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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

in turn.1-5 Due to a lack of a mandatory This practice guideline is a part of the larger screening program. criteria of underlying systematic reviews. genes. (RCT). including searches has an important influence on growth and the for information about patients’ values and immune system. information to prepare GRADE evidence-to- tients. 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. Risk of bias assessment of primary stud- type. The Saudi expert guideline panel selected the bisphosphonates and zinc supplementation in topic of this guideline and all healthcare ques- thalassemia patients. a group of inherited blood dis. This document focuses on iron chelation. iron chela. for information that was required to develop tors. available evidence supporting each recom- bined with iron chelation therapy.7 Zinc full guidelines for the KSA. 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. we only regarded randomised controlled trials Beta-thalassemia major.14 We used this use has been suggested in thalassemia pa. The guideline does not tions addressed herein using a formal prioriti- address patients with thalassemia and co. zation process. According to the inclusion dating existing systematic reviews. As a result of the additional was double-checked and adopted if appropri- iron load caused by transfusions. Marked variable frequencies of beta- thalassemia have been reported in different Methodology areas and populations of the Kingdom of Saudi Arabia (KSA). is caused by mutations in hemoglobin thalassemia patients. Em- for the synthesis of evidence consisted of up. Bisphosphonates and Zinc supplementation 1 Given the importance of this topic. Assessment. However. preferences. The guideline panel met in Riyadh on March 17 & 18. ate. Development sis may occur. We also conducted systematic searches tion therapy is essential. The guideline has this focused tematic reviews on management of thalasse- scope as the chosen methodological approach mia patients8-13 by searching MEDLINE. For all selected questions we morbidities other than thalassemia-associated updated the literature search of existing sys- osteoporosis. the more severe sub. 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). and costs and resource use spe- cific to the Saudi context.Management of Thalassemia – Iron chela- tion therapy. based decision-making on management of eases. KSA from 2004-2009. may cause zinc deficiency. 2015 and formulated all recommen- .5 for cases per ers and reduce unnecessary variation in clini- 1000 examined persons. Accordingly.4 cal practice across the Kingdom. iron chela.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. Based on the sys- While life expectancy can be increased tematic reviews we prepared summaries of through improved transfusion programs com. prevalence in the KSA is initiative of the Ministry of Health of the King- not precisely known. mendation following the GRADE (Grading of morbidities such as osteopenia or osteoporo.0 for carriers and 0. with thalassemia living in Saudi Arabia. requires lifelong frequent red blood cell ies included in the existing systematic reviews (RBC) transfusions. several co. base and CENTRAL. bisphosphonates and Evaluation) approach. Recommendations.

Management of Thalassemia – Iron chela-
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supplementation 2

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

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

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

Key questions

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

Management of Thalassemia – Iron chela-
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treatment or non-responsiveness to Recommendation 4:
deferoxamine
 In patients with severe iron overload For thalassemia patients with iron overload,
and/or significant cardiac/endocrine the panel suggests against treatment with
impairment or non-responsiveness to deferoxamine in combination with defer-
monotherapy intensified chelation iprone rather than treatment with defer-
therapy (e.g. combination therapy) iprone alone. (conditional recommendation
needs to be considered against, very low quality of evidence)

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

Recommendation 6: For children and adolescents with thalasse- mia major. jointly. the panel suggests against treatment with bisphosphonates. the panel suggests zinc supple- mentation rather than no zinc supplementa- tion. very low quality of evidence) Remarks:  Vitamin D. a decision about treat- ment with bisphosphonates in se- lected patients should be made. 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 . calcium and bone density should be monitored in patients with thalassemia  Prevention and first line treatment of thalassemia-associated osteoporosis should be based on vitamin D and calcium supplementation  Patients with a history of fractures and/or proven severe osteoporosis should be referred to an endocrinol- ogist.Management of Thalassemia – Iron chela- tion therapy. (conditional recommendation. (condition- al recommendation against. Bisphosphonates and Zinc supplementation 5 Recommendation 5: For patients with thalassemia-associated osteoporosis.

due to bined with iron chelation therapy. 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. hepatosplenomegaly and cians and other healthcare decision makers jaundice. (28. may cause zinc defi- 1000 births18 summing up to more than ciency. irritability.7 Zinc has an important influence on 40.0 py. bisphosphonates use trait prevalence in premarital couples living in has been suggested in thalassemia patients. sion-making. the Al-Hassa area was observed. the additional iron load caused by transfusions The worldwide birth rate for children with iron chelation therapy is essential. Observable symptoms ment of guidelines in the Kingdom.6 In morbidities such as osteopenia or osteoporosis 2004. symptomatic thalassemia is about 0. a screening of 6750 healthy persons in Jeddah.96% (8/834). Accordingly. is usually diagnosed in children between of rigorous adaptation and de novo develop. in turn.69%) had beta-thalassemia trait.140) for cases per 1000 examined includes both paediatric and adult haematolo.Management of Thalassemia – Iron chela- tion therapy.1-5 The preva. The guideline does not address patients with thalassemia and co- Given the importance of this topic. The target audience of this guideline (771/1. Other health care professionals and policy This document focuses on iron chelation. are pallor. growth retardation.4% (307/8918) beta-thalassemia may occur. bisphosphonates and zinc supplementation in lines. the Minis. Bisphosphonates and Zinc supplementation 6 lence of beta-thalassemia trait among neo- Scope and purpose nates in the same area was 0. a group of inherited blood dis. showed that 316 guidance for the management of patients with (4.4 gists in the Kingdom of Saudi Arabia (KSA). is caused by mutations in hemoglobin within the first years of life.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. through improved transfusion programs com- lence in the KSA is not precisely known. This practice guideline is a part of the larger initiative of the Ministry of Beta-thalassemia major. The objective of this document is to provide western Saudi Arabia. persons. the more severe sub- Health of Saudi Arabia to establish a program type. However. makers may also benefit from these guide. a 3. Marked variable growth and the immune system. dominal swelling. Given the . morbidities other than thalassemia-associated try of Health (MoH) of Saudi Arabia with the osteoporosis. the ulti.2 Additionally. 2009. and reduce unnecessary variability in clinical practice across the Kingdom. sisted of updating existing systematic reviews. bisphosphonates and zinc supplementa. 6 months and one year. several co- a lack of a mandatory screening program.572. frequencies of beta-thalassemia have been reported in different areas and populations of While life expectancy can be increased the Kingdom of Saudi-Arabia. the mean prevalence of couples testing mia patients focusing on iron chelation thera. thalassemia patients.140) for carriers and 0.572. The preva. Thalassemia. positive for beta-thalassemia was 18.235/1. Transfusion therapy has to be commenced eases.000 newborns per year19.5 tion. thalassemia living in Saudi Arabia. ab- mate goal being to provide guidance for clini. 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. But as a result of genes.44 per iron chelators.

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

Management of Thalassemia – Iron chela- tion therapy. resources. been externally peer reviewed by a methodo- logical expert who has not been involved in 1. As described in other guidelines fol. amine be used for iron overload in thalassemia patients? 2. iprone be used for iron overload in thalassemia patients? lines 3. equity. Question 1: Should deferasirox versus mendations as they may differ by product. Should bisphosphonates versus no mittees. oporosis? lowing the GRADE approach. 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. 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. Therefore. 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. the final report have dressed in this guideline. was determined by the panel to be irrelevant acceptability as well as other qualifying re. no mia major? one charged with evaluating clinicians’ actions should attempt to apply the recommenda. Should deferoxamine in combination for rational decisions about the treatment with deferiprone versus deferiprone with iron chelators. Should deferasirox versus deferox- this guideline development. to the KSA setting and it is not addressed in marks accompanying each recommendation this guideline. and adolescents with beta thalasse- vidual clinical circumstances. patients. Should deferoxamine versus defer- How to use these guide. selected by the Saudi expert panel and ad- line prior to publication. feasibility. the ques- blanket fashion. 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. The guideline panel did not specify doses for medications in its recom. Clinicians. deferoxamine be used for iron overload in . tion “Should deferoxamine bolus injection versus subcutaneous deferoxamine infusion be Statements about the underlying values and used for iron overload in thalassemia patients” preferences. Recommendations ommendation. other stakeholders. are its integral parts and serve to facilitate an accurate interpretation. lassemia patients? third-party payers. While initially identified during the prioritiza- tions from these guidelines by rote or in a tion process as potentially relevant. bisphosphonates and zinc alone be used for iron overload in tha- in thalassemia patients. or the courts bisphosphonates be used in manage- should never view these recommendations as ment of thalassemia-associated oste- dictates. 5. no guideline or 6.17 Understanding adjustments. 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. institutional review com. (see Table 1) The following is a list of the clinical questions As a quality measure for any practice guide. thalassemia patients? vide clinicians and their patients with a basis 4.

Although this might from one trial (172 patients) were unclear not be true for all patients (e.2. the reduction in serum ferri- guage. At a ratio of less than 1:2. 187 patients. of an updated version of the Cochrane sys.09 to 2.64.48. Bisphosphonates and Zinc supplementation 9 thalassemia patients? 95% CI: 1. Data from this trial reflect the dose- Summary of Findings: response and ratio effect: at a ratio of 1:1. For these patients) at 12 months was not significantly patients. An additional trial25 was identified as part higher in the deferoxamine group (3 trials. 95% CI: -1. Compliance (% of dose taken by insured through a government plan.07. effective. 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. In addition. events at 12 months (2 trials.8. moderate quality of evi- dence). Data preferences seems likely. published in Chinese lan. small children.6 and of these trials23. . who had not not statistically significant at 12 months (low achieved successful iron chelation with quality of evidence). MD -1. Data quality of evidence for our prioritised patient. We found two additional amine showed higher efficacy in the other trials23. with regard to left ventricular ejection fraction patients experiencing adverse effects of de- (%) at 12 months (MD -0. low quality of evidence). 95% semia patients. equal efficacy was achieved only in the highly iron-overloaded subgroup at a Benefits & Harms of the Option: mean ratio of 1:1. was patients from the Middle-East. 95% so cost considerations will influence choice of CI: -3. treatment. MD 415.84 to ferasirox. 95% CI: 0. however. The same trial tients would prefer oral application of iron demonstrated non-inferiority of deferasirox in chelation.1.44 to 1. highly iron overloaded people.5. from one trial (563 patients) showed a clear important critical outcomes was judged as dose-response effect for serum ferritin levels. 95% CI: 0.78. both treatment options are CI: from 22 more to 32 fewer. probably the majority of pa- 1. different (1 trial. while deferox- trolled trials21.Management of Thalassemia – Iron chela- tion therapy. absolute effect: 13 In government insured population of thalas- serious adverse events fewer per 1000. MD 2. etc. 541 patients.24 in the updated literature search.07 to tematic review by Meerpohl10. low quality of evidence). 1:3. 844 patients. The search strategy for values and pref.72.2 of deferasirox to erences led to the inclusion of one study26 deferoxamine. 1:5. One three subgroups at ratios of 1:2. no chelation treatment is covered. RR Given the different modes of application and 0.4.68 to 3. 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.95.).22.37.g. including two randomised con. low. the latter was statistically more conducted in the Middle East.63. 773 patients. The overall 536. Treatment with deferasirox for one groups in the number of serious adverse year led to high compliance and satisfaction. absolute effect: 5 the differing spectrum of possible adverse fewer patients per 1000. this is not the case for patients not evidence).37. 95% CI: 295. a variability of patient’s values and to 16 more. moderate quality of evidence). 95% CI: from 9 fewer effects.75 to 0. The evidence showed no deferoxamine and/or deferiprone (n=237) significant difference between treatment before. low quality of covered.38. This assumption is supported by a myocardial iron removal (myocardial T2*) and study26 including iron-overloaded thalassemia a trend for superiority which. RR 0. 873 patients. low quality of evidence). Mortality at 48 weeks and 1 year was report- ed to be not significantly different between Values and Preferences: treatment groups (3 trials. at 12 months (1 trial.

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

(conditional recommendation. both treatment options are  Informed patient choice is of para- covered. 95% CI: -2.82.  Patients need to be adequately edu- . small children. 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. very likely prefer deferiprone due to its oral admin- low quality of evidence) evaluated change in istration.8).). A meta-analysis of three trials (227 patients.g. 95% CI -313. etc. but many patients would meta-analysis of five trials (307 patients. For these  Iron overload.49) whether one No obvious barriers to implementation were drug is superior to the alternative with regard identified. A ment and physicians. 95% CI: -2. 12 and 24 months. Remarks: lassemia patients. pa. serum ferritin concentration (ng/ml) at 6. probably the majority of patients would prefer oral For thalassemia patients with iron overload. this might not be the panel suggests treatment with deferox- true for all patients (e. 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.02 to 0. low quality of evidence) In the government insured population of tha. effects should be monitored in pa- so the cheaper treatment option with tients while on chelation therapy.84. the KSA setting. for deferoxamine would likely be the preferred details see “Regional consensus choice.94 to . Although.61. 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. combined resources required for patients on deferiprone are likely higher. no chelation treatment is covered. better safety profile and the lower overall 0. Comparing deferoxamine absolute effect: 186 fewer participants per drug cost including administration cost to 1000.17). 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. the benefit of a of deferiprone (MD -1. 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. very low quality of evidence) suggests a signif.12 to 45. Bisphosphonates and Zinc supplementation 11 months (MD -0. the panel supposes quality of evidence). 95% CI: -4. Feasibility: 133.88 to 2. the differing spectrum of possible adverse effects. 95% CI: 0. a variability of patient’s values and Recommendation 2: preferences seems likely. this is not the case for patients not mount importance insured through a government plan. Data from one trial (61 that deferiprone might be cheaper.45. 95% CI: from 54 fewer to 257 fewer. low deferiprone drug cost. compliance and side patients. It remains unclear (MD . amine rather than treatment with defer- tients experiencing adverse effects of defer.88).24 to 0. iprone. at 12 months (MD -1.56.Management of Thalassemia – Iron chela- tion therapy. very iprone. patients. to change of serum ferritin (ng/ml). However. application of iron chelation.

reported in any of the trials. There are an alternative treatment in patients unclear data for this outcome. MD – 0. further RCTs evaluating the benefits ferritin concentration (ng/ml) between both and harms of the alternatives including long. 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. trial. Whereas.17. but 65 patients were randomised at the ment. 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. Only very low mote settings. 95% CI 0. very low iprone: easy access to monitoring fa.12 to -4. beginning) reported a significant benefit on amine treatment or non.32. in. The overall quality therapy group at 12 months. 95% CI: -0. verse events at 12 months was reported in the group treated with deferoxamine alone (2 trials. 107 pa- er-term patient relevant outcomes should be tients. 95% CI -469. There was Research Priorities: no significantly different change in serum Ideally. FBC).g. 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. 95% CI -8. 0.g. 20 patients. cluding nine randomised controlled trials27. treated with deferoxamine alone(MD -6.13 to Question 3: Should deferoxamine alone ver. Bisphosphonates and Zinc supplementation 12 cated and trained for deferoxamine important critical outcomes was judged as administration very low. Also. appropriate cost. 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. low iprone be used for iron overload in thalasse.11.  For patients treated with deferox- amine: regular ophthalmologic ex. adverse effects of deferox.86.22. 119 patients. A significantly effectiveness analyses in the KSA setting lower number of patients experiencing ad- should be considered. very low quality of evi- 30. 95% CI: 41 fewer to 221 fewer. MD -136. (number of patients at end of study was not cardiac and/or endocrine impair.84. very low quality of evidence). Liver damage was not cilities (e. clear. RR 0.45 to 0. quality of evidence).89. myocardial T2* in the combination group. needs to be ensured quality evidence was available for myocardial  Deferiprone should be considered as T2* (ms) at 12 months (2 trials). 59 patients. groups at 6 and 12 months (3 trials. of evidence based on our prioritized patient- Values and Preferences: . quality of evidence). We found one additional trial40 in the dence) when compared to the combination updated literature search.9. on deferiprone (1 trial.Management of Thalassemia – Iron chela- tion therapy. per 1000. combination therapy) treatment groups.61 to 195. in particular in re. very low quality of evidence). absolute effect: 170 fewer participants sus deferoxamine in combination with defer. 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.33. One trial with severe cardiac iron overload. conducted.35-39 .

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

In government insured population of thalas- tients. withdrawal of the randomised treatment. The same trial also re- ported five further deaths in patients who Acceptability: were relocated to treatment with deferox. Addi- treatment they were initially randomised to. due to varia. 95% CI: -1. updated literature search. A higher or lower left ventricular ejection frac. 95% important critical outcomes was judged as CI: 32 fewer to 213 more. evidence). very low quali. tients not insured through a government plan. of evidence based on our prioritized patient.39. 20 patients. the burden of administra- mean change was not possible.42 . possibly lower compliance.9.61. quality of evidence). covered. with deferiprone alone would likely be the due to arrhythmia in the group treated with preferred choice. died at the beginning of the trial due to ar. combination therapy. ference in risk for leucopenia. For these patients. No clear feriprone rather than deferiprone alone prob- benefit or harm of combination therapy com. deferiprone versus deferiprone alone in the ty of evidence. 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. Benefits & Harms of the Option: Values and Preferences: Mortality was reported in two trials (237 pa. identified. monotherapy and combina- (duration: 12 months) reported that one par. ably outweigh the desirable consequences in pared to deferiprone alone on serum ferritin most settings.87 to 30. The panel’s judgement was that many pa- amine alone due to adverse events of the tients would likely prefer monotherapy. 95% CI: -468. but calculating the consequences (i. 95% CI -3. 193 patients. this is not the case for pa- ticipant. Lastly. MD -1.25.42. absolute effect: 54 more cases per 1000. A benefit or harm of combination ther. tion. only graphic presentation of KSA setting. very low quality of evidence). tion are covered. so the cheaper treatment option The other trial reported one death in 5 years. . 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. the undesirable low quality of evidence). The panel. 95% CI: 0. We found no additional trials in the and/or agranulocytosis was found (3 trials.Management of Thalassemia – Iron chela- tion therapy. therapy at 12 months (1 trial. very low quality of very low.76 to 2.41. tionally. 33 patients. consequences: very low quality of evidence). However. in.2. very low quality of Resource Use: evidence).42 to 1. however. supposes data).41. Bisphosphonates and Zinc supplementation 14 concentration (ng/ml) at 6 and 12 months was Summary of Findings: evident in the data (3 trials. that a combination therapy requires more apy compared to deferiprone alone on liver resources than a monotherapy.36. combination therapy requires more these patients died 11 to 60 months after resources. MD The summary of evidence is based on two -219. RR 1. randomised to combination therapy. very patients with iron overload. no significant dif- cluding five randomised controlled trials27. no chelation treatment is rhythmia-induced congestive heart failure. very low Cochrane systematic reviews by Fisher8.99 to 12. neutropenia 29. MD 5.e. One trial semia patients. Feasibility: tion (%) in the combination therapy group was No obvious barriers to implementation were not clearly evident when compared to mono. higher re- ble durations of follow up. Myocardial T2* The panel considered that for thalassemia was reported by one trial (54 patients. 20 patients. iron concentration (mg/g dry weight) at 12 months could not be demonstrated clearly (1 Balance between desirable and undesirable trial. The overall quality 217 patients.

cardiac and/or endo.01 to 6. patients treated with zoledronic acid considered as an alternative treat. 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. cross-over of one trial47 was not considered.Management of Thalassemia – Iron chela- tion therapy. 207 patients. RR 0. We found no additional trial in the updated for details see “Regional consensus literature search. The follow-up48 after effects should be monitored in pa. (conditional recommendation ment of thalassemia-associated osteoporo- against. In the crine impairment or non. other trial. very low quality of evidence) sis? Remarks: Summary of Findings:  Informed patient choice is of para.02 to . further RCTs evaluating the benefits lumbar spine bone mineral density (g/cm²) in and harms of the alternatives including long.70. 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. the panel suggests against treatment with deferoxamine in combination with defer. patients. Bisphosphonates and Zinc supplementation 15 conducted. number of participants experiencing at least sured one vertebral or non-vertebral fracture at 12  For patients treated with deferox. appropriate cost- Recommendation 4: effectiveness analyses in the KSA setting should be considered.31. 95% CI: 0. 191 patients MD 0. quality of evidence). no bisphosphonates be used for manage- iprone alone. reported only narratively on back or bone pain amine administration at 12 months (low quality of evidence). For thalassemia patients with iron overload. very low  Patients need to be adequately ed. and 24 months was very imprecise (3 trials. amine: regular ophthalmologic ex. patients treated with bisphosphonates using er-term patient-relevant outcomes should be DXA at 12 and 24 months was reported (3 trials. compliance and side ised controlled trials43-47. needs to be en. amination and audiometry needs to absolute effect: 7 fewer patients per 1000. RR 8. A significantly higher Ideally.44 to 156. no change during the study period.g. showed a high reduction of pain scores. ment in patients with severe cardiac whereas patients in the control group showed iron overload. The summary of evidence is based on two mount importance systematic reviews11. 118 members. the evidence did not preclude a lower or tion therapy. Regarding flu-like symptoms Implementation Considerations: after a first infusion of neridronate 100mg. mean back pain scale score was responsiveness to monotherapy also significantly improved in patients treated with neridronate. FBC). Benefits & Harms of the Option: iprone: easy access to monitoring Comparing bisphosphonates to no bisphos- facilities (e.12 including five random-  Iron overload. 95% CI: 0.27. Also. In the  Combination therapy should be first trial. Question 5: Should bisphosphonates versus iprone rather than treatment with defer.03. 95% CI: 0. tients while on chelation therapy. For this recommendation against a combina. overload  For patients treated with defer. in particular in phonates the estimate for the difference in remote settings.85. be ensured 95% CI: from 10 fewer to 60 more.

and/or proven severe osteoporosis should be referred to an endocri- Acceptability: nologist. fractures) acceptability seems selected patients should be made likely. burden of administration. consequences: The panel considered that for thalassemia patients with osteoporosis. low quality of evidence). MD 0.08. acceptability will ing: likely vary. Also. the undesirable Question 6: Should zinc supplements versus .49 to osteoporosis. treatment with bisphosphonates in tients (e. Moni- No obvious barriers to implementation were toring of benefits and adverse effects in pa- identified. further RCTs evaluating the benefits bisphosphonates in the KSA setting. RR 10. ty should be monitored in patients tion with regard to the considered outcomes. panel members assumed some variability  Vitamin D. Howev. 89 patients. Standardized criteria for the use of bisphos- phonates in high-risk patients should be es- Feasibility: tablished and its application monitored.05 .96. a decision about For more severely affected thalassemia pa. very low Values and Preferences: quality of evidence) No published evidence with regard to the considered outcomes was identified. appropriate cost-effectiveness analyses in the Balance between desirable and undesirable KSA setting should be considered.05. and calcium supplementation therefore health inequities might be in. but were judged to be moderate. low quality of evidence). pain. Bisphosphonates and Zinc supplementation 16 0.  Patients with a history of fractures creased. higher femoral neck bone mineral density resource utilization.02 sirable consequences given unclear health to 0.e. relevant outcomes should be conducted. Resource Use: We found no economic evaluation addressing Research Priorities: the use of bisphosphonates versus no Ideally. with thalassemia Treatment with bisphosphonates is covered in  Prevention and first line treatment government insured thalassemia patients with of thalassemia-associated osteopo- osteoporosis.72. This is not the case for patients rosis should be based on vitamin D not insured through a government plan. 95% CI: 1. As prophylactic measure. 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. calcium and bone densi- in values within the KSA thalassemia popula. benefits. Remarks: er. 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. 95% CI: 0.g. treatment with bisphosphonates. given the ad- verse effects and potential costs for non. Implementation Considerations and Monitor- government insured people. tients treated with bisphosphonates should be established. low quality of evidence).Management of Thalassemia – Iron chela- tion therapy. (condi- tional recommendation against. A significantly consequences (i. the panel suggests against 76. 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. jointly. 191 patients.

No significantly higher or lower body mass Feasibility: index (kg/m²) at 3 months was observed (1 No obvious barriers to implementation identi- trial. 60 patients. very .50. adverse events (138 patients. stomach upset and nausea at 18 these cases are required. the panel suggests zinc supple- No published evidence with regard to the mentation rather than no zinc supplementa- considered outcomes was identified. 95% CI: implementation. tion. due to no relevant side effects.85. consequences: turbances in 1-8% of the study population at 9 Due to very low quality of evidence for bene- months.03) in the other trial at 9 months (low quality of evidence). No trial reported haemoglobin Recommendation 6: levels. Two studies reported serum zinc fits of zinc supplementation. 1.44) compared to no treatment use and prevention of zinc deficiency. Summary of Findings: in particular given the prophylactic nature of The summary of evidence is based on a this intervention. low quality of evidence). moderate to small resource 16.65 to fied. SMD 0. ever.63. feasible rum zinc at 3 months (MD 47. One trial did not observe signifi.0. very low quality of evidence). CI: -0. includ. In one trial (60 patients).19 to 0. Balance between desirable and undesirable The third trial mentioned gastrointestinal dis. SMD . while dispensing 30 panel suggests offering this option in children mg zincsulfate showed no difference (60 pa. but ing two randomised controlled trials49.47 to 0.25. We limited access to measurement and monitor- found two additional randomised controlled ing of zinc levels might increase health inequi- trials51. 95% ceptable given the unclear benefits. it might well be that some z-score) at 9 months. overall quality of evidence based on our prior- itized patient-important critical outcomes was Acceptability: judged as very low.6. months. MD 0. Data from two trials were unclear with regard to bodyweight Resource Use: (kg or z-score) at 9 and 18 months (92 pa. Cochrane systematic review by Swe13.60. low the use of zinc versus no zinc in the KSA set- quality of evidence). MD 0.Management of Thalassemia – Iron chela- tion therapy. Bisphosphonates and Zinc supplementation 17 no zinc supplements be used in children and er.30. How- use of 220 mg zincsulfate led to a higher se. tients. and adolescents with thalassemia major.11 .83 to 14. However. Cost of zinc supplements are likely low. uptake is not available at all medical centers in cant differences in adverse events including the KSA. For children and adolescents with thalasse- Values and Preferences: mia major. Monitoring zinc of evidence). 95% CI: -0. 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. 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.22. The second trial reported that no visible side effects were observed at 1-7 years. very low quality Costs are likely to be low. therefore additional resources in diarrhea. 95%CI: -0. (conditional recommendation. 95% CI: -12. The ties. Three trials reported ting. Howev.16 to 78. relevance of levels (µg/dl). panel members assumed some variability adolescents with beta thalassemia major? in values within the KSA thalassemia popula- tion with regard to the considered outcomes. We found no economic evaluation addressing tients.52 in the updated literature search. the with zinc supplements. the health benefits is somewhat uncertain.

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

et al. 4. Al-Suliman A. Memish ZA. Al Jaouni S. (Accessed February 7. Barua A. Roberts DJ. Saudi Arabia. Meerpohl JJ. Swe KM. East Mediterr Health J 1999. Rating the quality of evidence. Abas AB. Chowdhury O. Global epidemiology of haemoglobin disorders and derived service indicators. Deferasirox for managing iron overload in people with thalassaemia. Almazrou YY.who. Doree C.2:Cd007476. Cochrane Database Syst Rev 2012. Blood 2006. Brunskill SJ. Introduction-GRADE evidence profiles and summary of findings tables. Fisher SA. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review. et al. Canatan D. Owaidah TM. Akl EA. Gooding S.66:719-25. 13. Nair NS.Management of Thalassemia – Iron chela- tion therapy. A phase 3 study of deferasirox (ICL670). Oxman AD. Aylak F. Piga A. Alswaidi FM. Guyatt G. GRADE guidelines: 14. Helfand M.32:606-15. 11. Andrews J.1:43-6. Darlison M. Saeedi MY.1:61-8. J Bone Miner Metab 2014.21:183-7.8:Cd004839. Modell B. J Clin Epidemiol 2013. Prevalence of thalassemia disorders and hemoglobinopathies in Jeddah. World Health Organization. Kulkarni H. 19.6:Cd009415. WHO Handbook for Guideline Development. Bulletin of the World Health Organization 2008. 7. Vural H. Zinc supplements for treating thalassaemia and sickle cell disease. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.64:383-94. 2012. Oral deferiprone for iron chelation in people with thalassaemia. 21. Orphanet J Rare Dis 2013. 2. . Cochrane Database Syst Rev 2013. Qari MH. Prevalence of beta-thalassemia trait in premarital screening in Al-Hassa. et al.850:251-69.27:109-11. Chowdhury O.5:1147-53. BMJ 2008.86:480-7. El-Hazmi MA. Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials. 12. Angastiniotis M. 2014. Brunskill SJ. Cohen A. Oxman AD. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 2013. et al. Albagshi MH. et al. Oxman AD. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol 2011. Bisphosphonates and Zinc supplementation 19 References 1. Cappellini MD. Erdogan E. Warsy AS. Global epidemiology of hemoglobin disorders. Ann Saudi Med 2006. J Clin Epidemiol 2011. Guyatt G. 14. 20. Modell B. Choudhry AJ.64:401-6. Guyatt GH.9:372-7.107:3455-62. 9. Ormeci AR. Schunemann HJ. a once-daily oral iron chelator. Annals of the New York Academy of Sciences 1998. Cochrane Database Syst Rev 2013. 6. Mamtani M. Rucker G. Fisher SA.26:14-6. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. 5.336:924-6. 15. Osteoporos Int 2010. Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia. in patients with beta-thalassemia. Gooding S. Journal of Applied Hematology 2010. GRADE guidelines: 1.pdf. Bhardwaj A. 17. Antes G.8:Cd004450. et al. J Epidemiol Glob Health 2011. 8. Cochrane Database Syst Rev 2013. western Saudi Arabia. Vist GE. at http://apps. 18.int/iris/bitstream/10665/75146/1/9789241548441_eng. Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area. Roberts DJ. Alhamdan NA. Giusti A. GRADE guidelines: 3. Premarital screening for thalassemia and sickle cell disease in Saudi Arabia. The effects of chelators on zinc levels in patients with thalassemia major. Wali Y. 3. Balshem H. et al.) 16. Genet Med 2007.8:143. Doree C. 10. 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.

Sheikh-Taha M. double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Piga A. Comparison of therapeutic response and complications of oral Osveral and injection Desfereal chelating agent in patient with thalassemia major. Kattamis A. 26. Ling SC.12:577-85. Hermann C. 25.28:196-208. et al. Molavi MA DH. Indian Pediatr 2004. Evazi R. Hoffbrand AV. Final results of the randomized trial of deferiprone (L1) and deferoxamine (DFO) [abstract]. Comparison of deferasirox and deferoxamine treatment in iron-overloaded patients: Liver iron concentration determined by quantitative MRI-R2*. Hematology 2007. et al. Lancet 1990. Mourad FH. Haematologica 2006.Management of Thalassemia – Iron chela- tion therapy. Aydinok Y. Terzi A. Galanello R. El-Beshlawy A. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients.115:1876-84. Berdoukas V.12:655-9. Huang ZK. et al.123:220-5. Haematologica 2006. 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. Tamaddoni A RM. . Piga A. Madan N. [Chinese]. 29. Karagiorga M. Blood Cells Mol Dis 2002. 36.87:545-50.91:1241-3. Saxena R. in comparison to deferoxamine in thalassemia patients with transfusional iron overload. D'Amico G. Khoriaty AI. orally-administered iron chelator.106:2698-. Elalfy MS. Tanner MA.90:264a. 31.107:3738-44. deferiprone and in combination on iron chelation in thalassemic children. Peng P. Maggio A. ASH Annual Meeting Abstracts 2005. Morabito A. Gomber S. Randomized phase II trial of deferasirox (Exjade. Abdelrazik N. Koren G. Circulation 2007. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial. Dessi C.91:873-80. Ann Hematol 2008. 38.121:187-9. et al. Iranian Red Crescent Medical Journal 2010. Br J Haematol 2003. Koussa S. et al. Randomised Prospective Evaluation of Iron Balance. Galanello R. Asian Journal of Medical and Pharmaceutical Researches 2013. Chelation Efficiency. 39. Forni GL. placebo-controlled. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Hemoglobin 2006. 34. Comparative efficacy of desferrioxamine. Long LL. Porter JB. 27. et al. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Bisphosphonates and Zinc supplementation 20 22.41:21-7. Blood 2006. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA). Cetiner N. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Mansoori F. Taher A. Blood 1997. et al. Naja M. Olivieri NF BG. Manz C.336:1275-9. Pennell DJ.123:1447-54. ICL670). Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Evans P. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO.3:93-7. 30. 24. et al. et al. Chinese Journal of Radiology (China)2013:55-9.30:263-74. Olivieri NF. 35. Al Jefri A. 37. Chik KW. Pennell DJ. Piga A. Taher A. 33. Porter JB. Galanello R. et al. et al. 23. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. 28. 32. A randomized. Acta haematologica 2010. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. Blood 2014. Ha SY. a once-daily. Nazemi A.

Morabito N. Zinc supplementation improves bone density in patients with thalassemia: a double-blind.98:960-71. Am J Hematol 1987. Wood J. randomized. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2. 43. quality of life. Bentley A. Rodda CP. Maggio A. Rafraf M. Spina M. Strauss BJ. Br J Haematol 2012. et al. 54. Cost-utility analysis of deferiprone for the treatment of beta-thalassaemia patients with chronic iron overload: a UK perspective. Fiore CE. Terpos E. Forni GL. Tsiftsakis E. et al. Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalassemia major Patients. et al. Aboomardani M. Alexakos P. Riccobene S. 42.21:402-8. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial. Scalone L. . et al. 48. Nart D. Krol M. Gilfillan CP. Anagnostopoulos A. Haematologica 2008. 51. Br J Haematol 2009. 53. A randomized. Haematologica 2007. et al. Pharmacoeconomics 2013. Konstantopoulos K. 49. King JC. Tricta F. Calcif Tissue Int 2006. 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. Banihashem A. Olivieri N. randomized.92:1599-606. 45. Aydinok Y. Huang JN. placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia.79:138-44.Management of Thalassemia – Iron chela- tion therapy. Voskaridou E. Bisphosphonates in the treatment of thalassemia- induced osteoporosis. randomized. Ulger Z. Porter JB. et al. Giusti A. Mirhossini NZ. double-blind. Kwiatkowski JL. Effects of zinc supplementation on linear growth in beta- thalassemia (a new approach). Gillard S.31:807-22.13:644-9. Arefhosseini SR. treatment satisfaction and compliance in patients with beta-thalassemia major undergoing iron chelation therapy: the ITHACA study. Bisphosphonates and Zinc supplementation 21 40.24:1905-17. parallel-arm.15:38. Gildengorin G. Lasco A. et al. 44. Capra M. Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia major. Pennisi P. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. Keshtkar A. Joshaghani H. Rashidi M.24:127-36. Osteoporos Int 2002. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center. 47. Christoulas D. Current medical research and opinion 2008. Vitrano A. Costs. placebo-controlled trial. Konstantinidou M. 50. Spino M. Perrotta S. 52. Fung EB.21:8-14. open-label study. Cin S. Ghahramanlu E. Arcasoy A. placebo-controlled trial.91:1193-202. Cavdar A.19:113-9. Am J Clin Nutr 2013. Connelly J. Iran J Pediatr 2011. et al. Gaudio A. Mantovani LG. Haematologica 2006.145:245-54. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. Vichinsky EP. J Cardiovasc Magn Reson 2013.158:274-82. et al. 46.93:1588-90. placebo-controlled trial. J Bone Miner Metab 2003. Voskaridou E. et al. Hematology 2014. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. Pizzarelli G. 41.

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.

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. ○ Very low plication and the differing spec- trum of possible adverse effects.g. 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. Alt- hough this might not be true for ○ Moderate all patients (e. . 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. 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. small children.96% (8/834). Oral chelation Option: Deferasirox therapy with deferasirox is suggested to be at least similarly effective.1 ○ Varies The relative importance or values of the main outcomes of interest: Long term experience with defer- ○ No included asirox is limited.69%) had beta-thalassemia trait. Relative Certainty of the What is the studies Outcome Given the different modes of ap- Benefits & importance evidence (GRADE) harms of the overall cer. leading to increased patient compliance due to the more convenient application.Management of Thalassemia – Iron chela- tion therapy.4% (307/8918) beta-thalassemia trait prevalence in premarital couples Is there a ○ Uncertain living in the Al-Hassa area was observed.2 Problem problem pri- ority? ○ Probably yes A screening of 6750 healthy persons in Jeddah. western Saudi Arabia. The prevalence of beta-thalassemia trait ● Yes among neonates in the same area was 0. the standard iron chelating drug. showed that 316 (4. Background and Objective: Deferoxamine."6 ○ Probably no In 2004. a 3.

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

5 er).at lower to 1.6 [42. Because the lower bound of the 95% CI was greater than from baseline prespecified margin of 0.2 [32.3 [34.6] ms at baseline to 12.84 lower ventricular in the control intervention group to 1.e. A trend for months superiority of deferasirox compared with DFO was observed. mean change 1.056 (repeated 95% CI 0.37 large relative months) in the was 2.72 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. 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.6] ms at EOS) and ○ Varies Myocardial T2* (ms)- by 7% for DFO (11.9.4 was 0.998.07 ble effects? ○ Yes biopsy or LIC was 2. alt- hough this did not reach statistical significance.64 higher) Are the unde.68 higher - evaluated by -6. ● Uncertain 12 months sirable antici- pated effects ○ Probably yes "In the per-protocol population.07 at 8 and 12 and 12 months) in intervention group higher to . reduction in to 3. i.68 lower).64 ○ Probably no ejection frac. reduction was higher in deferoxamine group Mean change The range for Change in serum MD 415.133).e. Gmean (coefficient of variance) small? myocardial T2* improved after 1 year of treatment with deferasirox ○ Yes by 12 % (11. Bisphosphonates and Zinc supplementation 25 ○ No Cardiac: Left (%) at 12 months 12 months in the (1. The ratio of the Gmeans of deferasirox over DFO was 1.07 high.37 lower higher) SQUID . i.6 [30.68 higher to undesira- ○ Probably yes (mg Fe/g dw) control group was higher to 3. group was 66. by biopsy or SQUID at Are the desir.7] ms). ed by biopsy or 12 months) in the able effects ● Uncertain in liver iron concentration SQUID at 12 intervention group MD 2. noninferiority of deferasirox compared .1 lower (1.at 12 with DFO for myocardial iron removal was demonstrated.Management of Thalassemia – Iron chela- tion therapy.at ○ Varies 12 months (3. (1.84 higher) tion (%) .7] ms to 12.4-0.07 lower to 1.37 higher (1.

MD 1.4 (% of dose patients) at 12 tients) at 12 months lower taken by months in the in the intervention (3. reduction in serum ferritin was 415.78 adverse 45 per 1000 58 per 1000 (from 22 (0.07 lower).95 higher) higher) No research evidence specific to KSA setting identified.72 lower (536.e.37 higher). ○ Uncertain ment of beta-thalassemia patients with chronic iron overload esti- Resource use sources re- quired small? ● Probably yes mates 23.38) months fewer) Compliance (% of Compliance (% of Compliance dose taken by dose taken by pa.44 to event-at 12 (25 to 80) more to 32 1.at control group was group was 1. A cost-utility analy- sis of deferasirox for the treat- Are the re.4 lower to 0.75 lower - patients) .37 was -1277-211 (295.179 pounds per year treatment with deferasirox ○ Yes (Exjade®) versus 8. i. reduction was higher in deferoxamine group 13 fewer Any serious per 1000 RR 0.53 . Bisphosphonates and Zinc supplementation 26 months the control group was 415.e.72 higher 536.07 higher to higher) 536.75 lower to 0.025 pounds per one-year treatment with ge- ○ Varies neric deferoxamine including administration cost.Management of Thalassemia – Iron chela- tion therapy. i. No specific data on costs of defer- ○ No asirox or deferoxamine in KSA ○ Probably no setting found.37 lower to 295.4 (3.95 12 months 100.

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

6) %. 98. including iron-overloaded thalassemia pa.8% at end of study versus 21. 86. Bisphosphonates and Zinc supplementation 28 No research evidence specific to KSA setting identified. On a 5-point scale (ranging from "very satisfied" or "very conven- Acceptability key stake. ○ No tients from Saudi-Arabia.oral application. Most patients would likely prefer One study (Taher 2010)26 was identified.2) (mean (SD) h/month) at baseline to (3. who had not ○ Probably no achieved successful iron chelation with DFO and/or deferiprone (n=237). ○ Probably yes ient" to "very dissatisfied" or "very inconvenient") 90. 92. No research evidence specific to KSA setting identified. No obvious barriers to implemen- ○ No tation were identified.1% received at least 95% of their acceptable to scheduled doses.1 (44.3% patients still received deferasirox (persistence).6) h/month at end of study). ○ Probably no Is the option ○ Uncertain Feasibility feasible to implement? ○ Probably yes ● Yes ○ Varies .4 (4. Over- Is the option ○ Uncertain all (mean (SD)) compliance was 98. but also other patients from the Middle East.5% at baseline considered their therapy to be "convenient/very convenient".Management of Thalassemia – Iron chela- tion therapy. Time lost to therapy for daily activities was reduced ○ Varies (30.2 (8.2% at ● Yes baseline. Treated with deferasirox for one year.7% of all patients reported being holders? either "satisfied" or "very satisfied" with their iron chelation therapy versus 23.

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

.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. Bisphosphonates and Zinc supplementation 30 Ideally. Research possibilities Also.

64 higher) LOW Myocardial T2* (ms)-mean change from baseline .5%) (0.9.37 higher ⨁⨁⨁◯ CRITICAL trial gradient (1.68 higher to 3.at 12 months 3 4 1 randomised serious not serious not serious serious none 91 81 .3 [34. 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. LOW ment with deferasirox by 12 % (11.2 [32.at 12 months 3 4 1 randomised serious not serious not serious serious none 91 81 "In the per-protocol population.6 [42. Because the lower bound of the 95% CI was greater than prespecified margin of 0. A trend for superiority of deferasirox compared with DFO was ob- served. MD 0.056 (repeated 95% CI 0. 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.6[30.09 to LOW 2. noninferiority of deferasirox compared with DFO for myocardial iron removal was demonstrated.133).63) End-organ damage .7] ms).1 lower ⨁⨁◯◯ CRITICAL trial (1. 1.6] ms at base- line to 12.07 higher) MODERATE .at 12 months 5 6 7 1 randomised serious serious not serious not serious dose response 268 273 .998.Cardiac: Left ventricular ejection fraction (%) .48 5 fewer per 1000 (from 9 fewer to 16 more) ⨁⨁◯◯ CRITICAL trials (0.Management of Thalassemia – Iron chela- tion therapy.7] ms to 12. although this did not reach statistical signifi- cance.6] ms at EOS) and by 7% for DFO (11. MD 2. The ratio of the Gmeans of deferasirox over DFO was 1.84 lower to 1. 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 .0%) RR 0. Gmean (coefficient of ⨁⨁◯◯ CRITICAL trial variance) myocardial T2* improved after 1 year of treat.

I²=91%.Management of Thalassemia – Iron chela- tion therapy. High risk of bias due to lack of blinding of participants and personnel (3 studies). heterogeneity due to different ratio of drugs between subgroups 11. RR – relative risk. Only few patients were included in study 5. incomplete outcome data (1 study). incomplete outcome data (1 study).4 lower ⨁⨁◯◯ IMPORTANT trial (3. An additional study (Piga 2006) reported that "mean serum ferritin levels remained stable in the deferasirox 20 mg/kg/d and DFO groups. lack of blinding of outcome assessment (2 studies). p<0. Unclear: Random sequence generation. no SD mentioned 6. lack of blinding of outcome assessment. measured LIC (mg Fe/g dw) by MRI. allocation concealment (2 studies).000001.72 higher ⨁⨁⨁◯ IMPORTANT trials gradient (295. selective reporting (2 studies) 2. High risk of bias due to lack of blinding of participants and personnel.75 lower to 0. p<0.6%) (0. lack of blinding of outcome assessment (3 studies). High risk of bias due to lack of blinding of participants and personnel (3 studies).38) Compliance (% of dose taken by patients) . allocation concealment. incomplete outcome data (1 study). MD 415. Very wide confidence interval including both clinically relevant benefit as well as harm 3.37 higher) MODERATE Any serious adverse event . SD – standard deviation 1. Heterogeneity due to different ratio of drugs between subgroups 8.00001. including smaller study population. Unclear: Random sequence generation 4. Unclear: Random sequence generation (2 studies).at 12 months 3 4 1 randomised serious not serious not serious serious none 96 91 .95 higher) LOW MD – mean difference. MD 1. I²=84%. incomplete outcome data. lack of blinding of outcome assessment (3 studies). incomplete outcome data (1 study).07 higher to 536.44 to LOW 1. 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 (1 study). selective reporting (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 (2 studies). selective reporting (1 study) 10. selective reporting 7. lack of blinding of outcome assessment. An additional study (Pennell 2014). Unclear: Random sequence generation (3 studies).at 12 months 11 2 2 randomised serious not serious not serious serious none 18/392 22/381 (5. incomplete outcome data (2 studies). High risk of bias due to lack of blinding of participants and personnel (2 studies). a significant decrease with deferoxamine compared to deferasirox was shown. High risk of bias due to lack of blinding of participants and personnel.78 13 fewer per 1000 (from 22 more to 32 fewer) ⨁⨁◯◯ IMPORTANT trials (4. Another study (Piga 2006) reported average decreases of similar magnitudes measured by SQUID. incomplete outcome data (1 study). allocation concealment (1 study). Unclear: Random sequence generation (2 studies).8%) RR 0.

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

The prevalence of beta-thalassemia trait ● Yes among neonates in the same area was 0. Although. leading to increased patient compliance due to the more convenient application.” 6 ○ Probably no In 2004. Option: Deferoxamine Oral chelation therapy with deferiprone is suggested to be at least similarly effective.96% (8/834). ○ Probably A screening of 6750 healthy persons in Jeddah.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. 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. probably the Mortality CRITICAL majority of patients would pre- ○ Moderate VERY LOW fer oral application of iron che- .4% (307/8918) beta-thalassemia trait prevalence in premarital couples ○ Uncertain living in the Al-Hassa area was observed. western Saudi Arabia.2 Is there a Problem problem prior. a 3.Management of Thalassemia – Iron chela- tion therapy. Bisphosphonates and Zinc supplementation 34 Guideline Question 2: Should deferoxamine versus deferiprone be used for iron overload in thalassemia patients? Problem: Thalassemia patients with iron overload Background and Objective: Deferoxamine.69%) had beta-thalassemia trait. the standard iron-chelating drug. a variability of patient’s values and preferences seems options evidence? ○ Low ⨁◯◯◯ likely. 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. showed that ity? yes 316 (4.

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

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

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

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

0%) 1/6 (16.02 lower to 0. this death was at- tributed to cardiac complications and thought not to be related to deferiprone treatment" (Fisher 2013) End organ damage .at 6.8%) (0. One death occured in the deferiprone treatment VERY LOW arm after six months of treatment. none 0/7 (0.61 lower ⨁◯◯◯ CRITICAL trial ous 2 (2.Cardiac: Left ventricular ejection fraction: mean change from baseline (%) . none 15 21 . 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.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 0.98 higher) LOW Liver iron concentration: mean change from baseline (mg/g dry weight) using SQUID . 0 indicating no fibrosis): mean at endpoint .24 to fewer) LOW 0.1%) 24/71 RR 0.12 lower to 45.45 186 fewer per 1000 (from 54 fewer to 257 ⨁⨁◯◯ IMPORTANT trial (33.at 12 months 1 randomised not not serious not serious very seri.Liver: Liver fibrosis Ishak score (ranging from 0-6.17 lower) VERY LOW End organ damage . none 30 27 .8 higher) VERY LOW Serum ferritin concentration: mean change from baseline (ng/ml) . MD 0.Management of Thalassemia – Iron chela- tion therapy.84) . MD 0. 12 and 24 months 11 12 13 6 5 randomised serious serious not serious serious none 155 152 .1 higher ⨁⨁◯◯ CRITICAL trial serious ous 2 (0.49 higher) VERY LOW Adverse events .at 12 and 24 months 3 4 5 6 3 randomised serious serious not serious serious none 114 113 .78 lower to 0.82 lower ⨁◯◯◯ IMPORTANT trials (313. MD 1.7%) "Only one trial reported mortality as an outcome (Ha ⨁◯◯◯ CRITICAL trial ous 2 2006).56 lower ⨁◯◯◯ CRITICAL 7 trials (2.at 12 months 89 10 1 randomised serious not serious not serious very seri. 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. MD 133.

High risk of bias due to lack of blinding of participants and personnel. result statistically significant. liver iron concentration decreased from baseline to the end of the trial in both treatment groups in two additional trials. Using random-effects model. no SD mentioned 12. the greatest decrease was observed in the DFO group in El-Beshlawy 2008 and in the deferiprone group in Maggio 2002. Point estimates differ substantially. Four additional trials reported change from baseline in liver iron concentration (El-Beshlawy 2008. selective reporting (3 studies). other bias (1 study) 13. high I²-value (77%). p=0. but result was not statistically significant 10. lack of blinding of outcome assessment (2 studies). in a third trial (Maggio 2002). High risk of bias due to lack of blinding of participants and personnel (5 studies). lack of blinding of outcome assessment (4 studies). incomplete outcome data (1 study). selective reporting.at 12 months 15 16 1 randomised serious not serious not serious very seri. allocation concealment (4 studies). lack of blinding of outcome assessment. El-Beshlawy: val- ues of liver iron concentration in DFO treated patients were 1. the increase was greatest in the deferiprone treated group in both trials. selective reporting. lack of blinding of outcome assessment. An older study (Olivieri 1997) showed a significant better compliance in deferiprone patients after 3 years 16. favouring DFO (Ha 2006. with a greater decrease in the deferiprone group. SD – standard deviation 1. none 32 29 .5 times higher than in patients treated with deferiprone. Only very few patients were included in study/studies 3. 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. MD was not significant anymore 8. other bias (trial was stopped early due to an unexpected sudden death). selective reporting. other bias (1 study) 5. allocation concealment .88 higher) VERY LOW MD – mean difference. Ha 2006. Bisphosphonates and Zinc supplementation 43 Participant compliance (%) .45 times that in patients with DFO. Unclear: Allocation concealment 2. High risk of bias due to lack of blinding of participants and personnel 15.02 14.Management of Thalassemia – Iron chela- tion therapy.88 lower to 2. liver iron concentration in patients who re- ceived deferiprone was 1. Olivieri 1997). other bias (1 study). In Olivieri 1997. se- lective reporting (1 study). Only few patients were included in study/studies 7. Unclear: Random sequence generation. Unclear: Random sequence generation. An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" between treatment arms. Point estimates vary. Maggio 2002. allocation concealment 11. MD 1 lower ⨁◯◯◯ IMPORTANT trial ous 2 (4.01. Unclear: Random sequence generation (2 studies). mean liver iron concentration for DFO was 0. An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentration in both groups. no specific values were reported 4. Olivieri 1997) 9. lack of blinding of outcome assessment . High risk of bias due to lack of blinding of participants and personnel (3 studies). allocation concealment (2 studies). High risk of bias due to lack of blinding of participants and personnel. p=0. RR – relative risk. result statistically significant. Unclear: Random sequence generation (3 studies). using different methods of meas- urement. I²=67%. No clear clinical differences between the trials were identified which could account for this heterogeneity 6. incomplete outcome data (2 studies). Three trials which reported liver iron concentrations at end of trial were analysed on a log scale due to apparent skewing data in one trial (Maggio 2002).51 times that for deferiprone.

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

4% (307/8918) beta-thalassemia trait prevalence in premarital couples living ○ Uncertain in the Al-Hassa area was observed.1 ○ Varies The relative importance or values of the main outcomes of interest: No data specific to thalassemia ○ No included patients in KSA identified.96% (8/834). the standard iron chelating drug is suggested to be more effective in require treatment with iron chelators combination with deferiprone than alone."6 ○ Probably no In 2004.69%) had beta-thalassemia trait. a 3. 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. The prevalence of beta-thalassemia trait among neo- ● Yes nates in the same area was 0.Management of Thalassemia – Iron chela- tion therapy.2 Is there a prob- Problem lem priority? ○ Probably A screening of 6750 healthy persons in Jeddah. 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 . showed that 316 yes (4. western Saudi Arabia. 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.

○ Probably no baseline .Number of participants expe.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.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% . 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.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.at 6 and 12 months VERY LOW portant uncer- tainty of varia- bility Adverse events . ⨁⨁◯◯ IMPORTANT ○ No known riencing an adverse event . Serum ferritin concentration: mean change ⨁◯◯◯ IMPORTANT from baseline (ng/ml) . variability Liver iron concentration: mean change from portant uncer.

12 lower lower) control group was to 4.at 12 months) in the inter- vention group was (8.32 lower) able anticipated effects small? ● Probably 68. p=0.at 12 months months) in the 6. Porter 2013: " At 12 months. the mean change in myocar- months Are the desirable ○ Uncertain dial T2* was nearly identical in the two groups" (DFO + Deferiprone: 1. Liver iron concen.04 yes ○ Yes End-organ No data available damage: Liver ○ Varies Two trials reported myocardial T2* as an outcome measure at 12 months. line .Management of Thalassemia – Iron chela- tion therapy.22 lower ○ Probably no fraction: mean at endpoint (%) mean at endpoint (%) .22 lower (8. from baseline . DFO: 1.9 (1. tion fraction (mean at ○ No tricular ejection tion fraction ( endpoint (%) . The range for left Left ventricular ejec- age: Left ven. 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.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. with an estimate of a 10% increase myocardial T2* ● Probably no (ms) – at 12 compared with the deferoxamine group (95% CI 2% to 19%.4-78.9 (1.45 lower .SQUID ○ Varies from baseline . ventricular ejec.SQUID at 12 at 12 months (mg/g (0. 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.45 lower - to 0.6) ms.17 ○ Yes centration: tration: mean tion: mean change lower mean change change from base.4) ms effects large relative to unde- ○ Probably sirable effects? yes Liver iron con. while still on DFP" (Porter 2013) ○ Varies End-organ dam. ○ Uncertain .17 lower (0.02).12 lower - to 4. Liver iron concentra- MD 0.32 Are the undesir.at 12 MD 6.

84) adverse event - 221 fewer) at 12 months No research evidence specific to KSA setting identified.89 higher).86 lower (469. i.86 (ng/ml) . 195.13 to experiencing an fewer to 0.11 higher). No specific data on costs of ○ No deferoxamine alone or of com- bination therapy in KSA setting Resource Are the re.79 reduction in serum higher) ferritin was 136.Number of (33 to 214) per 1000 RR 0.33 participants (from 41 (0.e. Bisphosphonates and Zinc supplementation 48 wet weight) -0.45 higher) Serum ferritin The range for Serum ferritin concen- concentration: serum ferritin tration (mean change mean change concentration from baseline (ng/ml) from baseline (mean change at 6 and 12 months) in MD 136. ○ Probably no available.61 - 12 months) in the (469.11 lower to 0. A cost-utility analysis sources required for the treatment of beta- use small? ○ Uncertain thalassemia patients with chron- ○ Probably ic iron overload estimates 8.86 higher (195.17 higher (0.89 lower to 469.61 higher) Adverse events 254 per 1000 84 per 1000 170 fewer .at 6 from baseline the intervention group lower and 12 months (ng/ml) at 6 and was 136.61 lower to lower to control group was 195.07 to 0. i.025 pounds for treatment with ge- yes neric deferoxamine versus . reduction in LIC was 0.89 -987-28.e.Management of Thalassemia – Iron chela- tion therapy.

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

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

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

.45 lower to 0. the mean change in myocardial T2* was nearly identical in the two groups" (DFO + Deferiprone: 1. .at 12 months 3 4 5 6 2 randomised serious serious not serious serious none 60 58 .not measured .4) ms Liver iron concentration: mean change from baseline . Porter 2013: " At 12 months.6) ms.32 lower) VERY LOW End-organ damage: Liver . none 30 29 . 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.12 lower to 4. .Management of Thalassemia – Iron chela- tion therapy. .9 (1. MD 0. while still on DFP" VERY LOW (Porter 2013) End-organ damage: Left ventricular ejection fraction: mean at endpoint (%) . DFO: 1.11 higher) VERY LOW . none 9 11 "One patient in the combination arm died within ⨁◯◯◯ CRITICAL trial ous 2 a year of coming off the study. not estimable . ⨁◯◯◯ CRITICAL trials ous 10 come measure at 12 months. none 0/4 (0. .22 lower ⨁◯◯◯ CRITICAL 7 trials (8. .02).9 (1.0%) Two trials reported myocardial T2* as an out. p=0. . 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.SQUID at 12 months (mg/g wet weight) 12 13 1 randomised serious not serious not serious very seri.0%) 0/7 (0. with an estimate of a 10% increase compared with the deferoxamine group (95% CI 2% to 19%.17 lower ⨁◯◯◯ CRITICAL trial ous 10 (0. Tanner 2007: "The VERY LOW between group difference in geometric means of myocardial T2* was reported as significantly in favour of the combined treatment group. CRITICAL Myocardial iron concentration: myocardial T2* (ms) – at 12 months 8 9 11 11 2 randomised serious not serious not serious very seri.

3%) 15/59 (25. no clear clinical differences between these two trials were identified which could account for this heterogeneity 6.13 to 0.2) to 5. High risk of bias due to lack of blinding of participants and personnel (1 study). lack of blinding of outcome assessment (2 studies).61) mg/g dry wt with combination. no significant difference was measured between the treatment arms: MD=-0.008 17. lack of blinding of outcome assessment (1 study). incomplete outcome data (1 study). -48% to -28%. a third trial (Porter 2013) using different methods reported a reduction from 16. Point estimates differ.67 to 8. However.1 (4.13 (95%CI-8. Only few cases .002. Unclear risk of bias: Random sequence generation (1 study). High risk of bias due to lack of blinding of participants and personnel (2 studies). incomplete outcome data (2 studies) 9. therefore no numbers could be included. selective reporting. allocation concealment 14. another trial (Porter 2013) reported.61 lower to 195. incomplete outcome data (study was terminated due to slow patients accrual.4%) RR 0. 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. SD not stated 4.08 (3.Number of participants experiencing an adverse event .27 (3.3% in combination group and from 52.9% in DFO group at 12 months.001). I²=80%.86 lower ⨁◯◯◯ IMPORTANT trials (469. serum ferritin declined from 3601± 838 to 2132 ± 646 μg/L (n=7) in combination arm. allocation concealment (1 study). Only few patients included in study/studies 7. I²=89%.at 12 months 17 18 2 randomised serious not serious not serious serious none 5/60 (8. Unclear: Random sequence generation. Only very few cases 3.18).62 (2.8% to 56. selective reporting (3 studies). 95% CI. that LVEF increased from 49. P< 0. no data to calculate SD was available. 65 patients were randomised at beginning 12. p=0. pooled results showed significant difference favouring deferiprone combined with DFO. lack of blinding of outcome assessment. Data not pooled. blinding of outcome assessment (1 study). only 11 of 20 patients completed close to 12 months of treatment) 2. allocation concealment (2 studies) 18. Five additional trials reported reduction in serum ferritin in both treatment arms.Management of Thalassemia – Iron chela- tion therapy. in DFO monotherapy arm. but the difference in change between groups was not statistically significant 13. number of patients included in each outcome assessment was not clear.at 6 and 12 months 14 15 16 6 3 randomised serious serious not serious serious none 51 56 . Bisphosphonates and Zinc supplementation 53 Serum ferritin concentration: mean change from baseline (ng/ml) . An additional trial reported "no significant difference in cardiac function" (El-Beshlawy 2008). High risk of bias due to lack of blinding of participants and personnel. Tamaddoni 2010) on a log scale as ratio of geometric means due to skewed data in Mourad 2003. Unclear: Random sequence generation (2 studies). selective reporting (2 studies). incomplete outcome data (1 study) 5. from narrative information no obvious inconsistency present 10. MD 136.41). RR – relative risk. Only very few patients were included in studies 11. LIC decreased in both groups. 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. In one study (Tanner 2007). Differences remained significant under random-effects model 8. lack of blinding of outcome assessment (3 studies). a fourth trial (El- Beshlawy 2008) reported change in liver iron concentration graphically. serum ferritin increased from 1613 ± 537 to 2018 ± 898 μg/L (n=4) 15.9% to 58. other bias (1 study).67) to 9. analysing geometric means. selective reporting (1 study). Risk of bias: Unclear: Blinding of outcome assessment. Mourad 2003. SD – standard deviation 1. Tanner 2007 reported at 12 months "the between-group difference was significantly in favour of the combined treatment group (-40%.89 VERY LOW higher) Adverse events .84) fewer to 221 fewer) LOW MD – mean difference. and a reduction with DFO therapy from 5. blinding of outcome assessment (2 studies). at 12 months (Abdelrazik 2007. allocation concealment (3 studies) 16. another trial (Porter 2013) reported serum ferritin concentrations at 12 months. An additional trial (Ha 2006) using AAS reported liver iron concentration as mean change (mg/g dry weight) at 6 months. High risk of bias due to lack of blinding of participants and personnel (3 studies).33 170 fewer per 1000 (from 41 ⨁⨁◯◯ IMPORTANT trials (0. Unclear: Random sequence generation (2 studies). p=0. therefore difficult to assess.

Tanner MA. Hematology 2007. Saxena R.12:577-85. double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. 10. Randomised Prospective Evaluation of Iron Balance. et al. Ann Hematol 2008. Tamaddoni A RM. J Cardiovasc Magn Reson 2013.41:21-7.115:1876-84. Chelation Efficiency. Abdelrazik N.91:1241-3. Evans P. El-Beshlawy A.106:2698-. Ha SY.121:187-9. Chik KW. Bisphosphonates and Zinc supplementation 54 References 1. Comparative efficacy of desferrioxamine. Cetiner N. 3. 2.12:655-9. Indian Pediatr 2004. Haematologica 2006. Aydinok Y. A randomized. Mourad FH. Ling SC. Koussa S. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. Hoffbrand AV. Galanello R. Br J Haematol 2003. et al. Piga A.87:545-50. et al.30:263-74. Porter JB. Manz C. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO. Khoriaty AI. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Gomber S. Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. Sheikh-Taha M. 6. deferiprone and in combination on iron chelation in thalassemic children. Naja M. et al. Dessi C. 7. Hemoglobin 2006. Galanello R. et al. A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia. Taher A. Terzi A. ASH Annual Meeting Abstracts 2005. 5. 9. Madan N. Olivieri N.Management of Thalassemia – Iron chela- tion therapy. 8. Circulation 2007. Porter JB. placebo-controlled. . 4. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Wood J.15:38. Iranian Red Crescent Medical Journal 2010. Kattamis A.

”42 .” 6 ○ Probably no In 2004. a 3. western Saudi Arabia.1 ○ Yes ○ Varies What is the The relative importance or values of the main outcomes of interest: "Mean compliance with defer- Benefits & overall cer. the standard iron-chelating drug is suggested to be more effective in require treatment with iron chelators combination with deferiprone than deferiprone alone. showed that 316 (4.Management of Thalassemia – Iron chela- tion therapy.69%) had beta-thalassemia trait.6%. 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. The prevalence of beta-thalassemia trait yes among neonates in the same area was 0.96% (8/834).4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in the Al-Hassa area was observed. options Outcome Certainty of Relative evidence? ●Very low the evidence whereas mean compliance with DFO was 70. Bisphosphonates and Zinc supplementation 55 Guideline Question 4: Should deferoxamine in combination with deferiprone versus deferiprone alone be used for iron overload in tha- lassemia patients? Problem: Thalassemia patients with iron overload Background and Objective: Deferoxamine.2 Is there a ○ Uncertain Problem problem pri- ority? ● Probably A screening of 6750 healthy persons in Jeddah.

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

99 lower higher) able effects no to 12. 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. In this trial." (Fisher 2013) ○ Yes ○ Varies End organ damage Left ventricular Left ventricular . Maggio ○ No 2009). mortality occurred 11 to 60 months after withdrawal of the randomised treatment. one individual who was randomised to receive deferiprone and DFO in combination. In this latter trial. In the first trial.2 ventricular ejec.2 Are the desir. ○ Probably months was 67.at 12 (Aydinok 2007). the trial authors reported ○ Yes (ranging from 0 to that the fibrosis score "did not change significantly after one . ○ Uncertain years second trial (Maggio 2009). One death due to arrhythmia whilst receiving months and 5 deferiprone and DFO in combination was also reported in the Are the unde. a further five sirable antici.99 lower to 12.Management of Thalassemia – Iron chela- tion therapy. 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. scored accord- ing to the Ishak scoring system (Aydinok 2007).39 higher) large relative to undesira- ○ Uncertain ble effects? ● Probably End organ damage . died at the start ○ Probably of the trial due to arrhythmia-induced congestive heart failure no Mortality .at 12 control group group was 5. yes sis Ishak score results were presented graphically.39 - (%) . mean at endpoint higher tion fraction: point (%) at 12 (%) at 12 months) ○ No mean at endpoint months) in the in the intervention (1.4 higher (1.Cardiac: Left ejection fraction ejection fraction ( MD 5.Liver: Liver fibro- "One trial reported liver fibrosis as an outcome. (mean at end.

Bisphosphonates and Zinc supplementation 58 ○ Varies 6. Liver iron concen- tration: mean at centration tration (mean at endpoint (mg/g (mean at end.5 lower to 1.42 high- er) Myocardial iron "Maggio 2009: Myocardial iron concentration was measured by concentration: T2* MRI in a subset of patients with a mean (SD) duration Myocardial T2*: from entry into the trial until the final MRI scan of further 16 mean at endpoint (5) months in the combined deferiprone and DFO group and (ms): DFO + DFP: further 14 (6) months in patients receiving deferiprone alone. DFP: at patients prohibited calculation of the mean change in myocar- further 14 (6) dial iron concentration. at further (16(5) The difference in duration of follow up across this subset of months.87 lower to was 1633- .at 12 (3.25 mean at endpoint concentration (mean at endpoint lower (ng/ml) .42 was 7.Management of Thalassemia – Iron chela- tion therapy.42 lower months weight) at 12 months) in the - to 1. Liver iron con.at 6 and (mean at end. (ng/ml) at 6 and (468.36 high- months) in the was 219.87 - 12 months point (ng/ml) at 12 months in the lower to 6 and 12 intervention group) 30.25 lower er) control group (468. 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. 0 indicating no year in patients in any of the treatment arms" (Fisher 2013) fibrosis) .at 12 months Liver iron concen.at 12 point (mg/g dry dry weight) .42 months) in the intervention group higher) control group was 1 lower (3. endpoint (mg/g MD 1 lower dry weight) .

53 ○ Yes In a study in Italy.519 pounds per ○ Probably year treatment with deferiprone (Ferriprox®) versus 11. per 1000 RR 1. No specific data on costs of deferiprone alone or of combina- tion with deferoxamine in KSA setting found.Management of Thalassemia – Iron chela- tion therapy.61) tosis 213 more) No research evidence specific to KSA setting identified. cluding administration cost in quired small? ○ Probably combination with deferiprone yes (Ferriprox®). total cost of ○ Varies deferoxamine treatment in com- bination with deferiprone was estimated at 963 Euro per month including administration cost. 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.36 higher) Adverse Events . Bisphosphonates and Zinc supplementation 59 3422.76 to (100 to 345) and/or agranulocy. ○ Uncertain with generic deferoxamine in- Resource use sources re.41 186 per 1000 neutropenia 132 per 1000 (from 32 (0.7 30. fewer to 2. 54 more Risk of leucopenia. Cost of treatment with deferiprone was 480 Euro per month.54 The panel supposes that a com- .

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

Bisphosphonates and Zinc supplementation 61 No research evidence specific to KSA setting identified. No obvious barriers to imple- ○ No mentation were identified. Additionally. The panel’s judgement was that ○ No many patients would likely pre- ●Probably no fer monotherapy. combination therapy requires Is the option ○ Uncertain more resources. ○ 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.

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

42 lower to 1.39 higher) VERY LOW End organ damage .Cardiac: Left ventricular ejection fraction: mean at endpoint (%) . deferoxamine Absolute Inconsistency Indirectness Imprecision deferiprone (95% studies design bias erations + deferiprone (95% CI) CI) Mortality .at 12 months 4 5 1 randomised serious not serious not serious very seri. results were presented graphically. VERY LOW In this trial.42 higher) VERY LOW .at 12 months and 5 years 1 2 2 randomised serious not serious not serious very seri. one individual who was VERY LOW randomised to receive deferiprone and DFO in combi- nation.at 12 months 789 10 1 randomised serious not serious not serious very seri. none 16 17 . In the first trial. ⨁◯◯◯ CRITICAL trials ous 3 Maggio 2009). One death due to arrhythmia whilst receiving deferiprone and DFO in combination was also reported in the second trial (Maggio 2009)." (Fisher 2013) End organ damage . MD 1 lower ⨁◯◯◯ CRITICAL trial ous 6 (3.at 12 months 5 1 randomised serious not serious not serious very seri. none 117 120 "Mortality was reported in two trials (Aydinok 2007. died at the start of the trial due to arrhythmia- induced congestive heart failure (Aydinok 2007).99 lower to 12. 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.Management of Thalassemia – Iron chela- tion therapy.Liver: Liver fibrosis Ishak score (ranging from 0 to 6. 0 indicating no fibrosis) . 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. MD 5. In this latter trial. mortali- ty occurred 11 to 60 months after withdrawal of the randomised treatment.2 higher ⨁◯◯◯ CRITICAL trial ous 6 (1. none 8 12 "One trial reported liver fibrosis as an outcome. none 8 12 . 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) . scored ⨁◯◯◯ CRITICAL trial ous 6 according to the Ishak scoring system (Aydinok 2007).

calculation of mean change is not possible. Unclear: Allocation concealment (1 study) 2.36 higher) VERY LOW Adverse Events . Only very few cases 4. The difference in duration of follow up across this subset of patients prohibited calculation of the mean change in myocardial iron concentration. other bias (1 study). Another trial (Maggio 2009) reported liver iron concentration by liver T2*. none 17/96 (17. In an additional trial liver iron concentration was measured by atomic emission spectrophotometry (Aydinok 2007). none 100 93 . Bisphosphonates and Zinc supplementation 64 Myocardial iron concentration: Myocardial T2*: mean at endpoint (ms): DFO + DFP: at further (16(5) months. DFP: at further 14 (6) months (mean(SD)) 11 1 randomised serious not serious not serious very seri.76 to more) VERY LOW 2. the mean LIC value did not change significantly in patients treat- ed with DFP.at 6 and 12 months 12 13 14 3 randomised serious not serious not serious very seri.Management of Thalassemia – Iron chela- tion therapy. Only very few patients included in study/studies 7. lack of blinding of participants and personnel. RR – relative risk. neutropenia and/or agranulocytosis 16 3 randomised serious not serious not serious very seri.7%) 16/121 RR 1. Data not pooled.41 54 more per 1000 (from 32 fewer to 213 ⨁◯◯◯ IMPORTANT trials ous 3 (13.61) MD – mean difference. MD 219. lack of blinding of outcome assessment (1 study). 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 outcome assessment. High risk of bias due to lack of allocation concealment.2%) (0. therefore difficult to assess. selective reporting 6. end of study values were not significant 9.25 lower ⨁◯◯◯ IMPORTANT trials ous 15 (468. however the trial reported no signficant differences 8. High risk of bias due to lack of allocation concealment (1 study). Method used is not stated in this trial . An additional trial (El-Beshlawy 2008) reported that "there was no significant difference in cardiac function" 5. but decreased significantly in patients receiving combination therapy. a reduction was only observed in the deferiprone group compared with an increase in combination group. incom- plete outcome data (2 studies). incomplete outcome data. lack of blinding of participants and personnel (2 studies). due to differences in follow up time. from narrative information no obvious inconsistency present 3.Risk of leucopenia. no SD for change reported. selective reporting (Mortality was not pre-specified in one study).87 lower to 30. 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) . However. SD – standard deviation 1.

incomplete outcome data (differences in duration of follow up regarding myocardial iron concentration). there was no significant difference in mean change of serum ferritin concentra- tion between the two treatment arms. incomplete outcome data. Maggio 2009).92:1599-606.106:2698-.87:545-50. Mean change in serum ferritin from baseline can be calculated from data in two trials (Gomber 2004. Aydinok Y. Maggio A. deferiprone and in combination on iron chelation in thalassemic children. Aydinok Y. no standard deviations are mentioned 13. Comparative efficacy of desferrioxamine. Haematologica 2007. Indian Pediatr 2004. lack of blinding of outcome assessment (3 studies). An additional trial (El-Beshlawy 2008) reported graphically decreased serum ferritin concentrations in both groups. Naja M. Saxena R. incomplete outcome data (3 studies). lack of blinding of outcome assessment (2 studies). Randomised Prospective Evaluation of Iron Balance. 15. Br J Haematol 2009.Management of Thalassemia – Iron chela- tion therapy.41:21-7. allocation concealment (2 studies). Unclear: Allocation concealment. Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO.145:245-54. High risk of bias due to lack of allocation concealment (1 study). Unclear: Allocation concealment 12. Unclear: Random sequence generation (1 study). High risk of bias due to lack of blinding of participants and personnel. lack of blinding of participants and personnel (3 studies). Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ulger Z. Terzi A. Cetiner N. . 5. selective reporting (2 studies). 2. although number of patients was considerably reduced due to early termination of the trial 14. et al. a significant difference in mean change of serum ferritin concentra- tion in patients with combination therapy was maintained over four years of follow up. Chelation Efficiency. et al. 4. lack of blinding of outcome assessment. other bias (1 study). allocation concealment (2 studies) References 1. High risk of bias due to lack of blinding of participants and personnel. Small study population and wide confindence interval 16. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clin- ical trial. incom- plete outcome data (3 studies). et al. Vitrano A. Evans P. Unclear: Random sequence generation (1 study). at five years. Ann Hematol 2008. 3. Capra M. Gomber S. El-Beshlawy A. ASH Annual Meeting Abstracts 2005. No statistically significant difference was observed in Gomber 2004. Nart D. A reduction in serum ferritin concentration was maintained across five years of follow up in the combined treatment arm in Maggio 2009. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. High risk of bias due to lack of blinding of participants and personnel (3 studies). Madan N. other bias. random sequence generation 11. Bisphosphonates and Zinc supplementation 65 10. other bias (1 study). selective reporting (1 study). Manz C. Porter JB. in patients receiving deferiprone only a reduction in mean serum ferritin concentration from baseline values was observed at two and five years.

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. western Saudi Arabia.a 3.”6 ○ Probably no In 2004. 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.69%) had beta-thalassemia trait. The prevalence of beta-thalassemia trait among neo- nates in the same area was 0.Background and Objective: Thalassemia patients are at higher risk to suffer from osteoporosis. showed that 316 yes (4.2 Problem Is there a prob- lem priority? ● Probably A screening of 6750 healthy persons in Jeddah. studies identified.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in ○ Uncertain the Al-Hassa area was observed.96% (8/834). 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. . porosis Bisphosphonates are suggested to increase bone mineral density and prevent fractures in these patients.Management of Thalassemia – Iron chela- tion therapy.

at 12 and 24 months ○ High VERY LOW Number of participants experiencing at least ⨁◯◯◯ one non-vertebral fracture . uncertainty or Adverse events .Flu-like symptoms after first ⨁⨁◯◯ CRITICAL main outcomes? uncertainty of infusion neridronate 100 mg LOW variability ○ No im- portant uncer- Lumbar spine BMD [g/cm²] (DXA): mean at ⨁⨁◯◯ IMPORTANT endpoint .Management of Thalassemia – Iron chela- tion therapy.at 12 and 24 months LOW tainty of vari- ability ○ No known undesirable . variability zoledronic acid 4 mg LOW tainty about how much peo. ○ Probably no ple value the important Adverse events . Bisphosphonates and Zinc supplementation 67 Additional Criteria Judgements Research evidence considerations the options dence? ● Very low Outcome Relative Certainty of the Panel members assumed some variability in values importance evidence (GRADE) ○ Low within the KSA thalasse- mia population with re- ○ Moderate Number of participants experiencing at least ⨁◯◯◯ gard to the considered CRITICAL outcomes.at 12 and 24 CRITICAL ○ Important months VERY LOW uncertainty or variability Back or bone pain . one vertebral fracture .Fever after first infusion CRITICAL ⨁⨁◯◯ portant uncer.at 12 months CRITICAL ⨁⨁◯◯ LOW ●Possibly important Is there im.

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. Bisphosphonates and Zinc supplementation 68 Additional Criteria Judgements Research evidence considerations Femoral neck BMD [g/cm²] (DXA): mean at ⨁⨁◯◯ IMPORTANT endpoint .85) 12 and 24 months Are the desira- ble effects large ○ No .01 to 6.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 0.85) 60 more) ● Probably no ture .01 to non-vertebral (0 to 71) 10 fewer to ○ Varies fracture .31 3 per 1000 1000 (from ○ No at least one vertebral frac- 10 per 1000 (0 to 71) 10 fewer to (0.Management of Thalassemia – Iron chela- tion therapy.31 (0.at 60 more) 6. 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.

49 to events in zoledronic acid 76.72 due to 0 infusion (1.27 after first due to 0 (0. 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.Flu.03 - BMD [g/cm²] ([g/cm²] (DXA): ([g/cm²] (DXA): mean higher .Management of Thalassemia – Iron chela- tion therapy.6% (3/54) effect esti- like symptoms mate given RR 8.Fever RR mate given after first 10.96) control 4 mg group Adverse Control event rate: Experimental event No absolute events .8% (15/26) effect esti- events .002%). 0% (0/64) rate: 5.44 to infusion neri. 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.at 12 had no change in bone pain during the study period.] at 12 months ○ Varies (P=0. events in 156." Forni 2012: "The months mean back pain scale value was significantly higher (more favourable) in ○ Yes [intervention group] compared with [control group] [.. There were no differences in fects? ○ Uncertain pain score among the three studied groups.. A concomitant significant reduction (over 50%[intervention group].70) dronate 100 control mg group Lumbar spine Lumbar spine BMD Lumbar spine BMD MD 0. Bisphosphonates and Zinc supplementation 69 Additional Criteria Judgements Research evidence considerations relative to un- desirable ef- ● Probably no Voskaridou 2006:" At baseline patients hat mild to moderate pain ac- cording to the pain scoring system used. In contrast. [control group] patients yes pain .

79 0. ○ Probably various bisphosphonates quired small? yes drugs and respective Resource doses were not available use ○ Yes at the meeting.03 higher (0.Management of Thalassemia – Iron chela- tion therapy.723-0.02 higher - at 12 and 24 the control group was intervention group was to 0. Bisphosphonates and Zinc supplementation 70 Additional Criteria Judgements Research evidence considerations (DXA): mean mean at endpoint at at endpoint at 12 and (0.9 0.08 months 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 0.05 (DXA): mean mean at endpoint at at endpoint at 12 and higher at endpoint .02 higher) higher to 0. but were judged to be moderate.636-0. Unclear. Are the re. Specific cost data for sources re. No research evidence specific to KSA setting identified.02 higher at endpoint . 12 and 24 months) in 24 months) in the to 0.02 higher to 0. because signifi- tal cost small ○ No cant benefit was only relative to the seen in surrogate out- . We found no economic evaluation addressing the ○ Probably no use of bisphosphonates versus no bisphospho- ○ Uncertain nates in the KSA setting. ○ Varies Is the incremen.08 higher) ● No No research evidence specific to KSA setting identified.05 higher (0. 12 and 24 months) in 24 months) in the (0.

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

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

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

at 12 and 24 months 12 3 3 randomised serious not serious not serious very seri..0%) 1/97 (1.. 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.Management of Thalassemia – Iron chela- tion therapy.0%) RR 0.31 7 fewer per 1000 (from 10 fewer to 60 ⨁◯◯ CRITICAL trials ous 4 (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. There were no differences in pain score LOW among the three studied groups. 30% [control group]) in the use of analgesic drugs was noted starting from the third month" .01 to more) ◯ 6. In contrast. no bisphospho.31 7 fewer per 1000 (from 10 fewer to 60 ⨁◯◯ CRITICAL trials ous 4 (0. none 0/110 (0.0%) RR 0. none 0/110 (0. [control group] patients had no change in bone pain during the study period.] at 12 months (P=0." Forni 2012: "The mean back pain scale value was significantly higher (more favourable) in [interven- tion group] compared with [control group] [.85) VERY LOW Back or bone pain .0%) 1/97 (1.85) VERY LOW Number of participants experiencing at least one non-vertebral fracture . Absolute Inconsistency Indirectness Imprecision bisphosphonates (95% studies design bias erations nates (95% CI) CI) Number of participants experiencing at least one vertebral fracture . Bisphosphonates and Zinc supplementation 74 Evidence Profile: Question 5: Should bisphosphonates versus no bisphosphonates be used for management of thalassemia-associated osteoporo- sis? Quality assessment № of patients Effect Relative Quality Importance № of Study Risk of Other consid.at 12 and 24 months 12 3 3 randomised serious not serious not serious very seri.002%).

at 12 and 24 months 11 12 13 14 15 3 randomised serious not serious not serious serious none 105 86 .05 higher) ◯ LOW Femoral neck BMD [g/cm²] (DXA): mean at endpoint . High risk of bias due to lack of blinding of participants and personnel (1 study). All included studies don't differentiate between vertebral and non-vertebral fractures 2.08 higher) ◯ LOW MD – mean difference.0%) RR 8. High risk of bias due to lack of blinding of participants and personnel. Unclear: Random sequence generation (1 study).0%) RR No absolute effect estimate given due to ⨁⨁◯ CRITICAL trials 10. MD 0. Data not pooled. from narrative information.02 higher to 0. High risk of bias due to lack of blinding of participants and personnel (2 studies).02 higher to 0.6%) 0/64 (0. Only few patients were included in studies 8.27 No absolute effect estimate given due to ⨁⨁◯ CRITICAL trial (0.05 higher ⨁⨁◯ IMPORTANT trials (0.72 0 events in control group ◯ (1. lack of blinding of outcome assessment (2 studies). lack of blinding of outcome assessment. lack of blinding of outcome assessment (2 studies). Unclear: Allocation concealment .Flu-like symptoms after first infusion neridronate 100 mg 10 9 1 randomised serious not serious not serious serious none 3/54 (5.Fever after first infusion zoledronic acid 4 mg 8 9 2 randomised serious not serious not serious serious none 15/56 (26. allocation concealment (2 studies) 4. Bisphosphonates and Zinc supplementation 75 Adverse events . lack of blinding of outcome assessment (3 studies). MD 0. Unclear: Random sequence generation (1 study).44 to 0 events in control group ◯ 156. Unclear: Random sequence generation (2 study).49 to LOW 76. High risk of bias due to lack of blinding of participants and personnel (2 studies). allocation concealment (2 studies) 6.96) Adverse events .8%) 0/33 (0. SD – standard deviation 1. RR – relative risk.70) LOW Lumbar spine BMD [g/cm²] (DXA): mean at endpoint .03 higher ⨁⨁◯ IMPORTANT trials (0. no obvious inconsistency present 7. However.Management of Thalassemia – Iron chela- tion therapy. therefore difficult to assess. allocation concealment (1 study) 9. who discontinued the trial at 6 months after a road traffic accident". Only very few cases 5. One study (Forni 2012) reported that "no fractures were observed during the study period except for the patient [intervention group]. Only few patients were included in study/studies 10.at 12 and 24 months 12 16 17 14 15 3 randomised serious not serious not serious serious none 105 86 . We didn't count fractures as events due to unclear causation 3.

82) to -3. Two studies included two intervention groups.082 in pa- tients treated with zoledronic acid. alendronate 10 mg p.034. for the intervention group.Management of Thalassemia – Iron chela- tion therapy. in Vos- karidou 2006 both groups (zoledronic acid 4 mg i. Pennisi P. Riccobene S. p comparing both groups was 0. An additional study (Pennisi 2003) reported a decreased T-score from -2. placebo-controlled trial. Fiore CE. in the intervention group. Gilfillan CP. et al.01). Lasco A.01). p comparing both groups was <0. absolute change was 0. 3. randomized. parallel-arm.16 (SD: 0. for the intervention group. A randomized. J Bone Miner Metab 2003. Gaudio A.01.65).71 (SD: 0.13) 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. Bisphosphonates and Zinc supplementation 76 11.13:644-9. Forni GL. et al. Unclear: Random sequence generation (2 stud- ies).042 in patients treated with zoledronic acid.) were included separately in our analysis.01). absolute change was 0.001.. Rodda CP. Spina M. Pizzarelli G. Perrotta S. no specific values were reported 12.008. 2. in Morabito 2002.93) in the control group (p<0. Calcif Tissue Int 2006. double-blind.o. 4. every 3 months. but the difference between intervention and control group was significant at 12 months (p < 0. Giusti A.m.79:138-44. Anagnostopoulos A.88) in the control group (p< 0. High risk of bias due to lack of blinding of participants and personnel (3 studies). every 6 months) were combined in one group (zoledronic acid 4 mg i.01).91:1193-202.v. An additional study (Gilfillan 2006) reported absolute change in femoral neck BMD at 2 years. absolute change from baseline was 0. absolute change was -0. Morabito N. zoledronic acid 4 mg i. et al. in the intervention group BMD at lumbar spine didn't change significantly at 12 months (p=0. Konstantopoulos K. in placebo group.21:402-8. no SD were mentioned 14. lack of blinding of outcome assessment (3 studies). Br J Haematol 2012. no spe- cific values were reported 17. Bisphosphonates in the treatment of thalassemia-induced osteoporosis. Only few patients included in studies 16.74) to -2. randomized. allocation concealment (3 studies) 15. both groups (clodronate 100 mg i. Haematologica 2006. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2. Strauss BJ.92 (SD: 0. Voskaridou E. BMD at femoral neck didn't change significantly at 12 months (p=0. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center. et al.v. in placebo group.44 (SD: 0. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. An additional study (Pennisi 2003) reported a decreased T-score from -1.v. every 3 or 6 months) 13. open-label study.158:274-82. Osteoporos Int 2002. no SD were mentioned References 1. 5. . placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia- associated osteopenia.

2 ○ Uncertain Is there a problem A screening of 6750 healthy persons in Jeddah. Treatment with iron chelators may cause zinc deficiency in thalassemia patients. 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. showed that 316 Problem priority? ● Probably yes (4. a 3. Besides. Zinc is required for the synthesis of somatomedins and it is therefore hy- zinc deficiency.4% (307/8918) beta-thalassemia trait prevalence in premarital couples living in the Al-Hassa area was observed.1 ○ Yes No prevalence studies were identified describing growth retardation or zinc deficiency in ○ Varies thalassaemic patients in KSA. 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. treatment with iron chelators may cause zinc deficiency. The prevalence of beta-thalassemia trait among neonates in the same area was 0. western Saudi Arabia.69%) had beta-thalassemia trait. pothesized that supplementation supports growth in thalassemic children and adolescents.Management of Thalassemia – Iron chela- tion therapy. Iron chelation therapy may cause ing anemia and different endocrinopathies.”6 ○ No ○ Probably no In 2004.7 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).

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

4 (range vention group was higher) for absolute values) 0.33 (z-score) deviations lower anticipated effects small? ● Probably yes (0.5 was 0.6 endpoint .63 .5-90 at 1-7 years 22. 9 30 mg zincsulfate months 30 mg lower months 30 mg and 18 months 25 zincsulfate and 18 (0. value [cm] or z- or z-score at score at endpoint at score at endpoint ○ Varies endpoint .6 higher higher) Are the desirable ○ Probably no (0. ● Uncertain tive to undesirable effects? ○ Probably yes Weight .65 lower to 1.5-90 mg zinc.3-143.Management of Thalassemia – Iron chela- tion therapy.22 lute value [kg] value [kg] or z. 9 SMD 0. value [kg] or z- ○ Yes or z-score at score at endpoint score at endpoint higher - (0.at 9 months 30 mg at 9 months 30 mg zincsulfate and 18 at 9 months 30 mg zincsulfate and 18 to 0. Weight (absolute Weight (absolute SMD 0.65 lower - ○ No zincsulfate control group was intervention group to 1.abso. Height (absolute Height (absolute ○ Yes lute value [cm] value [cm] or z.47 lower to 0.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.at 1.85 19.85 higher) effects large rela.47 lower - ○ No zincsulfate and mg zinc) in the months 25 mg to 0. 1-7 years 22.11 mg zinc.19 lower ○ Varies endpoint . 9 months 90 mg zinc.5- 7 years 22.11 standard Are the undesirable ○ Uncertain and -1.abso. Bisphosphonates and Zinc supplementation 79 large? ● Probably no supplements supplements (95% CI) (RR) (95% ○ Uncertain CI) ○ Probably yes Height .25 higher) ○ Yes ○ Varies Body mass Body mass index ( Body mass index ( index .at 3 months 220 mg months 220 mg higher months 220 mg zincsulfate) in the zincsulfate) in the (0.

63 higher) One study didn't observe significant differences in adverse events Adverse events when presented as percentage of all subject visits between placebo . 95% CI: 16. 220 mg zincsul.37 0.at 1-7 years and zinc groups including diarrhea.16 to 78.19 lower to 0.44) compared to no treat- 9 months 30 mg ment with zinc supplements (60 patients).Management of Thalassemia – Iron chela- tion therapy. "The most common reported side effect in the 9 months 30 mg study population was gastrointestinal disturbances which were seen zincsulfate in only 1-8% of subjects" (at 9 months 30 mg zincsulfate. MD 0.2 (ab. while dispensing 30 mg and 3 months zincsulfate (Gharhamanlu 2014) showed no difference (60 patients. vention group was solute value) 1.5-90 mg months 25 mg zinc.83 to 14. 18 months observed at the doses used in the study" (22. Costs are ○ Probably no likely to be low.60. 95% CI: -12. stomach upset and nausea (18 22. Ghah- ramanlu 2014) Serum zinc [ɥg/dl] .03) fate Haemoglobin No data available level No research evidence specific to KSA setting identified.mean 220 mg zincsulfate (Rashidi 2011) led to a significant higher serum at endpoint .at zinc (MD 47. Arasoy 1987).22 standard (z-score) deviations higher (0.5-90 mg zinc at 1-7 25 mg zinc and years. "No visible side effects have been zinc. No specific data on costs Resource use Are the resources ○ No of zinc supplements in KSA required small? setting found. 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 -35.30. Fung 2013). Monitoring .

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

No obvious barriers to ○ No implementation identified. Treatment with zinc sup- ○ No plements was assumed to be acceptable for govern- ○ Probably no ment and physicians due to no/little side effects and Is the option ac. ○ Uncertain low cost. 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.Management of Thalassemia – Iron chela- tion therapy. Bisphosphonates and Zinc supplementation 82 No research evidence specific to KSA setting identified. However. ○ Probably no ○ Uncertain Is the option feasi- Feasibility ble to implement? ● Probably yes ○ Yes ○ Varies . No research evidence specific to KSA setting identified.

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

Ghahramanlu 2014) Serum zinc [ɥg/dl] . none 30 30 . none 77 61 One study didn't observe significant differences in ⨁◯◯◯ CRITICAL trials ous 9 adverse events when presented as percentage of all VERY LOW subject visits between placebo and zinc groups includ- ing diarrhea.5-90 mg zinc. Arasoy 1987). 95% CI: 16.at 9 months 30 mg and 3 months 220 mg zincsulfate 10 11 2 randomised not not serious not serious very seri.63 higher) 7 LOW Adverse events . while dispensing 30 mg zincsulfate (Ghar- .5-90 mg zinc. SMD 0.11 lower ⨁◯◯◯ CRITICAL trials ous 3 (0.absolute value [cm] or z-score at endpoint .65 lower to 1.at 1-7 years 22.Management of Thalassemia – Iron chela- tion therapy.47 lower to 0.6 higher ⨁⨁◯◯ CRITICAL trial serious ous 3 (0.22 higher ⨁⨁◯◯ CRITICAL trials serious ous 3 (0.44) LOW compared to no treatment with zinc supplements (60 patients).25 higher) 4 VERY LOW Body mass index .19 lower to 0.absolute value [kg] or z-score at endpoint .16 to 78. no zinc Relative Absolute Inconsistency Indirectness Imprecision studies design bias erations plements supplements (95% CI) (95% CI) Height . "No visible side effects have been observed at the doses used in the study" (22.5-90 mg zinc at 1-7 years. 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. Fung 2013).mean [kg/m²] at endpoint . 18 months 25 mg zinc and 9 months 30 mg zincsulfate 2 8 3 randomised serious not serious not serious very seri.mean at endpoint . none 69 55 . "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. none 60 60 220 mg zincsulfate (Rashidi 2011) led to a significant ⨁⨁◯◯ IMPORTANT trials serious ous 3 higher serum zinc (MD 47. MD 0. SMD 0.30.at 9 months 30 mg zincsulfate and 18 months 25 mg zinc 6 2 randomised not not serious not serious very seri.85 higher) LOW Weight . none 48 44 . somach upset and nausea (18 months 25 mg zinc. zinc sup.at 3 months 220 mg zincsulfate 5 1 randomised not not serious not serious very seri. 9 months 30 mg zincsulfate and 18 months 25 mg zinc 1 2 3 randomised serious not serious not serious very seri.at 1-7 years 22.

et al. lack of blinding of participants and personnel (1 study). 4. Bisphosphonates and Zinc supplementation 85 hamanlu 2014) showed no difference (60 patients.21:8-14. Rashidi M. from narrative information no obvious inconsistency present 9. Cavdar A.2% respectively. Study was not included in meta-analysis due to significant baseline difference (p=0.71 (95%CI: -1. randomized. Cin S. BMI z-score increased from . therefore difficult to assess.66 (95% CI: -0.14 (95%CI: -0.007. Hematology 2014.24:127-36. et al.0. back-transformation using SD of both baseline values in Arcasoy 1987 yields an effect size of -2. . Mirhossini NZ. . not . 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". Keshtkar A.Management of Thalassemia – Iron chela- tion therapy. Iran J Pediatr 2011. Kwiatkowski JL. 0. Unclear: Al- location concealment (3 studies).not measured . MD 0. Aboomardani M. . Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalasse- mia major Patients. Joshaghani H. An additional trial (Fung 2013) reported BMI z-scores. RR – relative risk.51 to 0. . 2. no specific values were reported.36). Arefhosseini SR. IMPORTANT estimable MD – mean difference.025) 6.60. Effects of zinc supplementation on linear growth in beta-thalassemia (a new approach). placebo-controlled trial. Gildengorin G.37) to -0. however differences are likely related to doses References 1.0. in the intervention group. blinding of outcome assessment (1 study) 3. . Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of 2. Data not pooled because of different doses. Vichinsky EP. However. in placebo group. High risk due to lack of random sequence generation (1 study). SD – standard deviation 1.70 cm. Arcasoy A.95 to -0. another study (Fung 2013) reported that "Plasma zinc increased by 14.18 cm 5.83 to 14. Rafraf M. Banihashem A. Absolute value from one study and z-score from one study were included 7. 3. lack of blinding of outcome assessment (1 study). .56. Ghahramanlu E.28). BMI z-score increased from -0. Am J Clin Nutr 2013. Only very few cases 10. 95% CI: -12. no additional values were reported 11. Data not pooled. although it did not change with time in the placebo group". King JC. .03) Haemoglobin level .16 (95% CI: . Am J Hematol 1987.98:960-71. if pooled meta-analysis showed high I²=86% and p = 0. blinding of participants and personnel (1 study). Only very few patients included in study/studies 4.06 to -0.7% and 15.19:113-9. 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. at 3 and 6 months in the zinc group. . Fung EB. Huang JN.4 kg 8. Back-transformation of SMD using mean baseline SD of both groups in Ghahramanlu 2014 yields an effect size of -1. Absolute value from two studies and z-score from one study were included 2.19) to -0.

(17291) 3 (cooley* and (anemi* or anaemi*)).tw. [mp=title. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). unique identifier] (662) 16 (icl adj 670*). deferiprone.mp.tw. (400) 4 ((hemoglobin or haemoglobin) adj3 disease). (9136) 10 or/1-9 (39162) 11 exp Iron Chelating Agents/ (19063) 12 Chelation Therapy/ (1152) 13 (deferoxamine* or deferoximine* or deferrioxamine* or desferioximine* or desferrioxamine* or desferrox- amine* or desferal* or desferral* or desferin* or desferol* or DFO or dfom).mp.tw. [mp=title. unique iden- tifier] (0) 18 or/11-17 (66801) 19 10 and 18 (3265) 20 limit 19 to yr="2013 -Current" (268) 21 limit 19 to ed=20130301-20141003 (248) 22 20 or 21 (299) 23 limit 22 to "therapy (maximizes sensitivity)" (193) Records Retrieved 193 Data base: Embase <1974 to 2014 October 07> Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (25389) 2 (thalassemi* or thalassaemi*).tw. (7420) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). (45370) 15 (exjade* or deferasirox*). original title. (10968) 10 or/1-9 (46063) .Management of Thalassemia – Iron chela- tion therapy.mp. subject heading word. keyword heading word. (1585) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). subject heading word. subject heading word.tw. (9979) 9 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis). abstract. name of substance word. abstract.tw.tw. name of substance word. name of substance 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*). (435) 4 ((hemoglobin or haemoglobin) adj3 disease).mp.tw. protocol supplementary concept word. (21563) 3 (cooley* and (anemi* or anaemi*)). deferasirox) for iron overload in thalassemia pa- tients Database: Ovid MEDLINE In-Process & Other Non-Indexed Citations.tw. (146) 6 or/1-5 (28859) 7 exp Iron Overload/ (10091) 8 (iron adj3 overload*). (8833) 14 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp). keyword heading word.tw. (162) 6 or/1-5 (24197) 7 exp Iron Overload/ (11956) 8 (iron adj3 overload*).tw. rare disease supplementary concept word.tw. rare disease supplementary concept word.) Interventions (deferoxamine. protocol supplementary concept word. [mp=title. abstract. key- word heading word. protocol supplementary concept word.mp. original title. unique identifier] (4) 17 (cgp adj "72670"). rare disease supplementary concept word. Bisphosphonates and Zinc supplementation 86 Appendix 2: Search Strategies and Results 1. original title.

original title. keyword] (187) 15 (cgp adj "72670"). drug manufacturer. device manufacturer. [mp=title. in Trials 33 Records Retrieved 33 .mp. [mp=title. device trade name. device manufacturer. keyword] (7) 16 iron chelation/ (4597) 17 iron chelating agent/ (2758) 18 chelation therapy/ (2788) 19 deferoxamine/ (11125) 20 deferoxamine mesylate/ (2080) 21 deferasirox/ (1920) 22 deferiprone/ (2173) 23 (iron adj5 (chelat* or reduc*)). drug manufacturer. device trade name. device manufacturer. original title. Bisphosphonates and Zinc supplementation 87 11 (deferoxamine* or deferoximine* or deferrioxamine* or desferioximine* or desferrioxamine* or desferrox- amine* or desferal* or desferral* or desferin* or desferol* or DFO or dfom).mp.mp.tw. [mp=title. subject headings. heading word. drug trade name. original title. heading word. abstract. drug manufacturer. (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. abstract. abstract. subject headings. drug trade name. subject headings. (49133) 13 (exjade* or deferasirox*). drug trade name. device trade name.Management of Thalassemia – Iron chela- tion therapy.mp.mp. heading word. (13924) 12 (deferiprone or L1* or kelfer or DMHP or ferriprox or cp20 or dmohpo or (hdmpp adj cpd) or hdpp). keyword] (1970) 14 (icl adj 670*).

Excluded: 308 Included for Full Text 7 review: Selection (Full Text Review) No.tw. No control group 4. (146) 6 or/1-5 (28859) 7 exp bisphosphonic acid derivative/ (46599) 8 bisphosphonate*.mp.Management of Thalassemia – Iron chela- tion therapy.tw. (17291) 3 (cooley* and (anemi* or anaemi*)).tw. (435) 4 ((hemoglobin or haemoglobin) adj3 disease). (1585) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). Comment 2.tw. Retrieved: 434 MEDLINE 193 Embase 208 CENTRAL 33 Duplicates: 119 No. (162) 6 or/1-5 (24197) 7 exp Diphosphonates/ (21267) 8 bisphosphonate*. (400) 4 ((hemoglobin or haemoglobin) adj3 disease). Observational study 3.) Bisphosphonates for thalassemia Data base: Ovid MEDLINE In-Process & Other Non-Indexed Citations. Excluded: 4 Reasons for exclusions: 1.tw. Broken randomisation 2. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). Ovid MEDLINE Daily and Ovid MEDLINE 1946 to Present Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (19716) 2 (thalassemi* or thalassaemi*). (12141) 9 exp Bone Density Conservation Agents/ (101021) 10 or/7-9 (107598) 11 6 and 10 (105) 12 limit 11 to yr="2012 -Current" (17) Records Retrieved 17 Data base: Embase <1974 to 2014 October 07> Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (25389) 2 (thalassemi* or thalassaemi*).tw. (17815) 9 7 or 8 (47829) . Bisphosphonates and Zinc supplementation 88 Summary of Searches: Total No.mp.tw. (21563) 3 (cooley* and (anemi* or anaemi*)). Total without 315 duplicates Screening (Title and Abstract Review) No.tw.

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

(109880) 8 6 and 7 (185) 9 limit 8 to yr="2013 -Current" (11) Records Retrieved 11 Data base: Embase <1974 to 2014 October 07> Search strategy: Date of search: 10/2014 1 exp Thalassemia/ (25389) 2 (thalassemi* or thalassaemi*).tw. (1864) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). (21563) 3 (cooley* and (anemi* or anaemi*)). Bisphosphonates and Zinc supplementation 90 4 ((hemoglobin or haemoglobin) adj3 disease).mp.tw. in Trials 4 Records Retrieved 4 Summary of Searches: Total No.tw.tw. (146) 6 or/1-5 (28859) 7 zinc. 31 trieved: Medline 11 Embase 16 CENTRAL 4 Duplicates: 7 .mp. Re. 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.tw.Management of Thalassemia – Iron chela- tion therapy. (1585) 5 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)). (162) 6 or/1-5 (24197) 7 Zinc/ or zinc.tw. (435) 4 ((hemoglobin or haemoglobin) adj3 disease).

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

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

mp. 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*). Total 180 without duplicates . or exp "quality of life"/ (29337) 14 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp.mp. or exp client participation/ (1533) 9 client$ satisfaction.mp. Re.in.in. (64) 6 (hemochromatosis or haemochromatosis or hemosiderosis or haemosiderosis).in.mp. (19) 4 ((mediterranean or erythroblastic) adj (anemi* or anaemi*)).in.in.mp.tw. (160) 2 (cooley* and (anemi* or anaemi*)).mp.in.Management of Thalassemia – Iron chela- tion therapy.mp.in.tw.mp. or Syria/ (16149) 38 Iraq$/ or Iraq.mp. or Egypt/ (69210) 37 Syria$. (8296) 12 (patient$ utilit$ or health utilit$).mp. (254818) 45 Algeria$.tw. 204 trieved MEDLINE 94 Embase 93 PsycInfo 17 Duplicates: 24 No.mp. (77) 7 or/1-6 (294) 8 client$ participation. or Morocco/ (18553) 40 Tunisia$. or Tunisia/ (25085) 41 Leban$. or Algeria/ (7980) 46 Arab$. (0) 5 iron overload.tw. or Iran/ (111023) 44 Turkey/ or (Turkey or Turkish).mp.in.mp. (1105) 43 Iran$.tw. (527) 13 health related quality of life. or Lebanon/ (27069) 42 West Bank.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$")). (10462) 39 Morocc$.mp. (4704) 16 or/8-15 (54515) 17 7 and 16 (17) Records Retrieved 17 Summary of Searches: Total No.mp.mp.in. (1) 3 ((hemoglobin or haemoglobin) adj3 disease).mp.in. or Libya/ (3001) 36 Egypt$. or exp client satisfaction/ (5022) 10 exp Health Attitudes/ (7993) 11 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$ or patient$ attitude$).in. Bisphosphonates and Zinc supplementation 93 35 Libya$.mp.in.

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

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

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