Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion‐dependent thalassaemia

David Roberts; David Rees; Jo Howard; Chris Hyde; Susan Brunskill

doi:10.1002/14651858.CD004450.pub2

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Analysis 1.1

Comparison 1 Desferrioxamine versus placebo, Outcome 1 Death.

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Analysis 1.2

Comparison 1 Desferrioxamine versus placebo, Outcome 2 Liver iron concentration.

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Analysis 2.1

Comparison 2 Desferrioxamine versus deferiprone, Outcome 1 Serum ferritin concentration (microg/ml).

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Analysis 2.2

Comparison 2 Desferrioxamine versus deferiprone, Outcome 2 Urinary iron excretion: mg/24 hours.

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Analysis 2.3

Comparison 2 Desferrioxamine versus deferiprone, Outcome 3 Urinary iron excretion: mg/24hrs.

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Analysis 2.4

Comparison 2 Desferrioxamine versus deferiprone, Outcome 4 Liver iron concentration.

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Analysis 2.5

Comparison 2 Desferrioxamine versus deferiprone, Outcome 5 Adverse events.

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Analysis 3.1

Comparison 3 Desferrioxamine versus desferrioxamine and deferiprone, Outcome 1 Serum ferritin concentration (Gomber: microg/ml, Mourad mg/l).

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Analysis 3.2

Comparison 3 Desferrioxamine versus desferrioxamine and deferiprone, Outcome 2 Urinary iron excretion: mg/24hrs.

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Table 1. Individual study data (mean +/‐ standard deviation): measures of iron overload

Trial details	Intervention	Serum ferritin:start	Serum ferritin: 6mth	Serum ferritin:12mth	Urinary iron: start	Urinary iron: end	Liver iron: start	Liver iron: end
Olivieri 1990	DFO	Not measured	Not measured	Not measured	Not measured	18.2 +/‐ 15.3 mg/kg/day	Not measured	Not measured
Olivieri 1990	Deferiprone	Not measured	Not measured	Not measured	Not measured	12.3 +/‐ 6.7 mg/kg/day	Not measured	Not measured
Borgna‐Pignatti 1997	DFO (bolus)	Not measured	Not measured	Not measured	Not measured	36.4 +/‐ 22.9 mg/kg/48 h	Not measured	Not measured
Borgna‐Pignatti 1997	DFO (continuous infusion)	Not measured	Not measured	Not measured	Not measured	36.5 +/‐ 23.1 mg/kg/48 h	Not measured	Not measured
Olivieri 1997	DFO	Not measured	Not measured	Not measured	Not measured	Not measured	6.9 +/‐ 3.82 mg/g dry liver	7.9 +/‐ 5.52 mg/g dry liver
Olivieri 1997	Deferiprone	Not measured	Not measured	Not measured	Not measured	Not measured	8.9 +/‐ 5.23 mg/g dry liver	13.7 +/‐ 5.23 mg/g dry liver
Maggio 2002	DFO	2019 +/‐ 678 ng/ml	Not measured	1787 +/‐ 893 ng/ml	15.7 +/‐ 12.8 mg/24 h	19.9 +/‐ 13.6 mg/24 h	3516 +/‐ 2974 microg/g/dry weight	3166 +/‐ 2519 microg/g/dry weight
Maggio 2002	Deferiprone	2283 +/‐ 754 ng/ml	Not measured	2061 +/‐ 853 ng/ml	11.4 +/‐ 8.3 mg/24 h	15.8 +/‐ 10.9 mg/24 h	3363 +/‐ 5490 microg/g/dry weight	2341 +/‐ 2197 microg/g/dry weight
Mourad 2003	DFO	5506 +/‐ 2375 microg/l	4856 +/‐ 2615 microg/l	3998 +/‐ 2409 microg/l	Not measured	Not measured	Not measured	Not measured
Mourad 2003	DFO + deferiprone	4153 +/‐ 1715 microg/l	3005+/‐ 1303 microg/l	2805 +/‐ 1084 microg/l	Not measured	22.9 +/‐ 19.2 mg/kg/24 h	Not measured	Not measured
Gomber 2004	DFO	5077 +/‐ 1715 ng/ml	3718 +/‐ 738 ng/ml	Not measured	Not measured	7.96 +/‐ 15.97 mg/day	Not measured	Not measured
Gomber 2004	Deferiprone	3348+/‐ 1526 ng/ml	3423 +/‐ 1581 ng/ml	Not measured	Not measured	4.78 +/‐ 6.70 mg/day	Not measured	Not measured
Gomber 2004	DFO + deferiprone	2673 +/‐ 886 ng/ml	3377 +/‐ 1222 ng/ml	Not measured	Not measured	7.14 +/‐ 15.78 mg/day	Not measured	Not measured

Footnotes ‐ DFO: desferrioxamine; mth: months

Table 1. Individual study data (mean +/‐ standard deviation): measures of iron overload

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Table 2. Methodological quality assessment criteria

Quality of methods	Adequate (A)	Unclear (B)	Inadequate (C)
Generation of random sequence.	If resulting sequences are unpredictable: computer‐generated random numbers; table of random numbers; drawing lots or envelopes; coin tossing; shuffling cards; throwing dice.	If generation of allocation sequence is not reported.	If resulting sequences are predictable: according to case record number; date of birth; date of admission or alteration.
Concealment treatment allocation.	If participants and enrolling investigators cannot foresee assignment: a priori numbered or coded drug; containers prepared by an independent pharmacy; central randomisation; sequentially numbered, sealed, opaque envelopes.	If concealment of allocation is not reported or does not fit in categories A or C.	If participants and enrolling investigators can foresee upcoming assignment: all procedures based on inadequate generation of allocation sequences; open allocation schedule; unsealed or non‐opaque envelopes.
Blinding to treatment allocation.	If the clinician/participant/outcome assessor is unaware of which treatment schedule the participant has been allocated to.	If there is information to state whether the clinician/participant/outcome assessor is blinded to the treatment allocation.	If the clinician/participant/outcome assessor is aware, or the method of concealment of treatment allocation schedule is not adequate to blind the clinician/participant/outcome assessor to the treatment allocated to the participant.

Table 2. Methodological quality assessment criteria

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Table 3. Methodological quality of included studies

Trial	Randomisation	Allocation concealed	Blind assessment	Randomised Int/Comp	Analysed int/comp	Power calculation	Baseline variables
Barry 1974	Unclear	Unclear	Unclear	10/10	9 /9	Not stated	Age (mean and range per treatment arm); exposure to red blood cell transfusion in year before and during trial; type of thalassaemia
Graziano 1978	Unclear	Unclear	Unclear	19/19	Not stated/not stated	Not stated	Age (range); type of thalassaemia
Olivieri 1990	Unclear	Unclear	Unclear	Cross‐over trial: 20 in total: 10 to each arm	Cross‐over trial: 20 in total: 10 in each arm	Not stated	Age (mean and range); prior exposure to DFO; type of thalassaemia
Borgna‐Pignatti 1997	Inadequate: alternation method	Inadequate: alternation	Unclear	Cross‐over trial: 20 in total: 10 to each arm	Cross‐over trial: 20 in total: 10 in each arm	Not stated	Age (median and range); prior exposure to DFO; type of thalassaemia
Olivieri 1997	Unclear	Unclear	Unclear	Not stated/not stated	19/19	Not stated	Type of thalassaemia
Maggio 2002	Adequate: computer generated random list in permuted blocks of 10	Adequate: randomisation list generated and maintained at a site external to the study site	Participants and clinicians not blinded. Outcome assessors blinded to treatment allocation	73/71	73/71	Stated and documented	Age (mean per treatment group); exposure to red blood cell transfusion in year before and during trial; prior exposure to DFO; type of thalassaemia
Mourad 2003	Unclear	Unclear	Unclear	not stated/not stated	14/11	Not stated	Age (range); exposure to red blood cells transfused during the study; prior exposure to DFO, type of thalassaemia
Gomber 2004	Unclear	Unclear	Unclear	10/10/10	7/11/10	Not stated	Type of thalassaemia

Footnotes ‐ Comp: comparator; Int: intervention

Table 3. Methodological quality of included studies

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Table 4. Liver iron concentration: baseline and end of trial values

Trial	No. DFO/deferiprone	Technique	DFO: baseline	DFO: end of trial	Deferiprone:baseline	Deferiprone:eos
Olivieri 1997	18/19	Magnetic suspectrometry (SQUID)	6.90 mg/g (SD 3.81)	7.90 mg/g (SD 5.52)	8.90 mg/g (SD 5.23)	3.70 mg/g (SD 5.23)
Maggio 2002	15/21	Atomic spectophotometry	3516 microg/g (SD 2.974)	3166 microg/g (SD 2519)	3363 microg/g (SD 5490)	2341 microg/g (SD 2197)

Footnotes ‐ eos: end of study; SD: standard deviation

Table 4. Liver iron concentration: baseline and end of trial values

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Table 5. Adverse events

Trial name	AE's in treatment gp	AE's in control gp
Maggio 2002	Pain/erythema at injection site (6), ototoxicity (2), infection (2), hypertransaminasemia (1)	Hypertransaminasemia (16), nausea (3), leukocytopenia (2), mild joint pain (1), infection (1)
Mourad 2003	Problems at site of injection (12/14)	Nausea (5/11), joint pain/swelling/stiffness (3/11)
Gomber 2004	Desferrioxamine: none recorded	Deferiprone: arthroplasty of knee joints (2)
AE: adverse events gp: group

Table 5. Adverse events

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Table 6. Relative cost of deferiprone treatment (participant = 10 kg): Gomber 2004

Variables	Gp1: DFO	Gp2: Deferiprone	Gp3: DFO+deferiprone
Cost of drug	180 = Rs.150 for vial of 500 mg + Rs. 30 for needle and syringe	Rs. 18 = Rs. 6 per capsule of 250 mg, 3 capsules daily	Rs. 198
Cost of treatment per week	Rs. 900	Rs. 126	Rs. 486
Cost of treatment for 6 months	Rs. 21600	Rs. 3024	Rs. 11664
Rs: Rupees

Table 6. Relative cost of deferiprone treatment (participant = 10 kg): Gomber 2004

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Comparison 1. Desferrioxamine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 At 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Liver iron concentration Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 At 6 years	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Desferrioxamine versus placebo

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Comparison 2. Desferrioxamine versus deferiprone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum ferritin concentration (microg/ml) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 At 12 months	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Urinary iron excretion: mg/24 hours Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 At 12 months	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Urinary iron excretion: mg/24hrs Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1 Early after starting treatment	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Liver iron concentration Show forest plot	2		Ratio of GM (Fixed, 95% CI)	Subtotals only

4.1 At 31‐36 months	2		Ratio of GM (Fixed, 95% CI)	0.70 [0.53, 0.93]
5 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Desferrioxamine versus deferiprone

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Comparison 3. Desferrioxamine versus desferrioxamine and deferiprone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum ferritin concentration (Gomber: microg/ml, Mourad mg/l) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 At 6 months	2	43	Mean Difference (IV, Fixed, 95% CI)	0.72 [‐0.07, 1.50]
1.2 At 12 months	1	25	Mean Difference (IV, Fixed, 95% CI)	1.19 [‐0.22, 2.60]
2 Urinary iron excretion: mg/24hrs Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 Early after starting treatment	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Desferrioxamine versus desferrioxamine and deferiprone

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