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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

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). Bisphosphonates and Zinc supplementation 1 Given the importance of this topic. Em- for the synthesis of evidence consisted of up.5 for cases per ers and reduce unnecessary variation in clini- 1000 examined persons. iron chela. criteria of underlying systematic reviews.1-5 Due to a lack of a mandatory This practice guideline is a part of the larger screening program. and costs and resource use spe- cific to the Saudi context. Development sis may occur. information to prepare GRADE evidence-to- tients. As a result of the additional was double-checked and adopted if appropri- iron load caused by transfusions. 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.Management of Thalassemia – Iron chela- tion therapy. Based on the sys- While life expectancy can be increased tematic reviews we prepared summaries of through improved transfusion programs com. base and CENTRAL. genes. with thalassemia living in Saudi Arabia. in turn.7 Zinc full guidelines for the KSA.4 cal practice across the Kingdom. Accordingly. is caused by mutations in hemoglobin thalassemia patients.14 We used this use has been suggested in thalassemia pa. Recommendations. may cause zinc deficiency. Assessment. (RCT). mendation following the GRADE (Grading of morbidities such as osteopenia or osteoporo. several co. zation process. based decision-making on management of eases. requires lifelong frequent red blood cell ies included in the existing systematic reviews (RBC) transfusions. ate. This document focuses on iron chelation. The guideline panel met in Riyadh on March 17 & 18. KSA from 2004-2009.0 for carriers and 0. available evidence supporting each recom- bined with iron chelation therapy. 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. Risk of bias assessment of primary stud- type. preferences. including searches has an important influence on growth and the for information about patients’ values and immune system. for information that was required to develop tors. the more severe sub. Marked variable frequencies of beta- thalassemia have been reported in different Methodology areas and populations of the Kingdom of Saudi Arabia (KSA). a group of inherited blood dis. For all selected questions we morbidities other than thalassemia-associated updated the literature search of existing sys- osteoporosis. bisphosphonates and Evaluation) approach. prevalence in the KSA is initiative of the Ministry of Health of the King- not precisely known. we only regarded randomised controlled trials Beta-thalassemia major.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. 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. However. The guideline does not tions addressed herein using a formal prioriti- address patients with thalassemia and co. According to the inclusion dating existing systematic reviews. We also conducted systematic searches tion therapy is essential. 2015 and formulated all recommen- .

Management of Thalassemia – Iron chela-
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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

jointly. the panel suggests zinc supple- mentation rather than no zinc supplementa- tion. a decision about treat- ment with bisphosphonates in se- lected patients should be made.Management of Thalassemia – Iron chela- tion therapy. (condition- al recommendation against. (conditional recommendation. very low quality of evidence) Remarks:  Practically all patients with thalas- semia major are receiving (or will re- ceive) iron chelation therapy which can interact with zinc metabolism  Serum zinc levels should be moni- tored in patients with iron chelation therapy  Patients with proven zinc deficiency should receive zinc supplementation . Bisphosphonates and Zinc supplementation 5 Recommendation 5: For patients with thalassemia-associated osteoporosis. 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. very low quality of evidence) Remarks:  Vitamin D. Recommendation 6: For children and adolescents with thalasse- mia major.

The preva.572. the mean prevalence of couples testing mia patients focusing on iron chelation thera. is usually diagnosed in children between of rigorous adaptation and de novo develop. Accordingly. frequencies of beta-thalassemia have been reported in different areas and populations of While life expectancy can be increased the Kingdom of Saudi-Arabia. several co- a lack of a mandatory screening program. sion-making. and reduce unnecessary variability in clinical practice across the Kingdom. may cause zinc defi- 1000 births18 summing up to more than ciency. Observable symptoms ment of guidelines in the Kingdom.0 py. ab- mate goal being to provide guidance for clini.Management of Thalassemia – Iron chela- tion therapy. The objective of this document is to provide western Saudi Arabia.7 Zinc has an important influence on 40.44 per iron chelators. thalassemia patients. the additional iron load caused by transfusions The worldwide birth rate for children with iron chelation therapy is essential. Thalassemia.1-5 The preva. in turn.69%) had beta-thalassemia trait. The guideline is focused on this support of the McMaster University working limited scope as the chosen methodological group produced practice guidelines to assist approach for the synthesis of evidence con- health care providers in evidence-based deci. sisted of updating existing systematic reviews. the more severe sub- Health of Saudi Arabia to establish a program type. the Al-Hassa area was observed. is caused by mutations in hemoglobin within the first years of life.000 newborns per year19. bisphosphonates and zinc supplementation in lines. bisphosphonates and zinc supplementa. growth retardation. bisphosphonates use trait prevalence in premarital couples living in has been suggested in thalassemia patients.96% (8/834). 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. symptomatic thalassemia is about 0. showed that 316 guidance for the management of patients with (4. Bisphosphonates and Zinc supplementation 6 lence of beta-thalassemia trait among neo- Scope and purpose nates in the same area was 0. irritability. thalassemia living in Saudi Arabia.140) for cases per 1000 examined includes both paediatric and adult haematolo. persons. This practice guideline is a part of the larger initiative of the Ministry of Beta-thalassemia major. 2009.235/1. dominal swelling. 6 months and one year.6 In morbidities such as osteopenia or osteoporosis 2004.4 gists in the Kingdom of Saudi Arabia (KSA). the Minis. positive for beta-thalassemia was 18. Other health care professionals and policy This document focuses on iron chelation.4% (307/8918) beta-thalassemia may occur. (28. makers may also benefit from these guide. due to bined with iron chelation therapy. the ulti. Transfusion therapy has to be commenced eases. The target audience of this guideline (771/1.2 Additionally.572. a group of inherited blood dis. However. Given the . hepatosplenomegaly and cians and other healthcare decision makers jaundice.140) for carriers and 0. But as a result of genes. are pallor.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. a 3. a screening of 6750 healthy persons in Jeddah. morbidities other than thalassemia-associated try of Health (MoH) of Saudi Arabia with the osteoporosis. through improved transfusion programs com- lence in the KSA is not precisely known. The guideline does not address patients with thalassemia and co- Given the importance of this topic. Marked variable growth and the immune system.5 tion.

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

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

low quality of evidence). 95% CI: -1. etc.).37. with regard to left ventricular ejection fraction patients experiencing adverse effects of de- (%) at 12 months (MD -0. For these patients) at 12 months was not significantly patients.95.07. RR 0.78. Data preferences seems likely. Treatment with deferasirox for one groups in the number of serious adverse year led to high compliance and satisfaction. An additional trial25 was identified as part higher in the deferoxamine group (3 trials.48. 95% CI: from 9 fewer effects. This assumption is supported by a myocardial iron removal (myocardial T2*) and study26 including iron-overloaded thalassemia a trend for superiority which. 95% CI: 0.38. of an updated version of the Cochrane sys. no chelation treatment is covered. Data quality of evidence for our prioritised patient. who had not not statistically significant at 12 months (low achieved successful iron chelation with quality of evidence).75 to 0.g. this is not the case for patients not evidence). however.09 to 2. while deferox- trolled trials21. moderate quality of evidence). has not been considered in this analysis tin (µg/l) at 8 and 12 months was significantly yet.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. 95% CI: 0. low. including two randomised con. 95% semia patients. The same trial tients would prefer oral application of iron demonstrated non-inferiority of deferasirox in chelation.63. 844 patients. 1:5.22. effective. 95% CI: 295.2 of deferasirox to erences led to the inclusion of one study26 deferoxamine. the latter was statistically more conducted in the Middle East. We found two additional amine showed higher efficacy in the other trials23. probably the majority of pa- 1. low quality of evidence). moderate quality of evi- dence).07 to tematic review by Meerpohl10. absolute effect: 5 the differing spectrum of possible adverse fewer patients per 1000. a variability of patient’s values and to 16 more. MD 2.4. equal efficacy was achieved only in the highly iron-overloaded subgroup at a Benefits & Harms of the Option: mean ratio of 1:1. 95% so cost considerations will influence choice of CI: -3. MD -1. Compliance (% of dose taken by insured through a government plan. The evidence showed no deferoxamine and/or deferiprone (n=237) significant difference between treatment before.8. from one trial (563 patients) showed a clear important critical outcomes was judged as dose-response effect for serum ferritin levels. published in Chinese lan.84 to ferasirox.37. 187 patients. MD 415. different (1 trial. was patients from the Middle-East. 873 patients. low quality of covered. One three subgroups at ratios of 1:2. treatment.72. RR Given the different modes of application and 0.1. both treatment options are CI: from 22 more to 32 fewer. Bisphosphonates and Zinc supplementation 9 thalassemia patients? 95% CI: 1. . Although this might from one trial (172 patients) were unclear not be true for all patients (e.6 and of these trials23.2. small children. At a ratio of less than 1:2. low quality of evidence). The search strategy for values and pref. absolute effect: 13 In government insured population of thalas- serious adverse events fewer per 1000.44 to 1.68 to 3. Mortality at 48 weeks and 1 year was report- ed to be not significantly different between Values and Preferences: treatment groups (3 trials. the reduction in serum ferri- guage.64. 541 patients.5. at 12 months (1 trial. 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. highly iron overloaded people. events at 12 months (2 trials. Data from this trial reflect the dose- Summary of Findings: response and ratio effect: at a ratio of 1:1. 1:3. In addition. 773 patients.24 in the updated literature search. The overall 536.Management of Thalassemia – Iron chela- tion therapy.

therapy (e. regard to liver fibrosis (Ishak score) at 12 py months (MD 0. er-term patient-relevant outcomes should be asirox. quality of evidence). Bisphosphonates and Zinc supplementation 10 Feasibility: amine: regular ophthalmologic ex- No obvious barriers to implementation were amination and audiometry needs to identified. lassemia patients? amine. cluding eight randomised controlled trials 27-34. further RCTs evaluating the benefits better compliance due to oral administration. opinion” (Qari et al)6  Dose of iron chelation drug needs to Benefits & Harms of the Option: be tailored according to iron over. low quality of evidence) Summary of Findings: The summary of evidence is based on two Remarks: Cochrane systematic reviews by Fisher8. Research Priorities: ter protection against free iron and probable Ideally. mount importance We found no additional trials in the updated  Iron overload. deferiprone for change in liver iron concentra- tion (mg/g dry weight) using SQUID at 12 . appropriate cost- effectiveness analyses in the KSA setting Recommendation 1: should be considered.1.g.Management of Thalassemia – Iron chela- tion therapy. compliance and side literature search. was as an alternative treatment in pa. from one trial (36 patients) were unclear with responsiveness to deferasirox thera.78 to 0. Due to longer half-life of deferasirox suggesting bet. low  Patients need to be adequately edu. Only one trial (13 patients) reported data on load mortality. dence based on our prioritized patient- tients while on chelation therapy. The overall quality of evi- effects should be monitored in pa. Question 2: Should deferoxamine versus the panel suggests treatment with defer. for important critical outcomes was judged as details see “Regional consensus very low.98. Data from one trial (57 cated and trained for deferoxamine patients. in-  Informed patient choice is of para. Data asirox treatment or non. 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 thalassemia patients with iron overload. sirable and undesirable consequences. however. deferiprone be used for iron overload in tha- asirox rather than treatment with deferox. not thought to be related to the deferiprone tients with adverse effects of defer. and harms of the alternatives including long- the panel suggests treatment with defer. One death occurred after 6 months  Deferoxamine should be considered in the deferiprone group which. (conditional recommendation. 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. very low quality of evidence) showed administration no superiority of deferoxamine compared to  For patients treated with deferox. treatment (very low quality of evidence).9. 95% CI: -0. conducted. for implementation of this recommendation. Also.

very iprone.  Patients need to be adequately edu- .17). Remarks: lassemia patients. small children. to change of serum ferritin (ng/ml).49) whether one No obvious barriers to implementation were drug is superior to the alternative with regard identified. A meta-analysis of three trials (227 patients.02 to 0. better safety profile and the lower overall 0. very low quality of evidence) suggests a signif.56. 95% CI -313. 95% CI: -2. compliance and side patients.94 to .88 to 2.12 to 45. patients. the panel supposes quality of evidence).84. effects should be monitored in pa- so the cheaper treatment option with tients while on chelation therapy. 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.61. combined resources required for patients on deferiprone are likely higher. 95% CI: -2. It remains unclear (MD . 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. both treatment options are  Informed patient choice is of para- covered.88). Bisphosphonates and Zinc supplementation 11 months (MD -0. application of iron chelation. Comparing deferoxamine absolute effect: 186 fewer participants per drug cost including administration cost to 1000. 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. 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. no chelation treatment is covered. this is not the case for patients not mount importance insured through a government plan. the KSA setting. the differing spectrum of possible adverse effects. low quality of evidence) In the government insured population of tha. For these  Iron overload. the benefit of a of deferiprone (MD -1. but many patients would meta-analysis of five trials (307 patients. (conditional recommendation. However. 12 and 24 months.). a variability of patient’s values and Recommendation 2: preferences seems likely. etc. pa.45. for deferoxamine would likely be the preferred details see “Regional consensus choice. Feasibility: 133. serum ferritin concentration (ng/ml) at 6. amine rather than treatment with defer- tients experiencing adverse effects of defer.82. A ment and physicians.8). 95% CI: -4. very likely prefer deferiprone due to its oral admin- low quality of evidence) evaluated change in istration. this might not be the panel suggests treatment with deferox- true for all patients (e. 95% CI: 0.Management of Thalassemia – Iron chela- tion therapy. 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. Data from one trial (61 that deferiprone might be cheaper. at 12 months (MD -1.g. Although. 95% CI: from 54 fewer to 257 fewer. iprone. probably the majority of patients would prefer oral For thalassemia patients with iron overload.24 to 0. low deferiprone drug cost.

low iprone be used for iron overload in thalasse. quality of evidence). absolute effect: 170 fewer participants sus deferoxamine in combination with defer. trial. of evidence based on our prioritized patient- Values and Preferences: . verse events at 12 months was reported in the group treated with deferoxamine alone (2 trials. but 65 patients were randomised at the ment. We found one additional trial40 in the dence) when compared to the combination updated literature search. Whereas. Only very low mote settings. A significantly effectiveness analyses in the KSA setting lower number of patients experiencing ad- should be considered. in.22. on deferiprone (1 trial. myocardial T2* in the combination group. FBC). very low iprone: easy access to monitoring fa.89.Management of Thalassemia – Iron chela- tion therapy. Bisphosphonates and Zinc supplementation 12 cated and trained for deferoxamine important critical outcomes was judged as administration very low. 95% CI: 41 fewer to 221 fewer. quality of evidence). 107 pa- er-term patient relevant outcomes should be tients.33. (number of patients at end of study was not cardiac and/or endocrine impair. cluding nine randomised controlled trials27. clear. adverse effects of deferox.45 to 0. 95% CI -469. MD -136.35-39 . treated with deferoxamine alone(MD -6. Liver damage was not cilities (e. 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. reported in any of the trials. 95% CI: -0. conducted. very low quality of evidence).g. needs to be ensured quality evidence was available for myocardial  Deferiprone should be considered as T2* (ms) at 12 months (2 trials). 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. MD – 0. 20 patients. 119 patients.61 to 195.9.12 to -4.32. per 1000. 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. There are an alternative treatment in patients unclear data for this outcome. 95% CI -8. beginning) reported a significant benefit on amine treatment or non. appropriate cost.g. Also.13 to Question 3: Should deferoxamine alone ver. 95% CI 0. very low quality of evidence). One trial with severe cardiac iron overload. The overall quality therapy group at 12 months.  For patients treated with deferox- amine: regular ophthalmologic ex.86. 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. 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. further RCTs evaluating the benefits ferritin concentration (ng/ml) between both and harms of the alternatives including long.11. groups at 6 and 12 months (3 trials. 59 patients. 0.17.84. combination therapy) treatment groups. very low quality of evi- 30. in particular in re. There was Research Priorities: no significantly different change in serum Ideally. RR 0.

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

We found no additional trials in the and/or agranulocytosis was found (3 trials. The same trial also re- ported five further deaths in patients who Acceptability: were relocated to treatment with deferox. 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. randomised to combination therapy. Addi- treatment they were initially randomised to. 193 patients. very low quality of very low.25. 95% CI -3. covered.87 to 30. deferiprone versus deferiprone alone in the ty of evidence. tionally. very low quality of Resource Use: evidence). Myocardial T2* The panel considered that for thalassemia was reported by one trial (54 patients. combination therapy. MD 5. Benefits & Harms of the Option: Values and Preferences: Mortality was reported in two trials (237 pa. Feasibility: tion (%) in the combination therapy group was No obvious barriers to implementation were not clearly evident when compared to mono. only graphic presentation of KSA setting.39. very low quali. Lastly. in. 95% CI: -468. died at the beginning of the trial due to ar. this is not the case for pa- ticipant. 20 patients. therapy at 12 months (1 trial.99 to 12. In government insured population of thalas- tients. possibly lower compliance. The panel.2.42 to 1. very low quality of evidence). quality of evidence).e. very patients with iron overload.36.41. no chelation treatment is rhythmia-induced congestive heart failure.Management of Thalassemia – Iron chela- tion therapy. the undesirable low quality of evidence). updated literature search. No clear feriprone rather than deferiprone alone prob- benefit or harm of combination therapy com. supposes data).41. The panel’s judgement was that many pa- amine alone due to adverse events of the tients would likely prefer monotherapy.76 to 2. that a combination therapy requires more apy compared to deferiprone alone on liver resources than a monotherapy. . MD -1. so the cheaper treatment option The other trial reported one death in 5 years. with deferiprone alone would likely be the due to arrhythmia in the group treated with preferred choice. the burden of administra- mean change was not possible. ference in risk for leucopenia. A higher or lower left ventricular ejection frac. but calculating the consequences (i. no significant dif- cluding five randomised controlled trials27. due to varia. combination therapy requires more these patients died 11 to 60 months after resources.9. neutropenia 29. 33 patients. withdrawal of the randomised treatment. monotherapy and combina- (duration: 12 months) reported that one par. tients not insured through a government plan. absolute effect: 54 more cases per 1000. higher re- ble durations of follow up. 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. A benefit or harm of combination ther. ably outweigh the desirable consequences in pared to deferiprone alone on serum ferritin most settings. RR 1. Bisphosphonates and Zinc supplementation 14 concentration (ng/ml) at 6 and 12 months was Summary of Findings: evident in the data (3 trials. identified. iron concentration (mg/g dry weight) at 12 months could not be demonstrated clearly (1 Balance between desirable and undesirable trial. evidence). MD The summary of evidence is based on two -219. consequences: very low quality of evidence). However. 95% important critical outcomes was judged as CI: 32 fewer to 213 more. of evidence based on our prioritized patient. 95% CI: 0.42. tion are covered. The overall quality 217 patients.42 . 95% CI: -1. tion. 20 patients. very low Cochrane systematic reviews by Fisher8.61. For these patients. however. One trial semia patients.

FBC). 118 members.70. The follow-up48 after effects should be monitored in pa. be ensured 95% CI: from 10 fewer to 60 more. very low quality of evidence) sis? Remarks: Summary of Findings:  Informed patient choice is of para. cardiac and/or endo. patients treated with zoledronic acid considered as an alternative treat. The summary of evidence is based on two mount importance systematic reviews11. needs to be en. RR 8.12 including five random-  Iron overload. tients while on chelation therapy. no change during the study period. 207 patients. In the crine impairment or non.27. amine: regular ophthalmologic ex. 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. Two trials (184 patients) ucated and trained for deferox. and 24 months was very imprecise (3 trials. quality of evidence). low Research Priorities: quality of evidence). implementation considerations higher incidence of symptoms compared to no are not considered to be relevant by the panel bisphosphonate treatment (one trial. We found no additional trial in the updated for details see “Regional consensus literature search. Bisphosphonates and Zinc supplementation 15 conducted. Also. showed a high reduction of pain scores. Regarding flu-like symptoms Implementation Considerations: after a first infusion of neridronate 100mg.85. ment in patients with severe cardiac whereas patients in the control group showed iron overload. patients. compliance and side ised controlled trials43-47. Question 5: Should bisphosphonates versus iprone rather than treatment with defer. appropriate cost- Recommendation 4: effectiveness analyses in the KSA setting should be considered.03. mean back pain scale score was responsiveness to monotherapy also significantly improved in patients treated with neridronate. 95% CI: 0.31. In the  Combination therapy should be first trial. 95% CI: 0. overload  For patients treated with defer. other trial. For this recommendation against a combina. the evidence did not preclude a lower or tion therapy. cross-over of one trial47 was not considered. in particular in phonates the estimate for the difference in remote settings. (conditional recommendation ment of thalassemia-associated osteoporo- against. amination and audiometry needs to absolute effect: 7 fewer patients per 1000.01 to 6. Benefits & Harms of the Option: iprone: easy access to monitoring Comparing bisphosphonates to no bisphos- facilities (e. patients treated with bisphosphonates using er-term patient-relevant outcomes should be DXA at 12 and 24 months was reported (3 trials.Management of Thalassemia – Iron chela- tion therapy. 95% CI: 0. number of participants experiencing at least sured one vertebral or non-vertebral fracture at 12  For patients treated with deferox. RR 0. the panel suggests against treatment with deferoxamine in combination with defer. reported only narratively on back or bone pain amine administration at 12 months (low quality of evidence).02 to . For thalassemia patients with iron overload. no bisphosphonates be used for manage- iprone alone. A significantly higher Ideally. further RCTs evaluating the benefits lumbar spine bone mineral density (g/cm²) in and harms of the alternatives including long.g.44 to 156. very low  Patients need to be adequately ed. 191 patients MD 0.

treatment with bisphosphonates.  Patients with a history of fractures creased. benefits. appropriate cost-effectiveness analyses in the Balance between desirable and undesirable KSA setting should be considered. Resource Use: We found no economic evaluation addressing Research Priorities: the use of bisphosphonates versus no Ideally.72. low quality of evidence). Remarks: er. given the ad- verse effects and potential costs for non. and calcium supplementation therefore health inequities might be in.g. pain. low quality of evidence). Also. Moni- No obvious barriers to implementation were toring of benefits and adverse effects in pa- identified. higher femoral neck bone mineral density resource utilization. and/or proven severe osteoporosis should be referred to an endocri- Acceptability: nologist. MD 0. RR 10. ty should be monitored in patients tion with regard to the considered outcomes.08.05. 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. consequences: The panel considered that for thalassemia patients with osteoporosis.e. A significantly consequences (i. 95% CI: 1. Howev. acceptability will ing: likely vary. 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. the panel suggests against 76. 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. (condi- tional recommendation against.96.02 sirable consequences given unclear health to 0. a decision about For more severely affected thalassemia pa.05 . burden of administration. 191 patients. Bisphosphonates and Zinc supplementation 16 0. 89 patients. treatment with bisphosphonates in tients (e. with thalassemia Treatment with bisphosphonates is covered in  Prevention and first line treatment government insured thalassemia patients with of thalassemia-associated osteopo- osteoporosis. very low Values and Preferences: quality of evidence) No published evidence with regard to the considered outcomes was identified. low quality of evidence). calcium and bone densi- in values within the KSA thalassemia popula. panel members assumed some variability  Vitamin D. Standardized criteria for the use of bisphos- phonates in high-risk patients should be es- Feasibility: tablished and its application monitored. relevant outcomes should be conducted.49 to osteoporosis. Implementation Considerations and Monitor- government insured people. further RCTs evaluating the benefits bisphosphonates in the KSA setting. As prophylactic measure. tients treated with bisphosphonates should be established. fractures) acceptability seems selected patients should be made likely. but were judged to be moderate. jointly. 95% CI: 0.Management of Thalassemia – Iron chela- tion therapy. This is not the case for patients rosis should be based on vitamin D not insured through a government plan. the undesirable Question 6: Should zinc supplements versus .

Management of Thalassemia – Iron chela- tion therapy. it might well be that some z-score) at 9 months. MD 0.19 to 0. low the use of zinc versus no zinc in the KSA set- quality of evidence). Monitoring zinc of evidence). Cost of zinc supplements are likely low. while dispensing 30 panel suggests offering this option in children mg zincsulfate showed no difference (60 pa.03) in the other trial at 9 months (low quality of evidence). Howev.83 to 14. The ties. the panel suggests zinc supple- No published evidence with regard to the mentation rather than no zinc supplementa- considered outcomes was identified.60. relevance of levels (µg/dl). low quality of evidence). 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.16 to 78. No trial reported haemoglobin Recommendation 6: levels. very low quality of evidence). panel members assumed some variability adolescents with beta thalassemia major? in values within the KSA thalassemia popula- tion with regard to the considered outcomes. However. due to no relevant side effects. 95%CI: -0. adverse events (138 patients. overall quality of evidence based on our prior- itized patient-important critical outcomes was Acceptability: judged as very low.85. and adolescents with thalassemia major. Three trials reported ting. The second trial reported that no visible side effects were observed at 1-7 years. uptake is not available at all medical centers in cant differences in adverse events including the KSA. We found no economic evaluation addressing tients. SMD . feasible rum zinc at 3 months (MD 47.65 to fied. 95% ceptable given the unclear benefits. 1.52 in the updated literature search. (conditional recommendation.22. very low quality Costs are likely to be low. tion.30. the health benefits is somewhat uncertain. 60 patients. How- use of 220 mg zincsulfate led to a higher se. months. One trial did not observe signifi. stomach upset and nausea at 18 these cases are required.25. MD 0.63. Data from two trials were unclear with regard to bodyweight Resource Use: (kg or z-score) at 9 and 18 months (92 pa.50. very .6.44) compared to no treatment use and prevention of zinc deficiency.11 . For children and adolescents with thalasse- Values and Preferences: mia major. We limited access to measurement and monitor- found two additional randomised controlled ing of zinc levels might increase health inequi- trials51. 95% CI: -0. Balance between desirable and undesirable The third trial mentioned gastrointestinal dis.0. Summary of Findings: in particular given the prophylactic nature of The summary of evidence is based on a this intervention. CI: -0. In one trial (60 patients). 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. moderate to small resource 16. SMD 0. Two studies reported serum zinc fits of zinc supplementation. consequences: turbances in 1-8% of the study population at 9 Due to very low quality of evidence for bene- months.47 to 0. 95% CI: -12. Cochrane systematic review by Swe13. but ing two randomised controlled trials49. tients. Bisphosphonates and Zinc supplementation 17 no zinc supplements be used in children and er. ever. therefore additional resources in diarrhea. the with zinc supplements. includ. No significantly higher or lower body mass Feasibility: index (kg/m²) at 3 months was observed (1 No obvious barriers to implementation identi- trial. 95% CI: implementation.

Also. Research Priorities: semia major are receiving (or will Ideally. should receive zinc supplementation Implementation considerations and Monitor- ing: . prevalence in zinc deficiency should be con- tored in patients with iron chelation ducted. Remarks: • Practically all patients with thalas. 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. Bisphosphonates and Zinc supplementation 18 low quality of evidence) There were no specific considerations relevant for implementation of this recommendation. further RCTs evaluating the benefits receive) iron chelation therapy and harms of zinc supplementation stratified which can interact with zinc metab. appropriate cost-effectiveness therapy analyses in the KSA setting should be consid- • Patients with proven zinc deficiency ered.

Bhardwaj A. 2. Rating the quality of evidence. El-Hazmi MA. 17.107:3455-62.66:719-25. Fisher SA. Modell B.1:43-6. Giusti A. J Epidemiol Glob Health 2011. J Clin Epidemiol 2013. Schunemann HJ. Choudhry AJ. in patients with beta-thalassemia. Memish ZA. 21. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. a once-daily oral iron chelator. Cohen A. Albagshi MH. Barua A. Going from evidence to recommendations: the significance and presentation of recommendations.who. 3.5:1147-53.850:251-69. Guyatt G. Doree C. . Premarital screening for thalassemia and sickle cell disease in Saudi Arabia. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 2013. Fisher SA.336:924-6. Akl EA.6:Cd009415. western Saudi Arabia. Global epidemiology of haemoglobin disorders and derived service indicators. Cochrane Database Syst Rev 2012. 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. 2012. Alswaidi FM. GRADE guidelines: 3. Saeedi MY. Gooding S. 7.64:383-94. A phase 3 study of deferasirox (ICL670). 15. Prevalence of thalassemia disorders and hemoglobinopathies in Jeddah. 18. Doree C. et al. Kulkarni H. Warsy AS. et al. Cochrane Database Syst Rev 2013.8:Cd004839. Chowdhury O. Guyatt G. Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area. GRADE guidelines: 14.8:143. Alhamdan NA. Brunskill SJ. Genet Med 2007. Oxman AD. (Accessed February 7. Al Jaouni S. et al. Erdogan E. Chowdhury O. J Clin Epidemiol 2011. Guyatt GH. GRADE guidelines: 1.21:183-7. Brunskill SJ. Journal of Applied Hematology 2010. et al. Introduction-GRADE evidence profiles and summary of findings tables. Gooding S. Aylak F. Osteoporos Int 2010. Meerpohl JJ. Oxman AD. 11. The effects of chelators on zinc levels in patients with thalassemia major. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. World Health Organization. Saudi Arabia. et al.8:Cd004450.1:61-8. Helfand M. Roberts DJ. Al-Suliman A. 20. Antes G.64:401-6. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review. Oral deferiprone for iron chelation in people with thalassaemia.2:Cd007476. Prevalence of beta-thalassemia trait in premarital screening in Al-Hassa. 4. Cappellini MD. Orphanet J Rare Dis 2013. 5. Wali Y. Cochrane Database Syst Rev 2013. 9. Nair NS. Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials. Ann Saudi Med 2006. Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia. Rucker G.27:109-11.26:14-6.32:606-15. et al. 13. Blood 2006. at http://apps.Management of Thalassemia – Iron chela- tion therapy. Darlison M. 10. BMJ 2008. 12. Balshem H. Owaidah TM. J Clin Epidemiol 2011. Global epidemiology of hemoglobin disorders. Ormeci AR. Modell B. Bisphosphonates and Zinc supplementation 19 References 1. Abas AB. Canatan D. Mamtani M.) 16. 6.pdf. Bulletin of the World Health Organization 2008. Roberts DJ. Vist GE.9:372-7.int/iris/bitstream/10665/75146/1/9789241548441_eng. WHO Handbook for Guideline Development. Angastiniotis M. 8. 19. Qari MH. Cochrane Database Syst Rev 2013.86:480-7. Almazrou YY. Deferasirox for managing iron overload in people with thalassaemia. Swe KM. Andrews J. Zinc supplements for treating thalassaemia and sickle cell disease. Annals of the New York Academy of Sciences 1998. 14. East Mediterr Health J 1999. J Bone Miner Metab 2014. Piga A. Vural H. Oxman AD. 2014. et al.

Piga A. ICL670). Terzi A. 25. Cetiner N. Madan N. Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial.91:873-80. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Tanner MA. Morabito A. . D'Amico G. et al. 31. et al. Olivieri NF BG. 36. A randomized. Peng P.30:263-74. Hemoglobin 2006.336:1275-9.115:1876-84. et al. Blood Cells Mol Dis 2002. Br J Haematol 2003. Final results of the randomized trial of deferiprone (L1) and deferoxamine (DFO) [abstract]. Pennell DJ.3:93-7. et al. Iranian Red Crescent Medical Journal 2010.12:655-9. Tamaddoni A RM. Comparison of deferasirox and deferoxamine treatment in iron-overloaded patients: Liver iron concentration determined by quantitative MRI-R2*.12:577-85. Blood 2006. Forni GL. Manz C. Mansoori F. et al. [Chinese]. 27. Chik KW. Taher A. ASH Annual Meeting Abstracts 2005.106:2698-. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong.123:1447-54. Saxena R. Randomised Prospective Evaluation of Iron Balance. Long LL. Gomber S. Sheikh-Taha M. Comparison of therapeutic response and complications of oral Osveral and injection Desfereal chelating agent in patient with thalassemia major. Olivieri NF. et al. Khoriaty AI. Haematologica 2006. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. 33. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. 28. et al. Acta haematologica 2010. 23. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. 37. Kattamis 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.91:1241-3. Huang ZK. et al. placebo-controlled. orally-administered iron chelator.107:3738-44. Nazemi A. Piga A. Elalfy MS. Comparative efficacy of desferrioxamine. Randomized phase II trial of deferasirox (Exjade. double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance.87:545-50. Blood 1997. 39. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). Hoffbrand AV. Ling SC. 32. a once-daily. 24. Koren G. et al. Hermann C. Galanello R. Blood 2014. et al.123:220-5.Management of Thalassemia – Iron chela- tion therapy. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience.121:187-9. Berdoukas V. Chelation Efficiency. Bisphosphonates and Zinc supplementation 20 22. Piga A. 34. Porter JB. Naja M. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. Ann Hematol 2008. Lancet 1990. 35. Galanello R. Evazi R. Karagiorga M. deferiprone and in combination on iron chelation in thalassemic children. Galanello R. Asian Journal of Medical and Pharmaceutical Researches 2013. 29. Mourad FH. Indian Pediatr 2004. Al Jefri A. 30. Dessi C.28:196-208. Circulation 2007. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Aydinok Y. Haematologica 2006. Chinese Journal of Radiology (China)2013:55-9. Evans P. Maggio A. Molavi MA DH. Porter JB. Koussa S.90:264a. 38.41:21-7. Pennell DJ. in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Ha SY. El-Beshlawy A. Abdelrazik N. Hematology 2007. 26. Taher A.

Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2. Tsiftsakis E. Costs. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. Olivieri N. Mantovani LG.13:644-9. Gilfillan CP. Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalassemia major Patients. Arcasoy A. Morabito N. Am J Hematol 1987. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. Spina M.79:138-44. Vitrano A.Management of Thalassemia – Iron chela- tion therapy. 46.98:960-71. 47. Gildengorin G. Osteoporos Int 2002. Am J Clin Nutr 2013. Forni GL. Bentley A. 49. Voskaridou E. Perrotta S. 41. Nart D. Rafraf M. placebo-controlled trial. Giusti A. 54. Br J Haematol 2009. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial.92:1599-606. Br J Haematol 2012. Alexakos P. Christoulas D. Keshtkar A. 52. Maggio A. double-blind. et al. Kwiatkowski JL.15:38. Haematologica 2007. 50. Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia major. Arefhosseini SR. Aydinok Y. 51. Ghahramanlu E. open-label study. Cost-utility analysis of deferiprone for the treatment of beta-thalassaemia patients with chronic iron overload: a UK perspective. King JC. Pizzarelli G. randomized. Bisphosphonates and Zinc supplementation 21 40. Fung EB.24:127-36. 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. et al. Riccobene S. Gaudio A. A randomized. Voskaridou E. Huang JN. Terpos E. Connelly J. Effects of zinc supplementation on linear growth in beta- thalassemia (a new approach). parallel-arm. placebo-controlled trial. et al. et al. Rashidi M. Spino M. Mirhossini NZ.158:274-82.24:1905-17. 43. Ulger Z. Fiore CE. J Cardiovasc Magn Reson 2013. Konstantopoulos K. placebo-controlled trial.19:113-9. Konstantinidou M. et al. Tricta F. Joshaghani H. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. 45.21:402-8. 48. Calcif Tissue Int 2006. et al. Cin S. Haematologica 2006. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center. Porter JB. Zinc supplementation improves bone density in patients with thalassemia: a double-blind. Cavdar A. Strauss BJ. Anagnostopoulos A. treatment satisfaction and compliance in patients with beta-thalassemia major undergoing iron chelation therapy: the ITHACA study. Iran J Pediatr 2011.91:1193-202. Bisphosphonates in the treatment of thalassemia- induced osteoporosis. 44. Krol M. Vichinsky EP. randomized. 53. et al. Capra M.31:807-22. Pennisi P. . Hematology 2014. Banihashem A. randomized. Haematologica 2008. et al. Scalone L. 42.21:8-14. et al. J Bone Miner Metab 2003. quality of life. Wood J. Pharmacoeconomics 2013. Lasco A. Rodda CP. Current medical research and opinion 2008. Aboomardani M. placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia.93:1588-90.145:245-54. Gillard S. et al.

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

Oral chelation Option: Deferasirox therapy with deferasirox is suggested to be at least similarly effective. Relative Certainty of the What is the studies Outcome Given the different modes of ap- Benefits & importance evidence (GRADE) harms of the overall cer. 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. a 3."6 ○ Probably no In 2004. leading to increased patient compliance due to the more convenient application.1 ○ Varies The relative importance or values of the main outcomes of interest: Long term experience with defer- ○ No included asirox is limited. ○ Very low plication and the differing spec- trum of possible adverse effects. showed that 316 (4. The prevalence of beta-thalassemia trait ● Yes among neonates in the same area was 0.2 Problem problem pri- ority? ○ Probably yes A screening of 6750 healthy persons in Jeddah. the standard iron chelating drug. Alt- hough this might not be true for ○ Moderate all patients (e. western Saudi Arabia.4% (307/8918) beta-thalassemia trait prevalence in premarital couples Is there a ○ Uncertain living in the Al-Hassa area was observed.Management of Thalassemia – Iron chela- tion therapy. . 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. 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. 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.g.69%) had beta-thalassemia trait. small children.96% (8/834). Background and Objective: Deferoxamine.

This assumption is ● Important Myocardial T2* (ms) .Cardiac: Left ven- ⨁⨁◯◯ effects of deferasirox.mean change from ⨁⨁◯◯ supported by a study26 including CRITICAL uncertainty or baseline . ity Mean change in serum ferritin (µg/l) .). 5 per 1000 1000 (from pated effects ○ Probably yes 48 weeks and 10 per 1000 1 year (1 to 26) 9 fewer to (0.at ⨁⨁⨁◯ ance and satisfaction. Any serious adverse event . who Mean change in liver iron concentration had not achieved successful iron ○ Possibly im.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.at 12 CRITICAL ably the majority of patients months LOW would prefer oral application of iron chelation. tainty or variabil.at 12 months fore. ○ Uncertain Mortality at 5 fewer per RR 0.09 to 2.at 12 months IMPORTANT LOW main out. Bisphosphonates and Zinc supplementation 24 patients experiencing adverse ○ High End-organ damage . ity comes? ○ No important Compliance (% of dose taken by pa- IMPORTANT ⨁⨁◯◯ uncertainty of tients) . (mg Fe/g dw) evaluated by biopsy or CRITICAL ⨁⨁⨁◯ chelation with deferoxamine MODERATE and/or deferiprone (n=237) be- portant uncer.at 12 months LOW iron-overloaded thalassemia pa- variability tients from the Middle-East.1 ○ Varies damage .Management of Thalassemia – Iron chela- tion therapy. etc. certainty IMPORTANT about how ○ Probably no 8 and 12 months MODERATE much people important uncer- ⨁⨁◯◯ value the tainty of variabil. for one year led to high compli- portant un.63) large? 16 more) ○ Yes End-organ Left ventricular Left ventricular ejec. MD 0.48 able antici. prob- tricular ejection fraction (%) . ejection fraction tion fraction (%) at lower - . SQUID . Treatment with deferasirox Is there im.

mean change 1.Management of Thalassemia – Iron chela- tion therapy.07 at 8 and 12 and 12 months) in intervention group higher to . i.e. Gmean (coefficient of variance) small? myocardial T2* improved after 1 year of treatment with deferasirox ○ Yes by 12 % (11. reduction in to 3. 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.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. The ratio of the Gmeans of deferasirox over DFO was 1.7] ms).3 [34.68 higher - evaluated by -6.6 [30. ed by biopsy or 12 months) in the able effects ● Uncertain in liver iron concentration SQUID at 12 intervention group MD 2.7] ms to 12.056 (repeated 95% CI 0.e. (1. i. Because the lower bound of the 95% CI was greater than from baseline prespecified margin of 0.84 lower ventricular in the control intervention group to 1.4 was 0.64 higher) Are the unde.84 higher) tion (%) . Bisphosphonates and Zinc supplementation 25 ○ No Cardiac: Left (%) at 12 months 12 months in the (1.6] ms at EOS) and ○ Varies Myocardial T2* (ms)- by 7% for DFO (11.37 large relative months) in the was 2. group was 66.68 higher to undesira- ○ Probably yes (mg Fe/g dw) control group was higher to 3.9.07 lower to 1. noninferiority of deferasirox compared .07 high.6] ms at baseline to 12.37 higher (1.64 ○ Probably no ejection frac.133).at lower to 1. alt- hough this did not reach statistical significance.at 12 with DFO for myocardial iron removal was demonstrated.68 lower).6 [42.5 er).2 [32. by biopsy or SQUID at Are the desir.998.1 lower (1. reduction was higher in deferoxamine group Mean change The range for Change in serum MD 415. ● Uncertain 12 months sirable antici- pated effects ○ Probably yes "In the per-protocol population.4-0.07 ble effects? ○ Yes biopsy or LIC was 2.at ○ Varies 12 months (3.37 lower higher) SQUID . A trend for months superiority of deferasirox compared with DFO was observed.

37 lower to 295.4 lower to 0.e. i.72 higher 536.53 .07 lower).179 pounds per year treatment with deferasirox ○ Yes (Exjade®) versus 8. A cost-utility analy- sis of deferasirox for the treat- Are the re.e.025 pounds per one-year treatment with ge- ○ Varies neric deferoxamine including administration cost.78 adverse 45 per 1000 58 per 1000 (from 22 (0.4 (3.07 higher to higher) 536. reduction was higher in deferoxamine group 13 fewer Any serious per 1000 RR 0. MD 1.4 (% of dose patients) at 12 tients) at 12 months lower taken by months in the in the intervention (3.37 was -1277-211 (295. Bisphosphonates and Zinc supplementation 26 months the control group was 415.37 higher). No specific data on costs of defer- ○ No asirox or deferoxamine in KSA ○ Probably no setting found.95 12 months 100.44 to event-at 12 (25 to 80) more to 32 1.72 lower (536. i. reduction in serum ferritin was 415.95 higher) higher) No research evidence specific to KSA setting identified.38) months fewer) Compliance (% of Compliance (% of Compliance dose taken by dose taken by pa.75 lower to 0.75 lower - patients) .at control group was group was 1. ○ Uncertain ment of beta-thalassemia patients with chronic iron overload esti- Resource use sources re- quired small? ● Probably yes mates 23.Management of Thalassemia – Iron chela- tion therapy.

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

including iron-overloaded thalassemia pa.2% at ● Yes baseline.7% of all patients reported being holders? either "satisfied" or "very satisfied" with their iron chelation therapy versus 23. but also other patients from the Middle East. 86. On a 5-point scale (ranging from "very satisfied" or "very conven- Acceptability key stake. No research evidence specific to KSA setting identified. Bisphosphonates and Zinc supplementation 28 No research evidence specific to KSA setting identified. Most patients would likely prefer One study (Taher 2010)26 was identified.Management of Thalassemia – Iron chela- tion therapy. 98.6) h/month at end of study).4 (4.5% at baseline considered their therapy to be "convenient/very convenient".2 (8. ○ Probably yes ient" to "very dissatisfied" or "very inconvenient") 90.6) %.3% patients still received deferasirox (persistence). Over- Is the option ○ Uncertain all (mean (SD)) compliance was 98. 92. ○ No tients from Saudi-Arabia.oral application.1% received at least 95% of their acceptable to scheduled doses. Treated with deferasirox for one year.8% at end of study versus 21. who had not ○ Probably no achieved successful iron chelation with DFO and/or deferiprone (n=237). No obvious barriers to implemen- ○ No tation were identified. Time lost to therapy for daily activities was reduced ○ Varies (30.1 (44. ○ Probably no Is the option ○ Uncertain Feasibility feasible to implement? ○ Probably yes ● Yes ○ Varies .2) (mean (SD) h/month) at baseline to (3.

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

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

056 (repeated 95% CI 0.07 higher) MODERATE . 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 (1.7] ms to 12.at 12 months 5 6 7 1 randomised serious serious not serious not serious dose response 268 273 .48 5 fewer per 1000 (from 9 fewer to 16 more) ⨁⨁◯◯ CRITICAL trials (0.998.6 [42.1 lower ⨁⨁◯◯ CRITICAL trial (1. A trend for superiority of deferasirox compared with DFO was ob- served.6[30.68 higher to 3. 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 .7] ms). 1. MD 2. Because the lower bound of the 95% CI was greater than prespecified margin of 0.2 [32.6] ms at EOS) and by 7% for DFO (11. MD 0.133). Gmean (coefficient of ⨁⨁◯◯ CRITICAL trial variance) myocardial T2* improved after 1 year of treat. LOW ment with deferasirox by 12 % (11. The ratio of the Gmeans of deferasirox over DFO was 1. noninferiority of deferasirox compared with DFO for myocardial iron removal was demonstrated.5%) (0.at 12 months 3 4 1 randomised serious not serious not serious serious none 91 81 "In the per-protocol population.37 higher ⨁⨁⨁◯ CRITICAL trial gradient (1. 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.63) End-organ damage .9.Management of Thalassemia – Iron chela- tion therapy. although this did not reach statistical signifi- cance.0%) RR 0.at 12 months 3 4 1 randomised serious not serious not serious serious none 91 81 .Cardiac: Left ventricular ejection fraction (%) .09 to LOW 2.6] ms at base- line to 12.3 [34.84 lower to 1.64 higher) LOW Myocardial T2* (ms)-mean change from baseline .

RR – relative risk.72 higher ⨁⨁⨁◯ IMPORTANT trials gradient (295. lack of blinding of outcome assessment (3 studies). no SD mentioned 6. a significant decrease with deferoxamine compared to deferasirox was shown. SD – standard deviation 1. 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). Very wide confidence interval including both clinically relevant benefit as well as harm 3.Management of Thalassemia – Iron chela- tion therapy. p<0. High risk of bias due to lack of blinding of participants and personnel (3 studies). I²=84%. Only few patients were included in study 5. lack of blinding of outcome assessment. I²=91%. including smaller study population. Another study (Piga 2006) reported average decreases of similar magnitudes measured by SQUID.38) Compliance (% of dose taken by patients) . lack of blinding of outcome assessment. allocation concealment (2 studies). MD 1.6%) (0.00001.75 lower to 0. selective reporting (2 studies) 2. whereas there was a tendency for ferritin values to increase modestly over time in patients randomised to deferasirox 10 mg/kg/day" 9. selective reporting 7.at 12 months 3 4 1 randomised serious not serious not serious serious none 96 91 . incomplete outcome data (1 study). selective reporting (1 study).07 higher to 536. High risk of bias due to lack of blinding of participants and personnel (3 studies). incomplete outcome data. Unclear: Random sequence generation (2 studies). selective reporting (1 study) . allocation concealment (1 study). selective reporting (1 study) 10. incomplete outcome data (1 study).4 lower ⨁⨁◯◯ IMPORTANT trial (3. Unclear: Random sequence generation. measured LIC (mg Fe/g dw) by MRI. Heterogeneity due to different ratio of drugs between subgroups 8. heterogeneity due to different ratio of drugs between subgroups 11. p<0. incomplete outcome data (1 study). MD 415.95 higher) LOW MD – mean difference. lack of blinding of outcome assessment (3 studies). 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 (2 studies). Unclear: Random sequence generation 4. An additional study (Pennell 2014).37 higher) MODERATE Any serious adverse event .000001. lack of blinding of outcome assessment (2 studies). allocation concealment (2 studies).78 13 fewer per 1000 (from 22 more to 32 fewer) ⨁⨁◯◯ IMPORTANT trials (4. High risk of bias due to lack of blinding of participants and personnel.at 12 months 11 2 2 randomised serious not serious not serious serious none 18/392 22/381 (5. incomplete outcome data (2 studies).8%) RR 0. Unclear: Random sequence generation (2 studies). incomplete outcome data (1 study). 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 . allocation concealment.44 to LOW 1. Unclear: Random sequence generation (3 studies).

3:93-7. Blood 2006.123:1447-54. et al. et al.Management of Thalassemia – Iron chela- tion therapy. Piga A.107:3455-62. A phase 3 study of deferasirox (ICL670). orally-administered iron chelator. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Pennell DJ. Mansoori F. 3. Randomized phase II trial of deferasirox (Exjade. . Bisphosphonates and Zinc supplementation 33 References 1. Haematologica 2006. Cappellini MD. Evazi R. Asian Journal of Medical and Pharmaceutical Researches 2013. a once-daily. Nazemi A. 4.91:873-80. 2. ICL670). Porter JB. Piga A. Molavi MA DH. Forni GL. Comparison of therapeutic response and complications of oral Osveral and injection Desfereal chelating agent in patient with thalassemia major. Cohen A. Galanello R. Piga A. in patients with beta-thalassemia. a once-daily oral iron chelator. Blood 2014. et al.

4% (307/8918) beta-thalassemia trait prevalence in premarital couples ○ Uncertain living in the Al-Hassa area was observed.96% (8/834). leading to increased patient compliance due to the more convenient application. Option: Deferoxamine Oral chelation therapy with deferiprone is suggested to be at least similarly effective. probably the Mortality CRITICAL majority of patients would pre- ○ Moderate VERY LOW fer oral application of iron che- . 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. ○ Probably A screening of 6750 healthy persons in Jeddah. showed that ity? yes 316 (4. 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.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. 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. the standard iron-chelating drug.2 Is there a Problem problem prior. a variability of patient’s values and preferences seems options evidence? ○ Low ⨁◯◯◯ likely. Although.” 6 ○ Probably no In 2004.Management of Thalassemia – Iron chela- tion therapy. western Saudi Arabia. The prevalence of beta-thalassemia trait ● Yes among neonates in the same area was 0. a 3.69%) had beta-thalassemia trait.

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

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

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

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

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

0%) 1/6 (16. 12 and 24 months 11 12 13 6 5 randomised serious serious not serious serious none 155 152 .49 higher) VERY LOW Adverse events .56 lower ⨁◯◯◯ CRITICAL 7 trials (2.12 lower to 45.at 12 months 89 10 1 randomised serious not serious not serious very seri.78 lower to 0.1%) 24/71 RR 0.at 12 months 1 randomised not not serious not serious very seri.98 higher) LOW Liver iron concentration: mean change from baseline (mg/g dry weight) using SQUID .02 lower to 0.7%) "Only one trial reported mortality as an outcome (Ha ⨁◯◯◯ CRITICAL trial ous 2 2006).at 12 and 24 months 3 4 5 6 3 randomised serious serious not serious serious none 114 113 .Cardiac: Left ventricular ejection fraction: mean change from baseline (%) . 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.24 to fewer) LOW 0.17 lower) VERY LOW End organ damage . MD 0.Liver: Liver fibrosis Ishak score (ranging from 0-6.82 lower ⨁◯◯◯ IMPORTANT trials (313. none 0/7 (0.84) . none 15 21 . this death was at- tributed to cardiac complications and thought not to be related to deferiprone treatment" (Fisher 2013) End organ damage .Management of Thalassemia – Iron chela- tion therapy. MD 0.1 higher ⨁⨁◯◯ CRITICAL trial serious ous 2 (0.61 lower ⨁◯◯◯ CRITICAL trial ous 2 (2.Number of participants experiencing an adverse event – at 12 months 14 6 1 randomised serious not serious not serious serious none 11/73 (15.94 lower to 0. none 30 27 .8 higher) VERY LOW Serum ferritin concentration: mean change from baseline (ng/ml) .8%) (0.at 6. 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. One death occured in the deferiprone treatment VERY LOW arm after six months of treatment.45 186 fewer per 1000 (from 54 fewer to 257 ⨁⨁◯◯ IMPORTANT trial (33. 0 indicating no fibrosis): mean at endpoint . MD 133. MD 1.

allocation concealment 11. An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentration in both groups. lack of blinding of outcome assessment. High risk of bias due to lack of blinding of participants and personnel. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" between treatment arms. High risk of bias due to lack of blinding of participants and personnel (5 studies). none 32 29 . allocation concealment (4 studies). favouring DFO (Ha 2006. allocation concealment . Using random-effects model. using different methods of meas- urement. SD – standard deviation 1.51 times that for deferiprone. Four additional trials reported change from baseline in liver iron concentration (El-Beshlawy 2008. incomplete outcome data (2 studies). Point estimates differ substantially. p=0. lack of blinding of outcome assessment. incomplete outcome data (1 study).88 lower to 2. liver iron concentration in patients who re- ceived deferiprone was 1. I²=67%. no specific values were reported 4. Ha 2006.5 times higher than in patients treated with deferiprone.Management of Thalassemia – Iron chela- tion therapy. the greatest decrease was observed in the DFO group in El-Beshlawy 2008 and in the deferiprone group in Maggio 2002. selective reporting. El-Beshlawy: val- ues of liver iron concentration in DFO treated patients were 1. Unclear: Random sequence generation (2 studies). allocation concealment (2 studies). RR – relative risk. high I²-value (77%). High risk of bias due to lack of blinding of participants and personnel. Unclear: Random sequence generation. Unclear: Random sequence generation. but result was not statistically significant 10. Unclear: Random sequence generation (3 studies). No clear clinical differences between the trials were identified which could account for this heterogeneity 6. other bias (1 study) 13. result statistically significant. Olivieri 1997).88 higher) VERY LOW MD – mean difference. Maggio 2002.02 14. p=0. lack of blinding of outcome assessment (4 studies). other bias (trial was stopped early due to an unexpected sudden death). selective reporting. Only very few patients were included in study/studies 3. lack of blinding of outcome assessment .01. in a third trial (Maggio 2002). liver iron concentration decreased from baseline to the end of the trial in both treatment groups in two additional trials. Only few patients were included in study/studies 7. se- lective reporting (1 study). other bias (1 study). selective reporting (3 studies). 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.45 times that in patients with DFO. other bias (1 study) 5. MD 1 lower ⨁◯◯◯ IMPORTANT trial ous 2 (4. Unclear: Allocation concealment 2. selective reporting. mean liver iron concentration for DFO was 0. High risk of bias due to lack of blinding of participants and personnel 15. lack of blinding of outcome assessment (2 studies). no SD mentioned 12. In Olivieri 1997.at 12 months 15 16 1 randomised serious not serious not serious very seri. 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). the increase was greatest in the deferiprone treated group in both trials. result statistically significant. Bisphosphonates and Zinc supplementation 43 Participant compliance (%) . with a greater decrease in the deferiprone group. Olivieri 1997) 9. An older study (Olivieri 1997) showed a significant better compliance in deferiprone patients after 3 years 16. Point estimates vary. MD was not significant anymore 8. High risk of bias due to lack of blinding of participants and personnel (3 studies).

et al. 5. Lancet 1990. Bisphosphonates and Zinc supplementation 44 References 1. Final results of the randomized trial of deferiprone (L1) and deferoxamine (DFO) [abstract]. Cetiner N. Koren G. Chik KW. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO.28:196-208. Hermann C. 8. Randomised Prospective Evaluation of Iron Balance. Porter JB. 3. Berdoukas V. Blood 1997. 7. Olivieri NF BG. Olivieri NF. Blood Cells Mol Dis 2002. ASH Annual Meeting Abstracts 2005. Evans P. deferiprone and in combination on iron chelation in thalassemic children. D'Amico G. Ha SY. Manz C. Indian Pediatr 2004. Naja M.106:2698-.90:264a. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Blood 2006. Maggio A. 2.87:545-50. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. et al. Gomber S. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Comparative efficacy of desferrioxamine. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. et al. 6.30:263-74. Madan N.336:1275-9. Hemoglobin 2006.41:21-7. Saxena R. Pennell DJ. . El-Beshlawy A. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. et al. Chelation Efficiency. Karagiorga M. Ling SC. Morabito A.107:3738-44. et al. 4. Ann Hematol 2008.Management of Thalassemia – Iron chela- tion therapy. Terzi A. Aydinok Y.

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 . a 3. the standard iron chelating drug is suggested to be more effective in require treatment with iron chelators combination with deferiprone than alone.Management of Thalassemia – Iron chela- tion therapy.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living ○ Uncertain in the Al-Hassa area was observed. showed that 316 yes (4.2 Is there a prob- Problem lem priority? ○ Probably A screening of 6750 healthy persons in Jeddah.1 ○ Varies The relative importance or values of the main outcomes of interest: No data specific to thalassemia ○ No included patients in KSA identified. 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. 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."6 ○ Probably no In 2004. western Saudi Arabia.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait among neo- ● Yes nates in the same area was 0.96% (8/834).

Bisphosphonates and Zinc supplementation 46 ○ Moderate Mortality CRITICAL ⨁◯◯◯ VERY LOW ○ High End-organ damage: Left ventricular ejection ⨁◯◯◯ CRITICAL fraction: mean at endpoint (%) .Management of Thalassemia – Iron chela- tion therapy. ⨁⨁◯◯ IMPORTANT ○ No known riencing an adverse event .at 12 months LOW undesirable Summary of findings: Deferoxamine alone compared to deferoxamine + deferiprone for iron overload in thalassemia patients Are the desirable ○No With Relative With Deferoxamine Difference anticipated ef- fects large? ● Probably no Outcome Deferoxamine and Deferiprone alone (95% CI) effect (RR) ○ Uncertain (95% .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. ○ Probably no baseline .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.Number of participants expe. Serum ferritin concentration: mean change ⨁◯◯◯ IMPORTANT from baseline (ng/ml) . variability Liver iron concentration: mean change from portant uncer.at 6 and 12 months VERY LOW portant uncer- tainty of varia- bility Adverse events .

The range for left Left ventricular ejec- age: Left ven.22 lower ○ Probably no fraction: mean at endpoint (%) mean at endpoint (%) .4) ms effects large relative to unde- ○ Probably sirable effects? yes Liver iron con. with an estimate of a 10% increase myocardial T2* ● Probably no (ms) – at 12 compared with the deferoxamine group (95% CI 2% to 19%. the mean change in myocar- months Are the desirable ○ Uncertain dial T2* was nearly identical in the two groups" (DFO + Deferiprone: 1.9 (1.Management of Thalassemia – Iron chela- tion therapy.22 lower (8.11 SQUID at 12 months (mg/g wet wet weight) in the higher) months (mg/g weight) in the intervention group was control group was 0.17 lower (0. Liver iron concentra- MD 0. DFO: 1. ○ Uncertain . Porter 2013: " At 12 months.at 12 months months) in the 6.12 lower - to 4.4-78. p=0. while still on DFP" (Porter 2013) ○ Varies End-organ dam.32 Are the undesir.SQUID ○ Varies from baseline .45 lower .12 lower lower) control group was to 4.6) ms. ventricular ejec.9 (1.SQUID at 12 at 12 months (mg/g (0. tion fraction (mean at ○ No tricular ejection tion fraction ( endpoint (%) .45 lower - to 0. from baseline .02).17 ○ Yes centration: tration: mean tion: mean change lower mean change change from base. 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.32 lower) able anticipated effects small? ● Probably 68. 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.at 12 months) in the inter- vention group was (8.04 yes ○ Yes End-organ No data available damage: Liver ○ Varies Two trials reported myocardial T2* as an outcome measure at 12 months. line .at 12 MD 6. Liver iron concen.

79 reduction in serum higher) ferritin was 136.86 higher (195.84) adverse event - 221 fewer) at 12 months No research evidence specific to KSA setting identified.17 higher (0.Management of Thalassemia – Iron chela- tion therapy.33 participants (from 41 (0.07 to 0.13 to experiencing an fewer to 0.e.Number of (33 to 214) per 1000 RR 0. i. 195. A cost-utility analysis sources required for the treatment of beta- use small? ○ Uncertain thalassemia patients with chron- ○ Probably ic iron overload estimates 8.86 lower (469.89 -987-28. reduction in LIC was 0.61 - 12 months) in the (469. i.86 (ng/ml) .025 pounds for treatment with ge- yes neric deferoxamine versus . Bisphosphonates and Zinc supplementation 48 wet weight) -0.61 lower to lower to control group was 195. ○ Probably no available.11 lower to 0.89 higher).89 lower to 469.at 6 from baseline the intervention group lower and 12 months (ng/ml) at 6 and was 136.61 higher) Adverse events 254 per 1000 84 per 1000 170 fewer .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.e.11 higher). No specific data on costs of ○ No deferoxamine alone or of com- bination therapy in KSA setting Resource Are the re.

net benefits? yes ○ Yes ○ Varies No research evidence specific to KSA setting identified. In government insured popula- Equity What would be ○ Increased tion of thalassemia patients.53 In a study in Italy. Cost of treatment with deferoxamine alone was 793 Euro per month including ad- ministration. No research evidence specific to KSA setting identified.939 pounds in combination with deferiprone (Ferriprox®) ○ Varies per one-year treatment includ- ing administration cost in both treatments. Based on very low quality of ○ No evidence no clear benefits of ○ Probably no one option over the other sug- gested.54 The panel supposes that a com- bination therapy requires more resources than a monotherapy.Management of Thalassemia – Iron chela- tion therapy. ●Uncertain costs of combination therapy tal cost small are higher than for therapy with relative to the ○ Probably deferoxamine alone. incremental Is the incremen. total cost of deferoxamine treatment in combination with deferiprone was estimated at 963 Euro per month including administration cost. ○ Probably monotherapy and combination . the impact on health inequi. Bisphosphonates and Zinc supplementation 49 ● Yes 11. However.

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

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

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. MD 6. none 9 11 "One patient in the combination arm died within ⨁◯◯◯ CRITICAL trial ous 2 a year of coming off the study.not measured . CRITICAL Myocardial iron concentration: myocardial T2* (ms) – at 12 months 8 9 11 11 2 randomised serious not serious not serious very seri.6) ms.Management of Thalassemia – Iron chela- tion therapy.0%) 0/7 (0. none 0/4 (0. .22 lower ⨁◯◯◯ CRITICAL 7 trials (8. MD 0. with an estimate of a 10% increase compared with the deferoxamine group (95% CI 2% to 19%. Porter 2013: " At 12 months.11 higher) VERY LOW .9 (1. not estimable . while still on DFP" VERY LOW (Porter 2013) End-organ damage: Left ventricular ejection fraction: mean at endpoint (%) . 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 trials ous 10 come measure at 12 months. p=0.0%) Two trials reported myocardial T2* as an out. DFO: 1.SQUID at 12 months (mg/g wet weight) 12 13 1 randomised serious not serious not serious very seri.9 (1.at 12 months 3 4 5 6 2 randomised serious serious not serious serious none 60 58 . .17 lower ⨁◯◯◯ CRITICAL trial ous 10 (0.45 lower to 0. . the mean change in myocardial T2* was nearly identical in the two groups" (DFO + Deferiprone: 1.4) ms Liver iron concentration: mean change from baseline . 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 .12 lower to 4. .32 lower) VERY LOW End-organ damage: Liver . .02).

lack of blinding of outcome assessment. allocation concealment 14. 65 patients were randomised at beginning 12. only 11 of 20 patients completed close to 12 months of treatment) 2. Risk of bias: Unclear: Blinding of outcome assessment. lack of blinding of outcome assessment (1 study). selective reporting (1 study). LIC decreased in both groups.67) to 9. a third trial (Porter 2013) using different methods reported a reduction from 16. SD – standard deviation 1. Unclear: Random sequence generation. High risk of bias due to lack of blinding of participants and personnel. blinding of outcome assessment (2 studies). An additional trial reported "no significant difference in cardiac function" (El-Beshlawy 2008). allocation concealment (2 studies) 18.18).33 170 fewer per 1000 (from 41 ⨁⨁◯◯ IMPORTANT trials (0. Differences remained significant under random-effects model 8.at 12 months 17 18 2 randomised serious not serious not serious serious none 5/60 (8. no data to calculate SD was available.at 6 and 12 months 14 15 16 6 3 randomised serious serious not serious serious none 51 56 . Five additional trials reported reduction in serum ferritin in both treatment arms.62 (2.89 VERY LOW higher) Adverse events . another trial (Porter 2013) reported serum ferritin concentrations at 12 months. incomplete outcome data (1 study) 5. therefore no numbers could be included. and a reduction with DFO therapy from 5. lack of blinding of outcome assessment (2 studies). pooled results showed significant difference favouring deferiprone combined with DFO. at 12 months (Abdelrazik 2007. SD not stated 4. High risk of bias due to lack of blinding of participants and personnel (3 studies). other bias (1 study). Only few cases . -48% to -28%. lack of blinding of outcome assessment (3 studies).86 lower ⨁◯◯◯ IMPORTANT trials (469. I²=80%.9% to 58.27 (3.41). serum ferritin declined from 3601± 838 to 2132 ± 646 μg/L (n=7) in combination arm.001).13 (95%CI-8. Mourad 2003. Unclear risk of bias: Random sequence generation (1 study). but the difference in change between groups was not statistically significant 13. from narrative information no obvious inconsistency present 10. incomplete outcome data (1 study).84) fewer to 221 fewer) LOW MD – mean difference. However. Tanner 2007 reported at 12 months "the between-group difference was significantly in favour of the combined treatment group (-40%.3% in combination group and from 52. High risk of bias due to lack of blinding of participants and personnel (2 studies). another trial (Porter 2013) reported. Point estimates differ. Only few patients included in study/studies 7. serum ferritin increased from 1613 ± 537 to 2018 ± 898 μg/L (n=4) 15. Data not pooled.4%) RR 0. 95% CI. Unclear: Random sequence generation (2 studies).61 lower to 195. that LVEF increased from 49.2) to 5. Bisphosphonates and Zinc supplementation 53 Serum ferritin concentration: mean change from baseline (ng/ml) . Unclear: Random sequence generation (2 studies). an additional trial (El-Beshlawy 2008) reported reduction in serum ferritin concentration for both treatment arms at 12 months. analysing geometric means.8% to 56. selective reporting. allocation concealment (3 studies) 16. Only very few cases 3. 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.Number of participants experiencing an adverse event .67 to 8. Tamaddoni 2010) on a log scale as ratio of geometric means due to skewed data in Mourad 2003. MD 136. RR – relative risk. blinding of outcome assessment (1 study). incomplete outcome data (study was terminated due to slow patients accrual. I²=89%. p=0.1 (4. therefore difficult to assess. allocation concealment (1 study).002. no significant difference was measured between the treatment arms: MD=-0.008 17. number of patients included in each outcome assessment was not clear. High risk of bias due to lack of blinding of participants and personnel (1 study). a fourth trial (El- Beshlawy 2008) reported change in liver iron concentration graphically. incomplete outcome data (2 studies) 9. An additional trial (Ha 2006) using AAS reported liver iron concentration as mean change (mg/g dry weight) at 6 months. Unclear: Random sequence generation (2 studies). no clear clinical differences between these two trials were identified which could account for this heterogeneity 6. Only very few patients were included in studies 11.08 (3.3%) 15/59 (25.61) mg/g dry wt with combination. In one study (Tanner 2007). selective reporting (2 studies). selective reporting (3 studies). P< 0.9% in DFO group at 12 months. in DFO monotherapy arm.Management of Thalassemia – Iron chela- tion therapy.13 to 0. p=0.

Aydinok Y. Mourad FH. Porter JB.12:577-85. . Hemoglobin 2006. et al. Randomised Prospective Evaluation of Iron Balance. Gomber S. Saxena R. 2. 7. et al. El-Beshlawy A.91:1241-3.41:21-7. Abdelrazik N. Haematologica 2006.30:263-74. Ha SY. ASH Annual Meeting Abstracts 2005. Iranian Red Crescent Medical Journal 2010. Porter JB. Dessi C. Terzi A.115:1876-84. Koussa S. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Chelation Efficiency. Tamaddoni A RM. 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. Madan N. et al. Taher A. A randomized. 6. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Olivieri N. Hematology 2007.12:655-9. Galanello R. Indian Pediatr 2004. Piga A. et al. Kattamis A. Wood J. placebo-controlled. et al. Naja M. Cetiner N. 4. 5. 9. double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation 2007. 3. Manz C. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Sheikh-Taha M. Evans P. Khoriaty AI.121:187-9. Hoffbrand AV. Tanner MA. J Cardiovasc Magn Reson 2013.87:545-50.Management of Thalassemia – Iron chela- tion therapy. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Galanello R. Chik KW. deferiprone and in combination on iron chelation in thalassemic children. Ann Hematol 2008. Comparative efficacy of desferrioxamine. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. 8. Br J Haematol 2003. 10. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. Bisphosphonates and Zinc supplementation 54 References 1.15:38.106:2698-.

4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in the Al-Hassa area was observed. The prevalence of beta-thalassemia trait yes among neonates in the same area was 0.6%.”42 . a 3.96% (8/834).69%) had beta-thalassemia trait. 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.” 6 ○ Probably no In 2004. showed that 316 (4. 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. ○ No included iprone was reported as over harms of the tainty of this studies 90% in both treatment arms.1 ○ Yes ○ Varies What is the The relative importance or values of the main outcomes of interest: "Mean compliance with defer- Benefits & overall cer. western Saudi Arabia.Management of Thalassemia – Iron chela- tion therapy. options Outcome Certainty of Relative evidence? ●Very low the evidence whereas mean compliance with DFO was 70. the standard iron-chelating drug is suggested to be more effective in require treatment with iron chelators combination with deferiprone than deferiprone alone.2 Is there a ○ Uncertain Problem problem pri- ority? ● Probably A screening of 6750 healthy persons in Jeddah.

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

one individual who was randomised to receive deferiprone and DFO in combination. yes sis Ishak score results were presented graphically. mean at endpoint higher tion fraction: point (%) at 12 (%) at 12 months) ○ No mean at endpoint months) in the in the intervention (1. In this latter trial.99 lower to 12. 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. ○ Uncertain years second trial (Maggio 2009).at 12 (Aydinok 2007). the trial authors reported ○ Yes (ranging from 0 to that the fibrosis score "did not change significantly after one . a further five sirable antici.Management of Thalassemia – Iron chela- tion therapy.2 Are the desir. died at the start ○ Probably of the trial due to arrhythmia-induced congestive heart failure no Mortality ." (Fisher 2013) ○ Yes ○ Varies End organ damage Left ventricular Left ventricular .at 12 control group group was 5. In this trial.99 lower higher) able effects no to 12. (mean at end. One death due to arrhythmia whilst receiving months and 5 deferiprone and DFO in combination was also reported in the Are the unde. mortality occurred 11 to 60 months after withdrawal of the randomised treatment. ○ Probably months was 67. 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. scored accord- ing to the Ishak scoring system (Aydinok 2007). Maggio ○ No 2009).39 higher) large relative to undesira- ○ Uncertain ble effects? ● Probably End organ damage . In the first trial.2 ventricular ejec.4 higher (1.Cardiac: Left ejection fraction ejection fraction ( MD 5.39 - (%) .Liver: Liver fibro- "One trial reported liver fibrosis as an outcome.

Bisphosphonates and Zinc supplementation 58 ○ Varies 6. 0 indicating no year in patients in any of the treatment arms" (Fisher 2013) fibrosis) .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. Liver iron con.at 12 (3.42 lower months weight) at 12 months) in the - to 1.25 mean at endpoint concentration (mean at endpoint lower (ng/ml) .at 12 months Liver iron concen.42 months) in the intervention group higher) control group was 1 lower (3.at 6 and (mean at end.at 12 point (mg/g dry dry weight) .Management of Thalassemia – Iron chela- tion therapy. DFP: at patients prohibited calculation of the mean change in myocar- further 14 (6) dial iron concentration.87 - 12 months point (ng/ml) at 12 months in the lower to 6 and 12 intervention group) 30. 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. Liver iron concen- tration: mean at centration tration (mean at endpoint (mg/g (mean at end. (ng/ml) at 6 and (468.42 was 7.87 lower to was 1633- .5 lower to 1.36 high- months) in the was 219.25 lower er) control group (468. at further (16(5) The difference in duration of follow up across this subset of months. endpoint (mg/g MD 1 lower dry weight) .

53 ○ Yes In a study in Italy. per 1000 RR 1. fewer to 2.519 pounds per ○ Probably year treatment with deferiprone (Ferriprox®) versus 11.Management of Thalassemia – Iron chela- tion therapy.76 to (100 to 345) and/or agranulocy.36 higher) Adverse Events . 54 more Risk of leucopenia. Bisphosphonates and Zinc supplementation 59 3422.54 The panel supposes that a com- .41 186 per 1000 neutropenia 132 per 1000 (from 32 (0.61) tosis 213 more) No research evidence specific to KSA setting identified. total cost of ○ Varies deferoxamine treatment in com- bination with deferiprone was estimated at 963 Euro per month including administration cost. Cost of treatment with deferiprone was 480 Euro per month. A cost-utility analysis of deferiprone for the treatment of beta-thalassemia ● No patients with chronic iron over- load estimates 5.939 no pounds per one-year treatment Are the re. cluding administration cost in quired small? ○ Probably combination with deferiprone yes (Ferriprox®).7 30. ○ Uncertain with generic deferoxamine in- Resource use sources re. No specific data on costs of deferiprone alone or of combina- tion with deferoxamine in KSA setting found.

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

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

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

none 8 12 "One trial reported liver fibrosis as an outcome. VERY LOW In this trial.2 higher ⨁◯◯◯ CRITICAL trial ous 6 (1. none 117 120 "Mortality was reported in two trials (Aydinok 2007. none 16 17 . results were presented graphically. 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. ⨁◯◯◯ CRITICAL trials ous 3 Maggio 2009). deferoxamine Absolute Inconsistency Indirectness Imprecision deferiprone (95% studies design bias erations + deferiprone (95% CI) CI) Mortality ." (Fisher 2013) End organ damage . MD 1 lower ⨁◯◯◯ CRITICAL trial ous 6 (3.at 12 months 789 10 1 randomised serious not serious not serious very seri. mortali- ty occurred 11 to 60 months after withdrawal of the randomised treatment.Cardiac: Left ventricular ejection fraction: mean at endpoint (%) .at 12 months 4 5 1 randomised serious not serious not serious very seri.Liver: Liver fibrosis Ishak score (ranging from 0 to 6.42 higher) VERY LOW . In the first trial.39 higher) VERY LOW End organ damage . the trial authors reported that the fibrosis score "did not change significantly after one year in patients in any of the treatment arms" (Fisher 2013) Liver iron concentration: mean at endpoint (mg/g dry weight) .at 12 months and 5 years 1 2 2 randomised serious not serious not serious very seri.Management of Thalassemia – Iron chela- tion therapy. In this latter trial.at 12 months 5 1 randomised serious not serious not serious very seri.99 lower to 12. one individual who was VERY LOW randomised to receive deferiprone and DFO in combi- nation. scored ⨁◯◯◯ CRITICAL trial ous 6 according to the Ishak scoring system (Aydinok 2007). MD 5.42 lower to 1. One death due to arrhythmia whilst receiving deferiprone and DFO in combination was also reported in the second trial (Maggio 2009). 0 indicating no fibrosis) . 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. died at the start of the trial due to arrhythmia- induced congestive heart failure (Aydinok 2007). none 8 12 .

MD 219. Unclear: Allocation concealment (1 study) 2.Risk of leucopenia.36 higher) VERY LOW Adverse Events . lack of blinding of participants and personnel (2 studies). High risk of bias due to lack of allocation concealment (1 study). end of study values were not significant 9. due to differences in follow up time. neutropenia and/or agranulocytosis 16 3 randomised serious not serious not serious very seri. DFP: at further 14 (6) months (mean(SD)) 11 1 randomised serious not serious not serious very seri. selective reporting (Mortality was not pre-specified in one study). Bisphosphonates and Zinc supplementation 64 Myocardial iron concentration: Myocardial T2*: mean at endpoint (ms): DFO + DFP: at further (16(5) months.25 lower ⨁◯◯◯ IMPORTANT trials ous 15 (468.Management of Thalassemia – Iron chela- tion therapy. selective reporting 6. 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. lack of blinding of participants and personnel. from narrative information no obvious inconsistency present 3. Method used is not stated in this trial . The difference in duration of follow up across this subset of patients prohibited calculation of the mean change in myocardial iron concentration. However. In an additional trial liver iron concentration was measured by atomic emission spectrophotometry (Aydinok 2007).61) MD – mean difference. calculation of mean change is not possible. therefore difficult to assess. 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) .76 to more) VERY LOW 2.2%) (0. incom- plete outcome data (2 studies). Only very few cases 4. but decreased significantly in patients receiving combination therapy. RR – relative risk. none 100 93 .87 lower to 30. however the trial reported no signficant differences 8. lack of blinding of outcome assessment (1 study). lack of blinding of outcome assessment. Only very few patients included in study/studies 7.41 54 more per 1000 (from 32 fewer to 213 ⨁◯◯◯ IMPORTANT trials ous 3 (13. no SD for change reported. a reduction was only observed in the deferiprone group compared with an increase in combination group. Another trial (Maggio 2009) reported liver iron concentration by liver T2*. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" 5. High risk of bias due to lack of allocation concealment. incomplete outcome data. Data not pooled. SD – standard deviation 1.7%) 16/121 RR 1. the mean LIC value did not change significantly in patients treat- ed with DFP. none 17/96 (17.at 6 and 12 months 12 13 14 3 randomised serious not serious not serious very seri. other bias (1 study).

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

a 3.Background and Objective: Thalassemia patients are at higher risk to suffer from osteoporosis. 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. 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.Management of Thalassemia – Iron chela- tion therapy. western Saudi Arabia. porosis Bisphosphonates are suggested to increase bone mineral density and prevent fractures in these patients.2 Problem Is there a prob- lem priority? ● Probably A screening of 6750 healthy persons in Jeddah.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 (4.96% (8/834). The prevalence of beta-thalassemia trait among neo- nates in the same area was 0.”6 ○ Probably no In 2004.69%) had beta-thalassemia trait. studies identified. .4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in ○ Uncertain the Al-Hassa area was observed.

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

31 (0.at 60 more) 6.Management of Thalassemia – Iron chela- tion therapy.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.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.01 to 6.01 to non-vertebral (0 to 71) 10 fewer to ○ Varies fracture . 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. Bisphosphonates and Zinc supplementation 68 Additional Criteria Judgements Research evidence considerations Femoral neck BMD [g/cm²] (DXA): mean at ⨁⨁◯◯ IMPORTANT endpoint .85) 60 more) ● Probably no ture .85) 12 and 24 months Are the desira- ble effects large ○ No .31 3 per 1000 1000 (from ○ No at least one vertebral frac- 10 per 1000 (0 to 71) 10 fewer to (0.

A concomitant significant reduction (over 50%[intervention group].] at 12 months ○ Varies (P=0.002%).Fever RR mate given after first 10.96) control 4 mg group Adverse Control event rate: Experimental event No absolute events .49 to events in zoledronic acid 76.at 12 had no change in bone pain during the study period... events in 156. 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: 26.44 to infusion neri.6% (3/54) effect esti- like symptoms mate given RR 8.Management of Thalassemia – Iron chela- tion therapy.8% (15/26) effect esti- events . 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.Flu. There were no differences in fects? ○ Uncertain pain score among the three studied groups.03 - BMD [g/cm²] ([g/cm²] (DXA): ([g/cm²] (DXA): mean higher ." Forni 2012: "The months mean back pain scale value was significantly higher (more favourable) in ○ Yes [intervention group] compared with [control group] [. In contrast.27 after first due to 0 (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.72 due to 0 infusion (1. [control group] patients yes pain .70) dronate 100 control mg group Lumbar spine Lumbar spine BMD Lumbar spine BMD MD 0. 0% (0/64) rate: 5.

723-0. ○ Probably various bisphosphonates quired small? yes drugs and respective Resource doses were not available use ○ Yes at the meeting. ○ Varies Is the incremen. Unclear.08 higher) ● No No research evidence specific to KSA setting identified.Management of Thalassemia – Iron chela- tion therapy. 12 and 24 months) in 24 months) in the to 0.02 higher) higher to 0.05 higher) Femoral neck Femoral neck BMD Femoral neck BMD BMD [g/cm²] ([g/cm²] (DXA): ([g/cm²] (DXA): mean MD 0.05 at 12 and 24 the control group was intervention group was higher) months 0. because signifi- tal cost small ○ No cant benefit was only relative to the seen in surrogate out- .02 higher - at 12 and 24 the control group was intervention group was to 0. We found no economic evaluation addressing the ○ Probably no use of bisphosphonates versus no bisphospho- ○ Uncertain nates in the KSA setting. Specific cost data for sources re. Are the re.03 higher (0. No research evidence specific to KSA setting identified.9 0.02 higher to 0.05 higher (0.636-0. Bisphosphonates and Zinc supplementation 70 Additional Criteria Judgements Research evidence considerations (DXA): mean mean at endpoint at at endpoint at 12 and (0.05 (DXA): mean mean at endpoint at at endpoint at 12 and higher at endpoint .79 0.08 months 0.02 higher at endpoint . 12 and 24 months) in 24 months) in the (0. but were judged to be moderate.

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

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

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

In contrast. [control group] patients had no change in bone pain during the study period.0%) RR 0.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. 30% [control group]) in the use of analgesic drugs was noted starting from the third month" . none 0/110 (0. A concomitant significant reduction (over 50%[intervention group].01 to more) ◯ 6. Patients in [inter- vention group 1 and 2] had dramatic reductions of pain score after 6 and 12 months of zoledronic acid treatment. Absolute Inconsistency Indirectness Imprecision bisphosphonates (95% studies design bias erations nates (95% CI) CI) Number of participants experiencing at least one vertebral fracture .002%). no bisphospho.01 to more) ◯ 6. 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.31 7 fewer per 1000 (from 10 fewer to 60 ⨁◯◯ CRITICAL trials ous 4 (0.85) VERY LOW Number of participants experiencing at least one non-vertebral fracture .] at 12 months (P=0.0%) RR 0.at 12 and 24 months 12 3 3 randomised serious not serious not serious very seri.0%) 1/97 (1.Management of Thalassemia – Iron chela- tion therapy.85) VERY LOW Back or bone pain .at 12 and 24 months 12 3 3 randomised serious not serious not serious very seri. There were no differences in pain score LOW among the three studied groups..31 7 fewer per 1000 (from 10 fewer to 60 ⨁◯◯ CRITICAL trials ous 4 (0. none 0/110 (0..0%) 1/97 (1." Forni 2012: "The mean back pain scale value was significantly higher (more favourable) in [interven- tion group] compared with [control group] [.

allocation concealment (2 studies) 6. Only few patients were included in studies 8. Unclear: Random sequence generation (1 study). Unclear: Allocation concealment .02 higher to 0. All included studies don't differentiate between vertebral and non-vertebral fractures 2. lack of blinding of outcome assessment.08 higher) ◯ LOW MD – mean difference.02 higher to 0. therefore difficult to assess. High risk of bias due to lack of blinding of participants and personnel (2 studies).6%) 0/64 (0.Fever after first infusion zoledronic acid 4 mg 8 9 2 randomised serious not serious not serious serious none 15/56 (26. Unclear: Random sequence generation (1 study). High risk of bias due to lack of blinding of participants and personnel (1 study).0%) RR No absolute effect estimate given due to ⨁⨁◯ CRITICAL trials 10.05 higher ⨁⨁◯ IMPORTANT trials (0. Unclear: Random sequence generation (2 study).49 to LOW 76.03 higher ⨁⨁◯ IMPORTANT trials (0. lack of blinding of outcome assessment (2 studies). no obvious inconsistency present 7. SD – standard deviation 1. High risk of bias due to lack of blinding of participants and personnel (2 studies). lack of blinding of outcome assessment (3 studies).at 12 and 24 months 11 12 13 14 15 3 randomised serious not serious not serious serious none 105 86 . MD 0.Flu-like symptoms after first infusion neridronate 100 mg 10 9 1 randomised serious not serious not serious serious none 3/54 (5.96) Adverse events . MD 0. Only very few cases 5. from narrative information. We didn't count fractures as events due to unclear causation 3.70) LOW Lumbar spine BMD [g/cm²] (DXA): mean at endpoint . Bisphosphonates and Zinc supplementation 75 Adverse events .8%) 0/33 (0.27 No absolute effect estimate given due to ⨁⨁◯ CRITICAL trial (0. RR – relative risk.44 to 0 events in control group ◯ 156. lack of blinding of outcome assessment (2 studies). who discontinued the trial at 6 months after a road traffic accident". Only few patients were included in study/studies 10. allocation concealment (2 studies) 4. One study (Forni 2012) reported that "no fractures were observed during the study period except for the patient [intervention group]. allocation concealment (1 study) 9.72 0 events in control group ◯ (1. High risk of bias due to lack of blinding of participants and personnel.at 12 and 24 months 12 16 17 14 15 3 randomised serious not serious not serious serious none 105 86 . However.Management of Thalassemia – Iron chela- tion therapy.05 higher) ◯ LOW Femoral neck BMD [g/cm²] (DXA): mean at endpoint . Data not pooled.0%) RR 8.

Spina M. Anagnostopoulos A.82) to -3.91:1193-202. Riccobene S. no spe- cific values were reported 17.65). no specific values were reported 12. Calcif Tissue Int 2006.13) but the difference between intervention group and control group was significant (p<0. An additional study (Gilfillan 2006) reported absolute change from baseline at 2 years.v. placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia- associated osteopenia. J Bone Miner Metab 2003.92 (SD: 0. Osteoporos Int 2002. Haematologica 2006.44 (SD: 0. double-blind. in the intervention group.m. et al. Morabito N. but the difference between intervention and control group was significant at 12 months (p < 0. BMD at femoral neck didn't change significantly at 12 months (p=0.21:402-8. Perrotta S. in the intervention group BMD at lumbar spine didn't change significantly at 12 months (p=0.. Fiore CE. Gaudio A. randomized. High risk of bias due to lack of blinding of participants and personnel (3 studies). Pennisi P. Konstantopoulos K. Pizzarelli G. every 3 or 6 months) 13. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2. every 3 months.74) to -2. for the intervention group.88) in the control group (p< 0. Rodda CP. et al. et al.001. Br J Haematol 2012. 3. parallel-arm.158:274-82.16 (SD: 0.042 in patients treated with zoledronic acid. Voskaridou E.082 in pa- tients treated with zoledronic acid. absolute change was 0. An additional study (Gilfillan 2006) reported absolute change in femoral neck BMD at 2 years. A randomized. absolute change from baseline was 0.79:138-44.01). et al.Management of Thalassemia – Iron chela- tion therapy. both groups (clodronate 100 mg i. open-label study. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. alendronate 10 mg p. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center. zoledronic acid 4 mg i. no SD were mentioned 14.01). placebo-controlled trial.o. Only few patients included in studies 16. randomized. An additional study (Pennisi 2003) reported a decreased T-score from -1. Lasco A.71 (SD: 0. Bisphosphonates in the treatment of thalassemia-induced osteoporosis. absolute change was 0. 4. p comparing both groups was 0. in placebo group.13:644-9. p comparing both groups was <0. Bisphosphonates and Zinc supplementation 76 11.v. . in Vos- karidou 2006 both groups (zoledronic acid 4 mg i. 5.01). allocation concealment (3 studies) 15. Forni GL. An additional study (Pennisi 2003) reported a decreased T-score from -2. no SD were mentioned References 1. lack of blinding of outcome assessment (3 studies).01.01). Unclear: Random sequence generation (2 stud- ies). absolute change was -0. Giusti A. for the intervention group.008.034. 2.v. in placebo group. every 6 months) were combined in one group (zoledronic acid 4 mg i. Strauss BJ.93) in the control group (p<0. Two studies included two intervention groups. Gilfillan CP. in Morabito 2002.) were included separately in our analysis.

”6 ○ No ○ Probably no In 2004. showed that 316 Problem priority? ● Probably yes (4. Treatment with iron chelators may cause zinc deficiency in thalassemia patients. The prevalence of beta-thalassemia trait among neonates in the same area was 0.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in the Al-Hassa area was observed.Management of Thalassemia – Iron chela- tion therapy. Besides.69%) had beta-thalassemia trait. Iron chelation therapy may cause ing anemia and different endocrinopathies. 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. western Saudi Arabia. Zinc is required for the synthesis of somatomedins and it is therefore hy- zinc deficiency.2 ○ Uncertain Is there a problem A screening of 6750 healthy persons in Jeddah. 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. a 3.1 ○ 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. treatment with iron chelators may cause zinc deficiency.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 .96% (8/834).

point . ⨁⨁◯◯ CRITICAL ○ Important at 3 months 220 mg zincsulfate LOW uncertainty or variability Weight .mean [kg/m²] at endpoint .Management of Thalassemia – Iron chela- tion therapy.mean at endpoint .at 1-7 years 22.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 .5-90 mg zinc.absolute value [cm] or z-score at end- ⨁◯◯◯ this intervention. 9 months CRITICAL ○ High 30 mg zincsulfate and 18 months 25 mg zinc VERY LOW Body mass index . in particular given the prophylactic nature of ○ Moderate Height .at 9 months 30 mg zincsulfate and 18 CRITICAL LOW months 25 mg zinc important uncer- tainty or varia- bility Adverse events . 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.5-90 mg zinc. Is there important ⨁◯◯◯ uncertainty about ○ Probably no 18 months 25 mg zinc and 9 months 30 mg zincsulfate CRITICAL VERY LOW how much people important uncer- value the main tainty of variabil- outcomes? ity Serum zinc [ɥg/dl] .at 1-7 years 22.absolute value [kg] or z-score at end- ⨁⨁◯◯ ● Possibly point .

22 lute value [kg] value [kg] or z.abso. value [cm] or z- or z-score at score at endpoint at score at endpoint ○ Varies endpoint .11 standard Are the undesirable ○ Uncertain and -1.11 mg zinc.6 higher higher) Are the desirable ○ Probably no (0.abso.65 lower to 1.5-90 mg zinc. Height (absolute Height (absolute ○ Yes lute value [cm] value [cm] or z.at 1.at 3 months 220 mg months 220 mg higher months 220 mg zincsulfate) in the zincsulfate) in the (0.5- 7 years 22.4 (range vention group was higher) for absolute values) 0.47 lower to 0. 1-7 years 22.6 endpoint . 9 30 mg zincsulfate months 30 mg lower months 30 mg and 18 months 25 zincsulfate and 18 (0. ● Uncertain tive to undesirable effects? ○ Probably yes Weight .3-143. Weight (absolute Weight (absolute SMD 0.25 higher) ○ Yes ○ Varies Body mass Body mass index ( Body mass index ( index .85 19.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 0.63 .85 higher) effects large rela. 9 months 90 mg zinc.mean mean [kg/m²] at mean [kg/m²] at [kg/m²] at endpoint at 3 endpoint at 3 MD 0.25 18 months 25 control group was zinc) in the inter- ○ Probably no mg zinc 125. value [kg] or z- ○ Yes or z-score at score at endpoint score at endpoint higher - (0.19 lower ○ Varies endpoint .5-90 at 1-7 years 22. 9 SMD 0.65 lower - ○ No zincsulfate control group was intervention group to 1. Bisphosphonates and Zinc supplementation 79 large? ● Probably no supplements supplements (95% CI) (RR) (95% ○ Uncertain CI) ○ Probably yes Height .33 (z-score) deviations lower anticipated effects small? ● Probably yes (0.47 lower - ○ No zincsulfate and mg zinc) in the months 25 mg to 0.5 was 0.

22 standard (z-score) deviations higher (0. "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.83 to 14. stomach upset and nausea (18 22. Arasoy 1987). 95% CI: -12.16 to 78.63 higher) One study didn't observe significant differences in adverse events Adverse events when presented as percentage of all subject visits between placebo .5-90 mg months 25 mg zinc. 95% CI: 16.19 lower to 0. while dispensing 30 mg and 3 months zincsulfate (Gharhamanlu 2014) showed no difference (60 patients. 18 months observed at the doses used in the study" (22.37 0.Management of Thalassemia – Iron chela- tion therapy. 220 mg zincsul.30.5-90 mg zinc at 1-7 25 mg zinc and years. Costs are ○ Probably no likely to be low. vention group was solute value) 1. MD 0. 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. Monitoring . No specific data on costs Resource use Are the resources ○ No of zinc supplements in KSA required small? setting found. Fung 2013).at 1-7 years and zinc groups including diarrhea.03) fate Haemoglobin No data available level No research evidence specific to KSA setting identified.2 (ab. Ghah- ramanlu 2014) Serum zinc [ɥg/dl] . "No visible side effects have been zinc.44) compared to no treat- 9 months 30 mg ment with zinc supplements (60 patients).mean 220 mg zincsulfate (Rashidi 2011) led to a significant higher serum at endpoint .60.at zinc (MD 47.

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

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

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

6 higher ⨁⨁◯◯ CRITICAL trial serious ous 3 (0.30. 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. SMD 0.19 lower to 0. Arasoy 1987). none 30 30 .absolute value [kg] or z-score at endpoint . MD 0.22 higher ⨁⨁◯◯ CRITICAL trials serious ous 3 (0. Fung 2013). zinc sup.at 1-7 years 22. 95% CI: 16. no zinc Relative Absolute Inconsistency Indirectness Imprecision studies design bias erations plements supplements (95% CI) (95% CI) Height .Management of Thalassemia – Iron chela- tion therapy.at 9 months 30 mg zincsulfate and 18 months 25 mg zinc 6 2 randomised not not serious not serious very seri. 18 months 25 mg zinc and 9 months 30 mg zincsulfate 2 8 3 randomised serious not serious not serious very seri.mean [kg/m²] at endpoint .at 9 months 30 mg and 3 months 220 mg zincsulfate 10 11 2 randomised not not serious not serious very seri.11 lower ⨁◯◯◯ CRITICAL trials ous 3 (0. SMD 0.25 higher) 4 VERY LOW Body mass index .absolute value [cm] or z-score at endpoint . none 48 44 . none 77 61 One study didn't observe significant differences in ⨁◯◯◯ CRITICAL trials ous 9 adverse events when presented as percentage of all VERY LOW subject visits between placebo and zinc groups includ- ing diarrhea. somach upset and nausea (18 months 25 mg zinc.44) LOW compared to no treatment with zinc supplements (60 patients). while dispensing 30 mg zincsulfate (Ghar- . none 69 55 .85 higher) LOW Weight .at 3 months 220 mg zincsulfate 5 1 randomised not not serious not serious very seri.at 1-7 years 22. none 60 60 220 mg zincsulfate (Rashidi 2011) led to a significant ⨁⨁◯◯ IMPORTANT trials serious ous 3 higher serum zinc (MD 47. 9 months 30 mg zincsulfate and 18 months 25 mg zinc 1 2 3 randomised serious not serious not serious very seri.5-90 mg zinc.5-90 mg zinc at 1-7 years.65 lower to 1.47 lower to 0. Ghahramanlu 2014) Serum zinc [ɥg/dl] .mean at endpoint . "No visible side effects have been observed at the doses used in the study" (22. "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.5-90 mg zinc.63 higher) 7 LOW Adverse events .16 to 78.

no specific values were reported. another study (Fung 2013) reported that "Plasma zinc increased by 14. Rashidi M.025) 6.2% respectively. BMI z-score increased from . lack of blinding of participants and personnel (1 study).7% and 15.28). blinding of outcome assessment (1 study) 3. . High risk due to lack of random sequence generation (1 study).95 to -0. Huang JN. in the intervention group. although it did not change with time in the placebo group". Fung EB. Iran J Pediatr 2011. Bisphosphonates and Zinc supplementation 85 hamanlu 2014) showed no difference (60 patients.24:127-36. Arcasoy A. .4 kg 8. Hematology 2014.16 (95% CI: . Aboomardani M. . Keshtkar A. in placebo group. MD 0. 95% CI: -12. Cavdar A.70 cm.71 (95%CI: -1.Management of Thalassemia – Iron chela- tion therapy. randomized. Absolute value from one study and z-score from one study were included 7. .60. Study was not included in meta-analysis due to significant baseline difference (p=0. 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". Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia major. Zinc supplementation improves bone density in patients with thalassemia: a double-blind. Only very few cases 10.66 (95% CI: -0. Ghahramanlu E. Kwiatkowski JL.007. IMPORTANT estimable MD – mean difference. et al.21:8-14.14 (95%CI: -0. 2. Data not pooled because of different doses.56. et al. Vichinsky EP. However. therefore difficult to assess. Mirhossini NZ. Joshaghani H. Am J Clin Nutr 2013. no additional values were reported 11.98:960-71. Rafraf M. . 4. . Unclear: Al- location concealment (3 studies). Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalasse- mia major Patients. RR – relative risk.51 to 0. lack of blinding of outcome assessment (1 study). Absolute value from two studies and z-score from one study were included 2.19:113-9.36). back-transformation using SD of both baseline values in Arcasoy 1987 yields an effect size of -2. BMI z-score increased from -0. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of 2. 3. from narrative information no obvious inconsistency present 9. not . An additional trial (Fung 2013) reported BMI z-scores. at 3 and 6 months in the zinc group. SD – standard deviation 1.0. Cin S. if pooled meta-analysis showed high I²=86% and p = 0. Effects of zinc supplementation on linear growth in beta-thalassemia (a new approach). Banihashem A. .0.not measured . Gildengorin G. however differences are likely related to doses References 1. Arefhosseini SR.06 to -0. Am J Hematol 1987.19) to -0. placebo-controlled trial.18 cm 5. Data not pooled.83 to 14.37) to -0. King JC. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of -1. .03) Haemoglobin level . 0. blinding of participants and personnel (1 study). Only very few patients included in study/studies 4.

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

drug trade name. original title. abstract. drug trade name. device manufacturer. (49133) 13 (exjade* or deferasirox*).mp. 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*)). abstract.mp. device manufacturer. (13924) 12 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp). heading word. keyword] (187) 15 (cgp adj "72670").Management of Thalassemia – Iron chela- tion therapy. Bisphosphonates and Zinc supplementation 87 11 (deferoxamine* or deferoximine* or deferrioxamine* or desferioximine* or desferrioxamine* or desferrox- amine* or desferal* or desferral* or desferin* or desferol* or DFO or dfom). abstract.mp. original title.mp. device trade name. heading word. keyword] (1970) 14 (icl adj 670*). subject headings. original title. drug trade name. device manufacturer. drug manufacturer. subject headings. subject headings. drug manufacturer. [mp=title. heading word.tw.mp. [mp=title. (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. [mp=title. drug manufacturer. in Trials 33 Records Retrieved 33 . device trade name. device trade name.

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

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

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

mp.in. or exp patient satisfaction/ (74926) 13 attitude to health.in. or Egypt/ (38709) 37 Syria$.in. (399) 4 ((hemoglobin or haemoglobin) adj3 disease). or Libya/ (1843) 36 Egypt$.in.mp. (1416) 16 health related quality of life. or United Arab Emirates/ (4471) 28 Qatar$.mp. (759) 24 Dammam.in.tw. Total 24 without duplicates: Screening (Title and Abstract Review) No.in. (7416) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). or exp patient participation/ (19647) 12 patient$ satisfaction. or Kuwait/ (6933) 27 United Arab Emirates.mp. Bisphosphonates and Zinc supplementation 91 No.mp.tw. or Bahrain/ (1250) 32 26 or 27 or 28 or 29 or 30 or 31 (20062) 33 Middle East$. or Qatar/ (2460) 29 Oman$. Excluded: 22 Included for Full 2 Text review: Selection (Full Text Review) No.in.mp. (3718) 23 Kh*bar. (25059) 15 (patient$ utilit$ or health utilit$). (1582) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).mp.mp.in.mp.mp. (1349) 25 20 or 21 or 22 or 23 or 24 (31341) 26 Kuwait$.mp.mp.in.mp.in.tw.mp.mp.in. or Oman/ (3876) 30 Yemen$.in.mp. or Saudi Arabia/ (30920) 21 Riyadh.tw.mp. (16216) 22 Jeddah.mp.mp. or exp "quality of life"/ (128400) 17 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).in. Excluded: 0 Patients’ Values and Preferences Searches: Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations. (162) 6 or/1-5 (24174) 7 exp Iron Overload/ (11956) 8 (iron adj3 overload*).mp.Management of Thalassemia – Iron chela- tion therapy. (17271) 3 (cooley* and (anemi* or anaemi*)). or Middle East/ (11866) 34 Jordan$.mp.tw.mp. or exp Health Status Indicators/ (204864) 18 11 or 12 or 13 or 14 or 15 or 16 or 17 (686777) 19 10 and 18 (847) 20 Saudi Arab$.in.in. or exp Attitude to health/ (377915) 14 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$).mp. or Yemen/ (1915) 31 Bahr*in$. Ovid MEDLINE Daily and Ovid MEDLINE 1946 to Present Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (19711) 2 (thalassemi* or thalassaemi*).tw. or Jordan/ (10272) 35 Libya$. or Syria/ (10739) . (9133) 10 or/1-9 (39133) 11 patient$ participation.in.

in. or United Arab Emirates/ (9883) 28 Qatar$.in.in.tw.mp.in.mp.mp. or Qatar/ (4798) 29 Oman$.in.in. or Iran/ (65729) 44 Turkey/ or (Turkey or Turkish).Management of Thalassemia – Iron chela- tion therapy. (146) 6 or/1-5 (28843) 7 exp Iron Overload/ (10086) 8 (iron adj3 overload*). (763) 43 Iran$.mp. or exp patient satisfaction/ (94477) 13 attitude to health. or Kuwait/ (11067) 27 United Arab Emirates.in.in.tw. or Bahrain/ (3086) 32 26 or 27 or 28 or 29 or 30 or 31 (34963) 33 Middle East$.mp.mp.mp.in.mp. (1255) 24 Dammam.in. or Tunisia/ (12790) 41 Leban$.in.in.mp.mp.mp.in.mp.in. or exp "quality of life"/ (279285) 17 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)). or Saudi Arabia/ (48722) 21 Riyadh. or exp Attitude to health/ (80874) 14 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$).tw. (9971) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).tw. or Jordan/ (30681) .in.in. (435) 4 ((hemoglobin or haemoglobin) adj3 disease). (8084) 39 Morocc$. (6792) 23 Kh*bar.tw. (153093) 45 Algeria$. or exp patient participation/ (18705) 12 patient$ satisfaction.tw. (10967) 10 or/1-9 (46040) 11 patient$ participation.in.mp.mp.mp. or Algeria/ (4301) 46 Arab$.mp.mp.mp.in. (21547) 3 (cooley* and (anemi* or anaemi*)).mp.in. or exp Health Status Indicators/ (8220) 18 11 or 12 or 13 or 14 or 15 or 16 or 17 (485079) 19 10 and 18 (745) 20 Saudi Arab$. or 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*).mp. (38280) 15 (patient$ utilit$ or health utilit$).mp. or Yemen/ (2585) 31 Bahr*in$. (1980) 16 health related quality of life. (1960) 25 20 or 21 or 22 or 23 or 24 (49018) 26 Kuwait$.mp. or Oman/ (5605) 30 Yemen$. Bisphosphonates and Zinc supplementation 92 38 Iraq$/ or Iraq.mp. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).in. (26446) 22 Jeddah. or Morocco/ (8642) 40 Tunisia$. or Lebanon/ (14812) 42 West Bank.mp.mp.mp.mp.in.in.mp.mp. or Middle East/ (15249) 34 Jordan$.

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

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

Management of Thalassemia – Iron chela- tion therapy. or Tunisia/ (12790) 47 Leban$.mp.tw.mp. (9673) 24 (health?care adj cost$).mp. (108400) 29 (economic$ or pharmacoeconomic$ or price$ or pricing). (763) 49 Iran$. (30329) 23 (high adj cost).mp.mp. (233512) 30 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 (375661) 31 21 or 30 (1425432) 32 20 or 30 (1349591) . or exp economic evaluation/ (217926) 12 fee$.tw. (9971) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).mp.mp.tw.tw. or Syria/ (10739) 44 Iraq$/ or Iraq. or exp "health care cost"/ (213142) 14 hospital cost$.mp.mp.in.mp. (8084) 45 Morocc$.in. (2060) 26 (cost adj variable$).mp. or Iran/ (65729) 50 Turkey/ or (Turkey or Turkish).in.mp. Bisphosphonates and Zinc supplementation 95 41 Libya$. (10967) 10 or/1-9 (46040) 11 economic evaluation$. (13883) 25 (cost adj estimate$).in. or Lebanon/ (14812) 48 West Bank. or Libya/ (1843) 42 Egypt$.in. or exp "hospital cost"/ (29327) 15 pharmacoeconomics. or budget/ (36219) 18 socioeconomics. or health economics/ (35972) 17 budget$.tw. (2516) 28 (fiscal or funding or financial or finance). or Egypt/ (38709) 43 Syria$.tw.tw.mp.mp.tw.mp. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). 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.in. (21547) 3 (cooley* and (anemi* or anaemi*)).mp.in.mp. (435) 4 ((hemoglobin or haemoglobin) adj3 disease).in. or exp pharmacoeconomics/ (170837) 16 health economics.mp. or socioeconomics/ (110656) 19 11 or 12 or 13 or 14 or 15 or 16 (1073744) 20 17 or 19 (1096280) 21 18 or 20 (1189909) 22 (low adj cost).in.in. (153093) 51 Algeria$.mp.in.mp.in. or Morocco/ (8642) 46 Tunisia$.mp.mp. (164) 27 (unit adj cost$). (146) 6 or/1-5 (28843) 7 exp Iron Overload/ (10086) 8 (iron adj3 overload*).mp.mp. or Algeria/ (4301) 52 Arab$. or exp fee/ (603340) 13 health care cost$.

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