi A. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. Olivieri N. ASH Annual Meeting Abstracts 2005. Chelation Efficiency. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. Gomber S.106:2698-. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Hemoglobin 2006. Taher A.

4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in the Al-Hassa area was observed. western Saudi Arabia. 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.2 Is there a ○ Uncertain Problem problem pri- ority? ● Probably A screening of 6750 healthy persons in Jeddah. the standard iron-chelating drug is suggested to be more effective in require treatment with iron chelators combination with deferiprone than deferiprone alone. a 3.69%) had beta-thalassemia trait. showed that 316 (4.”42 .1 ○ Yes ○ Varies What is the The relative importance or values of the main outcomes of interest: "Mean compliance with defer- Benefits & overall cer. options Outcome Certainty of Relative evidence? ●Very low the evidence whereas mean compliance with DFO was 70. 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. ○ No included iprone was reported as over harms of the tainty of this studies 90% in both treatment arms. The prevalence of beta-thalassemia trait yes among neonates in the same area was 0.” 6 ○ Probably no In 2004.Management of Thalassemia – Iron chela- tion therapy.96% (8/834).6%.

(mean(SD)) ability ○ No known Serum ferritin concentration: mean at endpoint ⨁◯◯◯ IMPORTANT undesirable (ng/ml) . Myocardial iron concentration: Myocardial T2*: comes? ○ No im.at 6 and 12 months VERY LOW Adverse Events . CRITICAL important VERY LOW sis) .at 12 months Is there im. Bisphosphonates and Zinc supplementation 56 The panel’s judgement was that ○ Low importance (GRADE) many patients would likely pre- ○ Moderate fer monotherapy. variability certainty ○ Probably Liver iron concentration: mean at endpoint CRITICAL ⨁◯◯◯ about how (mg/g dry weight) . ○ No and/or agranulocytosis VERY LOW pated effects large? ○ Probably no .Cardiac: Left ventricular ⨁◯◯◯ ○ Important ejection fraction: mean at endpoint (%) .at 12 months and 5 years CRITICAL VERY LOW End organ damage . DFP: at further 14 (6) months VERY LOW tainty of vari.Risk of leucopenia.at 12 months VERY LOW no important much people uncertainty of value the variability main out.Liver: Liver fibrosis Ishak ⨁◯◯◯ score (ranging from 0 to 6. uncertainty or portant un. 0 indicating no fibro.Management of Thalassemia – Iron chela- tion therapy. ⨁◯◯◯ ○ High Mortality . mean at endpoint (ms): DFO + DFP: at further CRITICAL ⨁◯◯◯ portant uncer.at 12 CRITICAL VERY LOW months uncertainty or variability ● Possibly End organ damage . IMPORTANT able antici. (16(5) months. neutropenia ⨁◯◯◯ Are the desir.

Liver: Liver fibro- "One trial reported liver fibrosis as an outcome. In this latter trial. scored accord- ing to the Ishak scoring system (Aydinok 2007). 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. a further five sirable antici.Cardiac: Left ejection fraction ejection fraction ( MD 5. (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. Maggio ○ No 2009)." (Fisher 2013) ○ Yes ○ Varies End organ damage Left ventricular Left ventricular .Management of Thalassemia – Iron chela- tion therapy. One death due to arrhythmia whilst receiving months and 5 deferiprone and DFO in combination was also reported in the Are the unde.39 higher) large relative to undesira- ○ Uncertain ble effects? ● Probably End organ damage .4 higher (1. died at the start ○ Probably of the trial due to arrhythmia-induced congestive heart failure no Mortality . one individual who was randomised to receive deferiprone and DFO in combination. In the first trial. yes sis Ishak score results were presented graphically.2 Are the desir. mortality occurred 11 to 60 months after withdrawal of the randomised treatment.at 12 control group group was 5. In this trial.at 12 (Aydinok 2007). ○ Probably months was 67.39 - (%) . ○ Uncertain years second trial (Maggio 2009). 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. the trial authors reported ○ Yes (ranging from 0 to that the fibrosis score "did not change significantly after one .99 lower higher) able effects no to 12.2 ventricular ejec.

endpoint (mg/g MD 1 lower dry weight) .36 high- months) in the was 219. 0 indicating no year in patients in any of the treatment arms" (Fisher 2013) fibrosis) .87 - 12 months point (ng/ml) at 12 months in the lower to 6 and 12 intervention group) 30.25 mean at endpoint concentration (mean at endpoint lower (ng/ml) .Management of Thalassemia – Iron chela- tion therapy. Liver iron concen- tration: mean at centration tration (mean at endpoint (mg/g (mean at end.42 lower months weight) at 12 months) in the - to 1. DFP: at patients prohibited calculation of the mean change in myocar- further 14 (6) dial iron concentration.5 lower to 1. (ng/ml) at 6 and (468.42 months) in the intervention group higher) control group was 1 lower (3.42 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. 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 lower er) control group (468.87 lower to was 1633- .42 was 7. Bisphosphonates and Zinc supplementation 58 ○ Varies 6. Liver iron con.at 12 (3.at 6 and (mean at end.at 12 point (mg/g dry dry weight) . at further (16(5) The difference in duration of follow up across this subset of months.at 12 months Liver iron concen.

A cost-utility analysis of deferiprone for the treatment of beta-thalassemia ● No patients with chronic iron over- load estimates 5. 54 more Risk of leucopenia.939 no pounds per one-year treatment Are the re.61) tosis 213 more) No research evidence specific to KSA setting identified.7 30.519 pounds per ○ Probably year treatment with deferiprone (Ferriprox®) versus 11. fewer to 2.76 to (100 to 345) and/or agranulocy. Bisphosphonates and Zinc supplementation 59 3422. ○ Uncertain with generic deferoxamine in- Resource use sources re. total cost of ○ Varies deferoxamine treatment in com- bination with deferiprone was estimated at 963 Euro per month including administration cost. per 1000 RR 1.41 186 per 1000 neutropenia 132 per 1000 (from 32 (0.Management of Thalassemia – Iron chela- tion therapy.36 higher) Adverse Events . No specific data on costs of deferiprone alone or of combina- tion with deferoxamine in KSA setting found. Cost of treatment with deferiprone was 480 Euro per month. cluding administration cost in quired small? ○ Probably combination with deferiprone yes (Ferriprox®).54 The panel supposes that a com- .53 ○ Yes In a study in Italy.

This is not the case increased for patients not insured through What would ○ Uncertain a government plan. ● No No research evidence specific to KSA setting identified. For these be the impact patients. However. In government insured popula- ○ Increased tion of thalassemia patients. ●Probably monotherapy and combination are covered. incremental no costs of combination therapy are Is the incre- mental cost ○ Uncertain higher than for therapy with deferiprone alone. Based on very low quality of evidence no clear benefits of ○ Probably one option over the other sug- gested. no chelation treatment Equity on health ○ Probably is covered. small relative to the net ○ Probably benefits? yes ○ Yes ○ Varies No research evidence specific to KSA setting identified. Bisphosphonates and Zinc supplementation 60 bination therapy requires more resources than a monotherapy.Management of Thalassemia – Iron chela- tion therapy. so the cheaper inequities? reduced treatment option with defer- iprone alone would likely be the ○ Reduced preferred choice. ○ Varies .

combination therapy requires Is the option ○ Uncertain more resources. Bisphosphonates and Zinc supplementation 61 No research evidence specific to KSA setting identified. The panel’s judgement was that ○ No many patients would likely pre- ●Probably no fer monotherapy. Additionally. No obvious barriers to imple- ○ No mentation were identified.Management of Thalassemia – Iron chela- tion therapy. acceptable to Acceptability key stake- ○ Probably holders? yes ○ Yes ○ Varies No research evidence specific to KSA setting identified. ○ Probably no Is the option ○ Uncertain Feasibility feasible to implement? ● Probably yes ○ Yes ○ Varies .

clearly outweigh undesirable and undesirable consequences consequences consequences in most set. Due to higher cost and assumed lower acceptability Justification of combination therapy and possibly higher compliance and better safety profile with deferiprone monotherapy. ation For patients treated with deferiprone: easy access to monitoring facilities (e. Ideally. 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. 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. Implementation con- For this recommendation against a combination therapy. the panel suggests against treatment with deferoxamine in combination with deferiprone rather than Recommendation treatment with deferiprone alone (conditional recommendation against. consequences in most set. siderations Informed patient choice is of paramount importance. further RCTs evaluating the benefits and harms of the alternatives including longer-term patient relevant outcomes should be conducted. appropriate cost-effectiveness analyses in the KSA setting should be considered. Monitoring and evalu- Dose of iron chelation drug needs to be tailored according to iron overload. cardiac and/or endocrine im- tions pairment or non-responsiveness to monotherapy. Combination therapy should be considered as an alternative treatment in patients with severe cardiac iron overload. FBC). Research possibilities Also. Patients need to be adequately educated and trained for deferoxamine administration. . needs to be ensured. This recommendation is conditional mainly due to the very limited evidence of very low quality.g. Subgroup considera. in particular in remote settings. for details see “Regional consensus opinion” (Qari et al)6. compliance and side effects should be monitored in patients while on chelation therapy. implementation considerations are not considered to be relevant by the panel members. Iron overload. the panel suggests against treat- ment with deferoxamine in combination with deferiprone. For patients treated with deferoxamine: regular ophthalmologic examination and audiometry needs to be ensured.Management of Thalassemia – Iron chela- tion therapy. very low quality of evidence).

died at the start of the trial due to arrhythmia- induced congestive heart failure (Aydinok 2007). 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) . In the first trial.42 lower to 1. results were presented graphically. mortali- ty occurred 11 to 60 months after withdrawal of the randomised treatment.39 higher) VERY LOW End organ damage .2 higher ⨁◯◯◯ CRITICAL trial ous 6 (1. ⨁◯◯◯ CRITICAL trials ous 3 Maggio 2009). scored ⨁◯◯◯ CRITICAL trial ous 6 according to the Ishak scoring system (Aydinok 2007). none 16 17 . one individual who was VERY LOW randomised to receive deferiprone and DFO in combi- nation. 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.at 12 months 789 10 1 randomised serious not serious not serious very seri.42 higher) VERY LOW .at 12 months 4 5 1 randomised serious not serious not serious very seri. One death due to arrhythmia whilst receiving deferiprone and DFO in combination was also reported in the second trial (Maggio 2009). MD 1 lower ⨁◯◯◯ CRITICAL trial ous 6 (3. none 8 12 . MD 5. 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.99 lower to 12.at 12 months and 5 years 1 2 2 randomised serious not serious not serious very seri." (Fisher 2013) End organ damage .Cardiac: Left ventricular ejection fraction: mean at endpoint (%) .Liver: Liver fibrosis Ishak score (ranging from 0 to 6. deferoxamine Absolute Inconsistency Indirectness Imprecision deferiprone (95% studies design bias erations + deferiprone (95% CI) CI) Mortality . In this latter trial.Management of Thalassemia – Iron chela- tion therapy.at 12 months 5 1 randomised serious not serious not serious very seri. VERY LOW In this trial. none 8 12 "One trial reported liver fibrosis as an outcome. 0 indicating no fibrosis) . none 117 120 "Mortality was reported in two trials (Aydinok 2007.

87 lower to 30.Risk of leucopenia. lack of blinding of outcome assessment (1 study). However. the mean LIC value did not change significantly in patients treat- ed with DFP. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" 5. MD 219. none 17/96 (17.at 6 and 12 months 12 13 14 3 randomised serious not serious not serious very seri.76 to more) VERY LOW 2. no SD for change reported. The difference in duration of follow up across this subset of patients prohibited calculation of the mean change in myocardial iron concentration. from narrative information no obvious inconsistency present 3. calculation of mean change is not possible.2%) (0. incomplete outcome data. Method used is not stated in this trial . RR – relative risk. however the trial reported no signficant differences 8. lack of blinding of participants and personnel. 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) . a reduction was only observed in the deferiprone group compared with an increase in combination group. Unclear: Allocation concealment (1 study) 2. In an additional trial liver iron concentration was measured by atomic emission spectrophotometry (Aydinok 2007). none 100 93 . 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. selective reporting (Mortality was not pre-specified in one study). other bias (1 study).61) MD – mean difference.Management of Thalassemia – Iron chela- tion therapy.25 lower ⨁◯◯◯ IMPORTANT trials ous 15 (468. DFP: at further 14 (6) months (mean(SD)) 11 1 randomised serious not serious not serious very seri. end of study values were not significant 9. neutropenia and/or agranulocytosis 16 3 randomised serious not serious not serious very seri. High risk of bias due to lack of allocation concealment. but decreased significantly in patients receiving combination therapy. Bisphosphonates and Zinc supplementation 64 Myocardial iron concentration: Myocardial T2*: mean at endpoint (ms): DFO + DFP: at further (16(5) months. High risk of bias due to lack of allocation concealment (1 study).36 higher) VERY LOW Adverse Events . due to differences in follow up time. Another trial (Maggio 2009) reported liver iron concentration by liver T2*. lack of blinding of outcome assessment. therefore difficult to assess. Only very few cases 4. lack of blinding of participants and personnel (2 studies).41 54 more per 1000 (from 32 fewer to 213 ⨁◯◯◯ IMPORTANT trials ous 3 (13.7%) 16/121 RR 1. SD – standard deviation 1. incom- plete outcome data (2 studies). Only very few patients included in study/studies 7. selective reporting 6. Data not pooled.

incomplete outcome data. in patients receiving deferiprone only a reduction in mean serum ferritin concentration from baseline values was observed at two and five years.106:2698-. Unclear: Random sequence generation (1 study). High risk of bias due to lack of allocation concealment (1 study). Saxena R. Manz C. lack of blinding of outcome assessment. Br J Haematol 2009. Chelation Efficiency. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clin- ical trial. no standard deviations are mentioned 13. Nart D. Aydinok Y. lack of blinding of outcome assessment (2 studies). allocation concealment (2 studies) References 1. random sequence generation 11. although number of patients was considerably reduced due to early termination of the trial 14. at five years. incomplete outcome data (differences in duration of follow up regarding myocardial iron concentration). Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. lack of blinding of participants and personnel (3 studies). a significant difference in mean change of serum ferritin concentra- tion in patients with combination therapy was maintained over four years of follow up. Randomised Prospective Evaluation of Iron Balance. Porter JB. incom- plete outcome data (3 studies). Gomber S. Maggio 2009). selective reporting (1 study). 5. et al. 4. lack of blinding of outcome assessment (3 studies). 15. deferiprone and in combination on iron chelation in thalassemic children. 3. Haematologica 2007. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. there was no significant difference in mean change of serum ferritin concentra- tion between the two treatment arms. Evans P. et al. ASH Annual Meeting Abstracts 2005.Management of Thalassemia – Iron chela- tion therapy.92:1599-606. Unclear: Random sequence generation (1 study). A reduction in serum ferritin concentration was maintained across five years of follow up in the combined treatment arm in Maggio 2009. El-Beshlawy A. High risk of bias due to lack of blinding of participants and personnel. . High risk of bias due to lack of blinding of participants and personnel (3 studies). Indian Pediatr 2004. Terzi A.41:21-7. Ulger Z. other bias (1 study). et al. Unclear: Allocation concealment. allocation concealment (2 studies).87:545-50. Comparative efficacy of desferrioxamine. other bias. Mean change in serum ferritin from baseline can be calculated from data in two trials (Gomber 2004. An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentrations in both groups. High risk of bias due to lack of blinding of participants and personnel. Aydinok Y. Madan N. other bias (1 study). Vitrano A. selective reporting (2 studies). Cetiner N. No statistically significant difference was observed in Gomber 2004. Unclear: Allocation concealment 12. Maggio A. incomplete outcome data (3 studies). Ann Hematol 2008. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience.145:245-54. Capra M. 2. Small study population and wide confindence interval 16. Bisphosphonates and Zinc supplementation 65 10. Naja M.

Management of Thalassemia – Iron chela- tion therapy.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. showed that 316 yes (4. .69%) had beta-thalassemia trait.”6 ○ Probably no In 2004.2 Problem Is there a prob- lem priority? ● Probably A screening of 6750 healthy persons in Jeddah.a 3.96% (8/834). western Saudi Arabia. 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. 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.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. studies identified.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in ○ Uncertain the Al-Hassa area was observed. The prevalence of beta-thalassemia trait among neo- nates in the same area was 0.

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.at 12 and 24 CRITICAL ○ Important months VERY LOW uncertainty or variability Back or bone pain .Fever after first infusion CRITICAL ⨁⨁◯◯ portant uncer. one vertebral fracture .at 12 and 24 months ○ High VERY LOW Number of participants experiencing at least ⨁◯◯◯ one non-vertebral fracture .at 12 months CRITICAL ⨁⨁◯◯ LOW ●Possibly important Is there im. uncertainty or Adverse events . variability zoledronic acid 4 mg LOW tainty about how much peo.Management of Thalassemia – Iron chela- tion therapy. ○ 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/cm²] (DXA): mean at ⨁⨁◯◯ IMPORTANT endpoint .at 12 and 24 months LOW tainty of vari- ability ○ No known undesirable .

01 to 6.31 3 per 1000 1000 (from ○ No at least one vertebral frac- 10 per 1000 (0 to 71) 10 fewer to (0.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.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. 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 0.85) 12 and 24 months Are the desira- ble effects large ○ No . Bisphosphonates and Zinc supplementation 68 Additional Criteria Judgements Research evidence considerations Femoral neck BMD [g/cm²] (DXA): mean at ⨁⨁◯◯ IMPORTANT endpoint .31 (0.at 60 more) 6.Management of Thalassemia – Iron chela- tion therapy.01 to non-vertebral (0 to 71) 10 fewer to ○ Varies fracture .

002%)." Forni 2012: "The months mean back pain scale value was significantly higher (more favourable) in ○ Yes [intervention group] compared with [control group] [. 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. A concomitant significant reduction (over 50%[intervention group].Fever RR mate given after first 10.27 after first due to 0 (0.Flu.at 12 had no change in bone pain during the study period.44 to infusion neri.] at 12 months ○ Varies (P=0.8% (15/26) effect esti- events .6% (3/54) effect esti- like symptoms mate given RR 8..03 - BMD [g/cm²] ([g/cm²] (DXA): ([g/cm²] (DXA): mean higher . In contrast. events in 156.Management of Thalassemia – Iron chela- tion therapy. 0% (0/64) rate: 5. There were no differences in fects? ○ Uncertain pain score among the three studied groups.70) dronate 100 control mg group Lumbar spine Lumbar spine BMD Lumbar spine BMD MD 0. 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..96) control 4 mg group Adverse Control event rate: Experimental event No absolute events .49 to events in zoledronic acid 76.72 due to 0 infusion (1. 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. [control group] patients yes pain .

Management of Thalassemia – Iron chela- tion therapy.723-0.79 0.636-0. Are the re.02 higher at endpoint . No research evidence specific to KSA setting identified.02 higher) higher to 0. ○ Varies Is the incremen. Unclear.05 (DXA): mean mean at endpoint at at endpoint at 12 and higher at endpoint . Bisphosphonates and Zinc supplementation 70 Additional Criteria Judgements Research evidence considerations (DXA): mean mean at endpoint at at endpoint at 12 and (0.03 higher (0. 12 and 24 months) in 24 months) in the (0. because signifi- tal cost small ○ No cant benefit was only relative to the seen in surrogate out- .05 at 12 and 24 the control group was intervention group was higher) months 0. but were judged to be moderate.05 higher (0. 12 and 24 months) in 24 months) in the to 0.08 months 0.9 0. Specific cost data for sources re.02 higher - at 12 and 24 the control group was intervention group was to 0. ○ Probably various bisphosphonates quired small? yes drugs and respective Resource doses were not available use ○ Yes at the meeting.02 higher to 0.05 higher) Femoral neck Femoral neck BMD Femoral neck BMD BMD [g/cm²] ([g/cm²] (DXA): ([g/cm²] (DXA): mean MD 0. We found no economic evaluation addressing the ○ Probably no use of bisphosphonates versus no bisphospho- ○ Uncertain nates in the KSA setting.08 higher) ● No No research evidence specific to KSA setting identified.

○ Probably ernment plan.Management of Thalassemia – Iron chela- tion therapy. ○ Reduced ○ Varies . however no long-term studies were yes identified. Treatment with bisphos- phonates is covered in ○ Probably government insured tha- lassemia patients with increased osteoporosis. Bisphosphonates and Zinc supplementation 71 Additional Criteria Judgements Research evidence considerations net benefits? ● Probably no comes. ○ Yes ○ Varies ● Increased No research evidence specific to KSA setting identified. Benefits in pain and fracture risk remain ○ Uncertain unclear. Observed ad- verse events remained ○ Probably moderate. This is not What would be ○ Uncertain the case for patients not the impact on insured through a gov- Equity health inequi. therefore ties? reduced health inequities might be increased.

acceptability will ○ Yes likely vary. ○ Varies No research evidence specific to KSA setting identified. Is the option ○ Uncertain As prophylactic measure. pain.g. No obvious barriers to ○ No implementation were ○ Probably no identified. Bisphosphonates and Zinc supplementation 72 Additional Criteria Judgements Research evidence considerations No research evidence specific to KSA setting identified. Is the option ○ Uncertain Feasibility feasible to im- plement? ●Probably yes ○ Yes ○ Varies . fractures) acceptability seems likely.Management of Thalassemia – Iron chela- tion therapy. given the adverse effects acceptable to Acceptability key stakehold- ○ Probably and potential costs for ers? yes non-government insured people. For more severely affect- ○ No ed thalassemia patients ● Probably no (e.

very low quality of evidence).Management of Thalassemia – Iron chela- tion therapy. 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. Standardized criteria for the use of bisphosphonates in high-risk patients should be established and its application monitored. However. clearly outweigh undesirable and undesirable consequences consequences consequences in most set. calcium and bone density should be monitored in patients with thalassemia. 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. Monitoring and evalu- Vitamin D. consequences in most set. . Also. ation Ideally. appropriate cost-effectiveness analyses in the KSA setting should be possibilitiess considered. burden of administra- Justification tion and unclear health benefits. the panel suggests no treatment with bisphosphonates in patients with thalassemia-associated osteoporosis. additional cost. Bisphosphonates and Zinc supplementation 73 Recommendation Should bisphosphonates vs. 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. the panel suggests against treatment with bisphosphonates (conditional recommendation Recommendation against. This recommendation against is based on very low quality of evidence. due to risk of side effects. Implementation con. a decision about treatment considerations with bisphosphonates in selected patients should be made. 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. siderations Monitoring of benefits and adverse effects in patients treated with bisphosphonates should be established.

There were no differences in pain score LOW among the three studied groups." Forni 2012: "The mean back pain scale value was significantly higher (more favourable) in [interven- tion group] compared with [control group] [. [control group] patients had no change in bone pain during the study period.at 12 and 24 months 12 3 3 randomised serious not serious not serious very seri. A concomitant significant reduction (over 50%[intervention group]. In contrast. Patients in [inter- vention group 1 and 2] had dramatic reductions of pain score after 6 and 12 months of zoledronic acid treatment..0%) 1/97 (1.. none 0/110 (0.31 7 fewer per 1000 (from 10 fewer to 60 ⨁◯◯ CRITICAL trials ous 4 (0. 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.at 12 and 24 months 12 3 3 randomised serious not serious not serious very seri.0%) 1/97 (1. no bisphospho.0%) RR 0.85) VERY LOW Back or bone pain . none 0/110 (0.01 to more) ◯ 6.002%).] at 12 months (P=0.31 7 fewer per 1000 (from 10 fewer to 60 ⨁◯◯ CRITICAL trials ous 4 (0. Absolute Inconsistency Indirectness Imprecision bisphosphonates (95% studies design bias erations nates (95% CI) CI) Number of participants experiencing at least one vertebral fracture . 30% [control group]) in the use of analgesic drugs was noted starting from the third month" .01 to more) ◯ 6.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.Management of Thalassemia – Iron chela- tion therapy.0%) RR 0.85) VERY LOW Number of participants experiencing at least one non-vertebral fracture .

RR – relative risk. Unclear: Random sequence generation (1 study). no obvious inconsistency present 7. We didn't count fractures as events due to unclear causation 3. Data not pooled. MD 0. MD 0.Management of Thalassemia – Iron chela- tion therapy. High risk of bias due to lack of blinding of participants and personnel. from narrative information. allocation concealment (1 study) 9.08 higher) ◯ LOW MD – mean difference.02 higher to 0. Unclear: Allocation concealment . lack of blinding of outcome assessment (3 studies).72 0 events in control group ◯ (1.8%) 0/33 (0. However.05 higher ⨁⨁◯ IMPORTANT trials (0. Unclear: Random sequence generation (1 study). One study (Forni 2012) reported that "no fractures were observed during the study period except for the patient [intervention group]. lack of blinding of outcome assessment (2 studies). Unclear: Random sequence generation (2 study).0%) RR 8. who discontinued the trial at 6 months after a road traffic accident".02 higher to 0.Flu-like symptoms after first infusion neridronate 100 mg 10 9 1 randomised serious not serious not serious serious none 3/54 (5. therefore difficult to assess.44 to 0 events in control group ◯ 156. SD – standard deviation 1. lack of blinding of outcome assessment.6%) 0/64 (0.at 12 and 24 months 12 16 17 14 15 3 randomised serious not serious not serious serious none 105 86 .27 No absolute effect estimate given due to ⨁⨁◯ CRITICAL trial (0. Bisphosphonates and Zinc supplementation 75 Adverse events . High risk of bias due to lack of blinding of participants and personnel (2 studies). High risk of bias due to lack of blinding of participants and personnel (1 study). High risk of bias due to lack of blinding of participants and personnel (2 studies).0%) RR No absolute effect estimate given due to ⨁⨁◯ CRITICAL trials 10.Fever after first infusion zoledronic acid 4 mg 8 9 2 randomised serious not serious not serious serious none 15/56 (26.70) LOW Lumbar spine BMD [g/cm²] (DXA): mean at endpoint .96) Adverse events .49 to LOW 76. lack of blinding of outcome assessment (2 studies). allocation concealment (2 studies) 4. allocation concealment (2 studies) 6.at 12 and 24 months 11 12 13 14 15 3 randomised serious not serious not serious serious none 105 86 .05 higher) ◯ LOW Femoral neck BMD [g/cm²] (DXA): mean at endpoint . All included studies don't differentiate between vertebral and non-vertebral fractures 2.03 higher ⨁⨁◯ IMPORTANT trials (0. Only few patients were included in studies 8. Only very few cases 5. Only few patients were included in study/studies 10.

allocation concealment (3 studies) 15.v. Br J Haematol 2012. no spe- cific values were reported 17. et al.93) in the control group (p<0.01). every 3 months.79:138-44. Lasco A. in the intervention group BMD at lumbar spine didn't change significantly at 12 months (p=0. 4.001.88) in the control group (p< 0. Only few patients included in studies 16. absolute change was 0.91:1193-202.v. An additional study (Pennisi 2003) reported a decreased T-score from -1. Rodda CP. placebo-controlled trial. 2. Gilfillan CP.) were included separately in our analysis. in Morabito 2002. An additional study (Gilfillan 2006) reported absolute change in femoral neck BMD at 2 years. no SD were mentioned 14. Anagnostopoulos A. no specific values were reported 12. absolute change from baseline was 0. 5. An additional study (Gilfillan 2006) reported absolute change from baseline at 2 years. for the intervention group. Riccobene S. Forni GL. every 6 months) were combined in one group (zoledronic acid 4 mg i.01).042 in patients treated with zoledronic acid. in placebo group.13) but the difference between intervention group and control group was significant (p<0. every 3 or 6 months) 13. Pizzarelli G. et al. Morabito N. High risk of bias due to lack of blinding of participants and personnel (3 studies). p comparing both groups was <0. Two studies included two intervention groups.92 (SD: 0.m.65). alendronate 10 mg p. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2. Voskaridou E. BMD at femoral neck didn't change significantly at 12 months (p=0. in placebo group. parallel-arm.01). absolute change was 0. p comparing both groups was 0. Konstantopoulos K. Haematologica 2006. lack of blinding of outcome assessment (3 studies). Pennisi P. zoledronic acid 4 mg i. Fiore CE. absolute change was -0. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center. 3. et al.82) to -3. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia- associated osteopenia.74) to -2.21:402-8.Management of Thalassemia – Iron chela- tion therapy.034.44 (SD: 0. double-blind. A randomized. An additional study (Pennisi 2003) reported a decreased T-score from -2. randomized. Spina M. Strauss BJ. open-label study. in Vos- karidou 2006 both groups (zoledronic acid 4 mg i. in the intervention group. Unclear: Random sequence generation (2 stud- ies).o. Bisphosphonates and Zinc supplementation 76 11. . Osteoporos Int 2002.158:274-82.16 (SD: 0.71 (SD: 0. no SD were mentioned References 1.v. but the difference between intervention and control group was significant at 12 months (p < 0. J Bone Miner Metab 2003. Perrotta S.082 in pa- tients treated with zoledronic acid. randomized.008.01. Gaudio A.13:644-9. for the intervention group. Bisphosphonates in the treatment of thalassemia-induced osteoporosis. both groups (clodronate 100 mg i.01). Calcif Tissue Int 2006. Giusti A. et al..

”6 ○ No ○ Probably no In 2004.96% (8/834). Treatment with iron chelators may cause zinc deficiency in thalassemia patients.Management of Thalassemia – Iron chela- tion therapy.1 ○ Yes No prevalence studies were identified describing growth retardation or zinc deficiency in ○ Varies thalassaemic patients in KSA. pothesized that supplementation supports growth in thalassemic children and adolescents. Zinc is required for the synthesis of somatomedins and it is therefore hy- zinc deficiency.69%) had beta-thalassemia trait. showed that 316 Problem priority? ● Probably yes (4. 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. The prevalence of beta-thalassemia trait among neonates in the same area was 0.7 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 . a 3.2 ○ Uncertain Is there a problem A screening of 6750 healthy persons in Jeddah. Besides.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in the Al-Hassa area was observed. western Saudi Arabia. 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.

at 1-7 years 22.at 9 months 30 mg zincsulfate and 18 CRITICAL LOW months 25 mg zinc important uncer- tainty or varia- bility Adverse events .5-90 mg zinc.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 . 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 [ɥg/dl] .absolute value [cm] or z-score at end- ⨁◯◯◯ this intervention. point . ⨁⨁◯◯ CRITICAL ○ Important at 3 months 220 mg zincsulfate LOW uncertainty or variability Weight . in particular given the prophylactic nature of ○ Moderate Height . 9 months CRITICAL ○ High 30 mg zincsulfate and 18 months 25 mg zinc VERY LOW Body mass index .at 1-7 years 22.Management of Thalassemia – Iron chela- tion therapy.5-90 mg zinc.mean at endpoint .mean [kg/m²] at endpoint .absolute value [kg] or z-score at end- ⨁⨁◯◯ ● Possibly point . 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.

85 higher) effects large rela.11 standard Are the undesirable ○ Uncertain and -1.11 mg zinc. ● Uncertain tive to undesirable effects? ○ Probably yes Weight .Management of Thalassemia – Iron chela- tion therapy.at 9 months 30 mg at 9 months 30 mg zincsulfate and 18 at 9 months 30 mg zincsulfate and 18 to 0.22 lute value [kg] value [kg] or z. Bisphosphonates and Zinc supplementation 79 large? ● Probably no supplements supplements (95% CI) (RR) (95% ○ Uncertain CI) ○ Probably yes Height .abso.25 18 months 25 control group was zinc) in the inter- ○ Probably no mg zinc 125.at 3 months 220 mg months 220 mg higher months 220 mg zincsulfate) in the zincsulfate) in the (0.abso. 9 SMD 0.5-90 mg zinc.6 higher higher) Are the desirable ○ Probably no (0. Height (absolute Height (absolute ○ Yes lute value [cm] value [cm] or z.33 (z-score) deviations lower anticipated effects small? ● Probably yes (0.25 higher) ○ Yes ○ Varies Body mass Body mass index ( Body mass index ( index .5 was 0.4 (range vention group was higher) for absolute values) 0. 9 30 mg zincsulfate months 30 mg lower months 30 mg and 18 months 25 zincsulfate and 18 (0.5-90 at 1-7 years 22. 9 months 90 mg zinc.3-143. 1-7 years 22. Weight (absolute Weight (absolute SMD 0.65 lower to 1. value [kg] or z- ○ Yes or z-score at score at endpoint score at endpoint higher - (0.5- 7 years 22.47 lower - ○ No zincsulfate and mg zinc) in the months 25 mg to 0.85 19.65 lower - ○ No zincsulfate control group was intervention group to 1.at 1. value [cm] or z- or z-score at score at endpoint at score at endpoint ○ Varies endpoint .63 .47 lower to 0.6 endpoint .mean mean [kg/m²] at mean [kg/m²] at [kg/m²] at endpoint at 3 endpoint at 3 MD 0.19 lower ○ Varies endpoint .

18 months observed at the doses used in the study" (22. Ghah- ramanlu 2014) Serum zinc [ɥg/dl] .Management of Thalassemia – Iron chela- tion therapy. "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.5-90 mg zinc at 1-7 25 mg zinc and years. Costs are ○ Probably no likely to be low. 95% CI: 16.at 1-7 years and zinc groups including diarrhea. No specific data on costs Resource use Are the resources ○ No of zinc supplements in KSA required small? setting found. Arasoy 1987).5-90 mg months 25 mg zinc.22 standard (z-score) deviations higher (0.37 0. Fung 2013). vention group was solute value) 1.at zinc (MD 47.03) fate Haemoglobin No data available level No research evidence specific to KSA setting identified.mean 220 mg zincsulfate (Rashidi 2011) led to a significant higher serum at endpoint . 220 mg zincsul.16 to 78. Monitoring . MD 0. 95% CI: -12. stomach upset and nausea (18 22.83 to 14.19 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 . 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. while dispensing 30 mg and 3 months zincsulfate (Gharhamanlu 2014) showed no difference (60 patients.2 (ab. "No visible side effects have been zinc.30.44) compared to no treat- 9 months 30 mg ment with zinc supplements (60 patients).60.

○ Varies No research evidence specific to KSA setting identified. Bisphosphonates and Zinc supplementation 81 zinc uptake is not available ○ Uncertain at all medical centers in ● Probably yes KSA. ○ 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. since no obvi- ○ No ous. significant health benefits. therefore additional resources in these cases ○ Yes are required.Management of Thalassemia – Iron chela- tion therapy. Uncertain. Equity impact on health inequities? ○ Probably reduced ○ Reduced ○ Varies . but limited ● Probably access to measurement and monitoring of zinc increased levels might increase What would be the ○ Uncertain health inequities.

However. ○ Probably no ○ Uncertain Is the option feasi- Feasibility ble to implement? ● Probably yes ○ Yes ○ Varies . No obvious barriers to ○ No implementation 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. Bisphosphonates and Zinc supplementation 82 No research evidence specific to KSA setting identified. No research evidence specific to KSA setting identified. ○ Uncertain low cost.Management of Thalassemia – Iron chela- tion therapy. 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.

relevance of health benefits is somewhat uncertain. siderations Monitoring and eval. Also. consequences in most set. very low quality of evidence) Due to very low quality of evidence for benefits of zinc supplementation. Subgroup considera- Patients with proven zinc deficiency should receive zinc supplementation. feasible implementation. . 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. Ideally. However. the panel suggests zinc supplementation rather than no zinc supplementation. the panel suggests offering this option in children and adolescents with thalassemia major. Bisphosphonates and Zinc supplementation 83 Recommendation Should zinc supplements vs.Management of Thalassemia – Iron chela- tion therapy. so uation serum zinc levels should be monitored in patients with iron chelation therapy. due to no Justification relevant side effects. Practically all patients with thalassemia major are receiving (or will receive) iron chelation therapy which can interact with zinc metabolism. (conditional Recommendation recommendation. 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. ble consequences in most consequences in most set- is closely balanced or uncertain tings tings settings tings ○ ○ ● ○ ○ Type of recommenda. tions Implementation con- No specific considerations relevant for implementation of this recommendation. 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. clearly outweigh undesirable and undesirable consequences consequences consequences in most set. moderate to small resource use and prevention of zinc deficiency. appropriate cost-effectiveness analyses in the KSA setting should be considered.

65 lower to 1.at 3 months 220 mg zincsulfate 5 1 randomised not not serious not serious very seri.22 higher ⨁⨁◯◯ CRITICAL trials serious ous 3 (0. none 30 30 .absolute value [cm] or z-score at endpoint .at 1-7 years 22.5-90 mg zinc. "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. MD 0.85 higher) LOW Weight .6 higher ⨁⨁◯◯ CRITICAL trial serious ous 3 (0.19 lower to 0.at 9 months 30 mg zincsulfate and 18 months 25 mg zinc 6 2 randomised not not serious not serious very seri.mean [kg/m²] at endpoint . none 60 60 220 mg zincsulfate (Rashidi 2011) led to a significant ⨁⨁◯◯ IMPORTANT trials serious ous 3 higher serum zinc (MD 47.Management of Thalassemia – Iron chela- tion therapy.5-90 mg zinc. zinc sup.absolute value [kg] or z-score at endpoint . Fung 2013).at 9 months 30 mg and 3 months 220 mg zincsulfate 10 11 2 randomised not not serious not serious very seri. 95% CI: 16.at 1-7 years 22.63 higher) 7 LOW Adverse events .30. 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. 18 months 25 mg zinc and 9 months 30 mg zincsulfate 2 8 3 randomised serious not serious not serious very seri. somach upset and nausea (18 months 25 mg zinc. none 48 44 . 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. 9 months 30 mg zincsulfate and 18 months 25 mg zinc 1 2 3 randomised serious not serious not serious very seri.47 lower to 0. Arasoy 1987). no zinc Relative Absolute Inconsistency Indirectness Imprecision studies design bias erations plements supplements (95% CI) (95% CI) Height . "No visible side effects have been observed at the doses used in the study" (22.44) LOW compared to no treatment with zinc supplements (60 patients).mean at endpoint . SMD 0.25 higher) 4 VERY LOW Body mass index . SMD 0.16 to 78.11 lower ⨁◯◯◯ CRITICAL trials ous 3 (0. none 69 55 .5-90 mg zinc at 1-7 years. while dispensing 30 mg zincsulfate (Ghar- . Ghahramanlu 2014) Serum zinc [ɥg/dl] .

36). Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalasse- mia major Patients.025) 6.06 to -0.7% and 15. blinding of participants and personnel (1 study).03) Haemoglobin level . .19:113-9. randomized. BMI z-score increased from . Am J Hematol 1987.51 to 0. in the intervention group. Rashidi M.60. MD 0.24:127-36. High risk due to lack of random sequence generation (1 study). et al.56. Am J Clin Nutr 2013. SD – standard deviation 1. Vichinsky EP. not . 0. lack of blinding of outcome assessment (1 study).71 (95%CI: -1. from narrative information no obvious inconsistency present 9. Data not pooled because of different doses. Aboomardani M. Banihashem A. 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".18 cm 5. Absolute value from two studies and z-score from one study were included 2. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of -1.0. however differences are likely related to doses References 1. placebo-controlled trial. RR – relative risk. Bisphosphonates and Zinc supplementation 85 hamanlu 2014) showed no difference (60 patients.95 to -0. Arefhosseini SR.14 (95%CI: -0.66 (95% CI: -0.37) to -0. Unclear: Al- location concealment (3 studies). Effects of zinc supplementation on linear growth in beta-thalassemia (a new approach). .0. .16 (95% CI: . . Ghahramanlu E. Only very few cases 10. Hematology 2014. However.19) to -0. 4. 95% CI: -12. blinding of outcome assessment (1 study) 3. another study (Fung 2013) reported that "Plasma zinc increased by 14. BMI z-score increased from -0. . Mirhossini NZ. IMPORTANT estimable MD – mean difference. if pooled meta-analysis showed high I²=86% and p = 0. 2. King JC. et al. Fung EB.Management of Thalassemia – Iron chela- tion therapy.21:8-14. although it did not change with time in the placebo group". Iran J Pediatr 2011. Study was not included in meta-analysis due to significant baseline difference (p=0.70 cm. Only very few patients included in study/studies 4. .98:960-71. Kwiatkowski JL. lack of blinding of participants and personnel (1 study). no additional values were reported 11.007. 3. Joshaghani H. therefore difficult to assess. An additional trial (Fung 2013) reported BMI z-scores. Absolute value from one study and z-score from one study were included 7. Cavdar A.4 kg 8. back-transformation using SD of both baseline values in Arcasoy 1987 yields an effect size of -2. Gildengorin G. Zinc supplementation improves bone density in patients with thalassemia: a double-blind. Data not pooled. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of 2. no specific values were reported. in placebo group. . Rafraf M.2% respectively. Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia major.83 to 14.not measured . . Cin S. Huang JN. Arcasoy A. at 3 and 6 months in the zinc group.28). Keshtkar A.

abstract. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). key- word heading word. (7420) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). subject heading word.tw. abstract. name of substance 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*). subject heading word. deferasirox) for iron overload in thalassemia pa- tients Database: Ovid MEDLINE In-Process & Other Non-Indexed Citations. [mp=title.mp. protocol supplementary concept word. (9979) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). (400) 4 ((hemoglobin or haemoglobin) adj3 disease).tw. (45370) 15 (exjade* or deferasirox*). (162) 6 or/1-5 (24197) 7 exp Iron Overload/ (11956) 8 (iron adj3 overload*).tw. Bisphosphonates and Zinc supplementation 86 Appendix 2: Search Strategies and Results 1.tw.mp. (17291) 3 (cooley* and (anemi* or anaemi*)).tw. abstract. (10968) 10 or/1-9 (46063) . protocol supplementary concept word. unique identifier] (4) 17 (cgp adj "72670"). original title. keyword heading word. 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. name of substance word. deferiprone. (146) 6 or/1-5 (28859) 7 exp Iron Overload/ (10091) 8 (iron adj3 overload*).mp. (435) 4 ((hemoglobin or haemoglobin) adj3 disease). unique identifier] (662) 16 (icl adj 670*). (8833) 14 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp). subject heading word.tw. original title. (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. original title.tw. rare disease supplementary concept word.) Interventions (deferoxamine. rare disease supplementary concept word. [mp=title. protocol supplementary concept word. rare disease supplementary concept word. (21563) 3 (cooley* and (anemi* or anaemi*)). [mp=title. name of substance word. keyword heading word. (1585) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).mp.tw.tw.tw.tw.Management of Thalassemia – Iron chela- tion therapy.

drug trade name. original title. device manufacturer. drug trade name. device trade name. [mp=title. keyword] (187) 15 (cgp adj "72670"). drug manufacturer. heading word. in Trials 33 Records Retrieved 33 . (49133) 13 (exjade* or deferasirox*). device manufacturer. device trade name. [mp=title. subject headings. keyword] (1970) 14 (icl adj 670*). subject headings. device manufacturer. drug manufacturer. 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. (13924) 12 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp).mp. original title.mp. abstract. [mp=title. subject headings. abstract.mp. 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). drug trade name. original title. abstract. drug manufacturer. heading word.mp.mp.Management of Thalassemia – Iron chela- tion therapy. heading word. device trade name. (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.

(1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). Comment 2. Broken randomisation 2. (435) 4 ((hemoglobin or haemoglobin) adj3 disease).tw.tw.tw. (1585) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). (400) 4 ((hemoglobin or haemoglobin) adj3 disease). (17291) 3 (cooley* and (anemi* or anaemi*)). (162) 6 or/1-5 (24197) 7 exp Diphosphonates/ (21267) 8 bisphosphonate*.) Bisphosphonates for thalassemia Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations. Excluded: 4 Reasons for exclusions: 1.tw.tw. No control group 4. Total without 315 duplicates Screening (Title and Abstract Review) No.tw. Retrieved: 434 MEDLINE 193 Embase 208 CENTRAL 33 Duplicates: 119 No. (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*). Ovid MEDLINE Daily and Ovid MEDLINE 1946 to Present Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (19716) 2 (thalassemi* or thalassaemi*). (146) 6 or/1-5 (28859) 7 exp bisphosphonic acid derivative/ (46599) 8 bisphosphonate*.mp.mp.tw. Observational study 3. (17815) 9 7 or 8 (47829) . (21563) 3 (cooley* and (anemi* or anaemi*)).Management of Thalassemia – Iron chela- tion therapy. Excluded: 308 Included for Full Text 7 review: Selection (Full Text Review) No. Bisphosphonates and Zinc supplementation 88 Summary of Searches: Total No.tw.

tw. (400) . inTrials 2 Records Retrieved 2 Summary of Searches: Total No. (17291) 3 (cooley* and (anemi* or anaemi*)). Observational study (n=2) 2. Excluded: 3 Reasons for exclusions: 1. Ovid MEDLINE Daily and Ovid MEDLINE 1946 to Present Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (19716) 2 (thalassemi* or thalassaemi*).) Zinc for thalassemia Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations. 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.tw.Management of Thalassemia – Iron chela- tion therapy. Already included in systematic review 3. Total 47 without duplicates: Screening (Title and Abstract Review) No. Excluded: 42 Included for Full Text 3 review: Selection (Full Text Review) No. Retrieved: 64 MEDLINE 17 Embase 45 CENTRAL 2 Duplicates: 17 No.

(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*). Bisphosphonates and Zinc supplementation 90 4 ((hemoglobin or haemoglobin) adj3 disease). 31 trieved: Medline 11 Embase 16 CENTRAL 4 Duplicates: 7 .tw.tw. (435) 4 ((hemoglobin or haemoglobin) adj3 disease). Re.tw. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). (1585) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).mp.tw.mp.Management of Thalassemia – Iron chela- tion therapy. (162) 6 or/1-5 (24197) 7 Zinc/ or zinc. (21563) 3 (cooley* and (anemi* or anaemi*)). in Trials 4 Records Retrieved 4 Summary of Searches: Total No. 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. (146) 6 or/1-5 (28859) 7 zinc.tw.tw.

or Bahrain/ (1250) 32 26 or 27 or 28 or 29 or 30 or 31 (20062) 33 Middle East$. or Saudi Arabia/ (30920) 21 Riyadh. Excluded: 22 Included for Full 2 Text review: Selection (Full Text Review) No.tw. (3718) 23 Kh*bar. Bisphosphonates and Zinc supplementation 91 No.in.mp. or United Arab Emirates/ (4471) 28 Qatar$.in. or Middle East/ (11866) 34 Jordan$.in.mp. Excluded: 0 Patients’ Values and Preferences Searches: Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations.in.mp. (25059) 15 (patient$ utilit$ or health utilit$).in. or exp Health Status Indicators/ (204864) 18 11 or 12 or 13 or 14 or 15 or 16 or 17 (686777) 19 10 and 18 (847) 20 Saudi Arab$.mp.mp.in. (759) 24 Dammam. Total 24 without duplicates: Screening (Title and Abstract Review) No. or Jordan/ (10272) 35 Libya$. or Yemen/ (1915) 31 Bahr*in$.tw.mp. or exp "quality of life"/ (128400) 17 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).in.tw.mp. or exp patient satisfaction/ (74926) 13 attitude to health. or Qatar/ (2460) 29 Oman$. (16216) 22 Jeddah.mp.mp.mp.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$).mp.mp.in.in. (1416) 16 health related quality of life. or Syria/ (10739) .tw.mp. or Oman/ (3876) 30 Yemen$.Management of Thalassemia – Iron chela- tion therapy.in. (162) 6 or/1-5 (24174) 7 exp Iron Overload/ (11956) 8 (iron adj3 overload*). (1582) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).mp. (1349) 25 20 or 21 or 22 or 23 or 24 (31341) 26 Kuwait$. (399) 4 ((hemoglobin or haemoglobin) adj3 disease).in.in.mp.in.tw. (9133) 10 or/1-9 (39133) 11 patient$ participation. (7416) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).mp. (17271) 3 (cooley* and (anemi* or anaemi*)).mp. or Kuwait/ (6933) 27 United Arab Emirates. Ovid MEDLINE Daily and Ovid MEDLINE 1946 to Present Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (19711) 2 (thalassemi* or thalassaemi*).mp. or Egypt/ (38709) 37 Syria$.in. or Libya/ (1843) 36 Egypt$.in.in.mp.mp.tw. or exp patient participation/ (19647) 12 patient$ satisfaction.mp.mp.

mp. (1960) 25 20 or 21 or 22 or 23 or 24 (49018) 26 Kuwait$.in.mp.in. or Oman/ (5605) 30 Yemen$. (763) 43 Iran$. or Kuwait/ (11067) 27 United Arab Emirates.tw. or Morocco/ (8642) 40 Tunisia$. (435) 4 ((hemoglobin or haemoglobin) adj3 disease). 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$. or exp Attitude to health/ (80874) 14 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$). (8084) 39 Morocc$.mp.mp. Bisphosphonates and Zinc supplementation 92 38 Iraq$/ or Iraq. (1980) 16 health related quality of life. (1255) 24 Dammam. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). (21547) 3 (cooley* and (anemi* or anaemi*)).mp.in. or Lebanon/ (14812) 42 West Bank.mp.tw.tw.Management of Thalassemia – Iron chela- tion therapy.in.mp. or Arabs/ (122834) 47 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 (331078) 48 46 or 47 (445204) 49 25 or 32 or 48 (457645) 50 19 and 49 (94) Records Retrieved 94 Data base: Embase <1974 to 2014 October 02> Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (25374) 2 (thalassemi* or thalassaemi*).in. or exp patient participation/ (18705) 12 patient$ satisfaction.in.mp.mp. or Iran/ (65729) 44 Turkey/ or (Turkey or Turkish).mp.mp. (10967) 10 or/1-9 (46040) 11 patient$ participation.mp. or Yemen/ (2585) 31 Bahr*in$.mp. or exp "quality of life"/ (279285) 17 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).in.mp. or Tunisia/ (12790) 41 Leban$. (153093) 45 Algeria$.in.mp. (38280) 15 (patient$ utilit$ or health utilit$).in.mp.mp. or Qatar/ (4798) 29 Oman$. (26446) 22 Jeddah.in.in. (6792) 23 Kh*bar. or Saudi Arabia/ (48722) 21 Riyadh.in. or Bahrain/ (3086) 32 26 or 27 or 28 or 29 or 30 or 31 (34963) 33 Middle East$. or United Arab Emirates/ (9883) 28 Qatar$.in.in.mp.mp. or Middle East/ (15249) 34 Jordan$.in.tw.tw.in. or Jordan/ (30681) .mp.tw. or Algeria/ (4301) 46 Arab$. (146) 6 or/1-5 (28843) 7 exp Iron Overload/ (10086) 8 (iron adj3 overload*).mp.mp.mp.in.in.mp.mp.in.mp. (9971) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).mp.in.in. or exp patient satisfaction/ (94477) 13 attitude to health.mp.in.mp.

or Lebanon/ (27069) 42 West Bank. 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$).mp.in.mp. (77) 7 or/1-6 (294) 8 client$ participation. Bisphosphonates and Zinc supplementation 93 35 Libya$. (8296) 12 (patient$ utilit$ or health utilit$).mp. or Tunisia/ (25085) 41 Leban$. (1) 3 ((hemoglobin or haemoglobin) adj3 disease).tw. (254818) 45 Algeria$. (527) 13 health related quality of life.in. (19) 4 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).mp.mp.in.Management of Thalassemia – Iron chela- tion therapy. or Syria/ (16149) 38 Iraq$/ or Iraq.mp.in. Re.mp. (1105) 43 Iran$.mp.tw.mp.in. or Arabs/ (157020) 47 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 (572180) 48 46 or 47 (707715) 49 25 or 32 or 48 (726932) 50 19 and 49 (93) Records Retrieved 93 Data base: PsycINFO <1987 to October Week 1 2014 Search strategy: Date of search: 10/2014 1 (thalassemi* or thalassaemi*). (10462) 39 Morocc$.tw.in.mp.in. (0) 5 iron overload.mp. or Egypt/ (69210) 37 Syria$.mp. or Algeria/ (7980) 46 Arab$. (4704) 16 or/8-15 (54515) 17 7 and 16 (17) Records Retrieved 17 Summary of Searches: Total No.mp.tw.tw.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$")). (64) 6 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). or Morocco/ (18553) 40 Tunisia$. (160) 2 (cooley* and (anemi* or anaemi*)).in.in.mp. or exp "quality of life"/ (29337) 14 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. 204 trieved MEDLINE 94 Embase 93 PsycInfo 17 Duplicates: 24 No.in. or exp client participation/ (1533) 9 client$ satisfaction.mp. Total 180 without duplicates . or Libya/ (3001) 36 Egypt$.in. or Iran/ (111023) 44 Turkey/ or (Turkey or Turkish).in.mp.mp.mp.

(7416) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). (1505) 20 (cost adj variable$). or Budgets/ (25521) 16 (low adj cost).in. (185340) 24 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 (497461) 25 10 and 24 (495) 26 Saudi Arab$.in.mp.mp.tw.mp. (4933) 19 (cost adj estimate$). Excluded: 179 Included for Full 1 Text review: Selection (Full Text Review) No.mp. (759) 30 Dammam. Bisphosphonates and Zinc supplementation 94 Screening (Title and Abstract Review) No. (1349) 31 26 or 27 or 28 or 29 or 30 (31341) 32 Kuwait$.mp. (1582) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). medical/ or economics.mp. nursing/ or economics.tw.in.tw.mp. (3718) 29 Kh*bar. (162) 6 or/1-5 (24174) 7 exp Iron Overload/ (11956) 8 (iron adj3 overload*). Ovid MEDLINE Daily and Ovid MEDLINE 1946 to Present Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (19711) 2 (thalassemi* or thalassaemi*).in. or Kuwait/ (6933) 33 United Arab Emirates.tw. (399) 4 ((hemoglobin or haemoglobin) adj3 disease). pharmaceutical/ (66169) 12 exp "Costs and Cost Analysis"/ (185622) 13 Value-Based Purchasing/ (210) 14 exp "Fees and Charges"/ (27373) 15 budget$.tw. or Jordan/ (10272) . or Bahrain/ (1250) 38 32 or 33 or 34 or 35 or 36 or 37 (20062) 39 Middle East$.tw.in.mp. (87888) 23 (economic$ or pharmacoeconomic$ or price$ or pricing). or Qatar/ (2460) 35 Oman$.mp.in.in.in.Management of Thalassemia – Iron chela- tion therapy. (8495) 18 (health?care adj cost$).mp.tw.in.mp.in. Excluded: 0 Cost-Effectiveness Search: Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations.mp.tw. or Middle East/ (11866) 40 Jordan$.mp.mp. hospital/ or exp economics. (1667) 22 (fiscal or funding or financial or finance). (110) 21 (unit adj cost$).mp.mp. or United Arab Emirates/ (4471) 34 Qatar$.mp. or Yemen/ (1915) 37 Bahr*in$. or Saudi Arabia/ (30920) 27 Riyadh.mp. (26833) 17 (high adj cost). (17271) 3 (cooley* and (anemi* or anaemi*)). (16216) 28 Jeddah.mp.mp.in. (9133) 10 or/1-9 (39133) 11 economics/ or exp economics. or Oman/ (3876) 36 Yemen$.in.in.

(763) 49 Iran$.in. or Iran/ (65729) 50 Turkey/ or (Turkey or Turkish).in.mp. (2060) 26 (cost adj variable$).mp.mp.tw. (21547) 3 (cooley* and (anemi* or anaemi*)). or Morocco/ (8642) 46 Tunisia$.mp.mp.in.mp.mp.in.in.in. (9673) 24 (health?care adj cost$). or exp pharmacoeconomics/ (170837) 16 health economics. (435) 4 ((hemoglobin or haemoglobin) adj3 disease).tw.in. (30329) 23 (high adj cost). or exp "hospital cost"/ (29327) 15 pharmacoeconomics. or Algeria/ (4301) 52 Arab$. or Libya/ (1843) 42 Egypt$. (164) 27 (unit adj cost$). Bisphosphonates and Zinc supplementation 95 41 Libya$. (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) .tw.mp. (13883) 25 (cost adj estimate$).mp. or Arabs/ (122834) 53 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 (331078) 54 52 or 53 (445204) 55 31 or 38 or 54 (457645) 56 25 and 55 (62) Records Retrieved 62 Data base: Embase <1974 to 2014 October 02> Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (25374) 2 (thalassemi* or thalassaemi*).mp.mp.mp. (146) 6 or/1-5 (28843) 7 exp Iron Overload/ (10086) 8 (iron adj3 overload*).mp.in.mp. (9971) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). or Syria/ (10739) 44 Iraq$/ or Iraq.mp.mp.mp.tw.mp.mp.tw. (2516) 28 (fiscal or funding or financial or finance).mp. or exp "health care cost"/ (213142) 14 hospital cost$.Management of Thalassemia – Iron chela- tion therapy.in.mp.tw. or Lebanon/ (14812) 48 West Bank. or exp economic evaluation/ (217926) 12 fee$.in. (108400) 29 (economic$ or pharmacoeconomic$ or price$ or pricing). (8084) 45 Morocc$.tw. or socioeconomics/ (110656) 19 11 or 12 or 13 or 14 or 15 or 16 (1073744) 20 17 or 19 (1096280) 21 18 or 20 (1189909) 22 (low adj cost). or Tunisia/ (12790) 47 Leban$.in. or Egypt/ (38709) 43 Syria$.mp. or budget/ (36219) 18 socioeconomics. (10967) 10 or/1-9 (46040) 11 economic evaluation$.mp.mp. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).mp. or exp fee/ (603340) 13 health care cost$. (153093) 51 Algeria$. or health economics/ (35972) 17 budget$.tw.mp.in.

mp.mp. Bisphosphonates and Zinc supplementation 96 33 19 or 30 (1331392) 34 10 and 33 (1585) 35 Saudi Arab$. or Algeria/ (7980) 61 Arab$.mp.in. or Qatar/ (4798) 44 Oman$.mp.mp.mp.mp.in. or Bahrain/ (3086) 47 41 or 42 or 43 or 44 or 45 or 46 (34963) 48 Middle East$. (1255) 39 Dammam.in.in.mp.mp.in.in. (1105) 58 Iran$. Excluded: 165 Included for Full Text 0 review: . or Libya/ (3001) 51 Egypt$.in.in. or Saudi Arabia/ (48722) 36 Riyadh.in.in.mp. or United Arab Emirates/ (9883) 43 Qatar$.in.mp.mp. or Kuwait/ (11067) 42 United Arab Emirates.mp.mp.in. or Arabs/ (157020) 62 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 (572180) 63 61 or 62 (707715) 64 40 or 47 or 63 (726932) 65 34 and 64 (149) Records Retrieved 149 Summary of Searches: Total No.in.mp.in. or Iran/ (111023) 59 Turkey/ or (Turkey or Turkish).in.in. (254818) 60 Algeria$. or Oman/ (5605) 45 Yemen$.in.in. Retrieved: 211 MEDLINE: 62 Embase: 149 Duplicates: 46 No.in. or Yemen/ (2585) 46 Bahr*in$.in.in.mp. Total 165 without duplicates: Screening (Title and Abstract Review) No.mp. or Middle East/ (15249) 49 Jordan$.in. or Tunisia/ (25085) 56 Leban$. or Jordan/ (30681) 50 Libya$.Management of Thalassemia – Iron chela- tion therapy. or Syria/ (16149) 53 Iraq$/ or Iraq. (6792) 38 Kh*bar.mp. or Morocco/ (18553) 55 Tunisia$. or Egypt/ (69210) 52 Syria$.mp. (1960) 40 35 or 36 or 37 or 38 or 39 (49018) 41 Kuwait$.mp. or Lebanon/ (27069) 57 West Bank.mp.in.mp.in.in.mp.mp.mp. (26446) 37 Jeddah. (10462) 54 Morocc$.