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Intervenciones para la hemocromatosis hereditaria

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References

Referencias de los estudios incluidos en esta revisión

Rombout‐Sestrienkova 2012 {published data only}

Rombout‐Sestrienkova E, Nieman FH, Essers BA, Noord PA, Janssen MC, Deursen CT, et al. Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial. Transfusion 2012;52(3):470‐7. CENTRAL
Rombout‐Sestrienkova E, Noord P, Reuser E, Heeremans J, Deursen C, Janssen M, et al. Therapeutic erythrocytapheresis (TE) versus phlebotomy (P) in the treatment of hereditary hemochromatosis (HH) patients: preliminary results from an ongoing randomized clinical trial (NCT 00202436). Transfusion and Apheresis Science 2009;40(2):135‐6. CENTRAL

Rombout‐Sestrienkova 2016 {published data only}

Rombout‐Sestrienkova E, Winkens B, Essers BA, Nieman FH, Noord PA, Janssen MC, et al. Erythrocytapheresis versus phlebotomy in the maintenance treatment of HFE hemochromatosis patients: results from a randomized crossover trial. Transfusion 2016;56(1):261‐70. CENTRAL

Sundic 2014 {published data only}

Sundic T, Hervig T, Hannisdal S, Assmus J, Ulvik RJ, Olaussen RW, et al. Erythrocytapheresis compared with whole blood phlebotomy for the treatment of hereditary haemochromatosis. Blood Transfusion 2014;12(Suppl 1):S84‐9. CENTRAL

Referencias de los estudios en curso

Ong 2015 {published data only}

Ong SY, Dolling L, Dixon JL, Nicoll AJ, Gurrin LC, Wolthuizen M, et al. Should HFE p.C282y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi‐iron). BMJ Open 2015;5(8):e008938. CENTRAL

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Rombout‐Sestrienkova 2012

Methods

Randomised clinical trial.

Participants

Country: Netherlands.

Number randomised: 38.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 38.

Mean age: 52 years.

Number of women: 10 (26.3%).

Symptomatic: not stated.

Asymptomatic: not stated.

Mean follow‐up period: 8 months.

Target used for iron reduction: serum ferritin ≤ 50 μg/L.

Inclusion criteria:

  • Homozygosis for C282Y.

  • Participants treatment naive.

  • Aged 18 to 80 years.

  • Weight ≥ 50 kg.

  • Transferrin saturation > 50%.

  • Serum ferritin > 450 mg/L.

  • Haemoglobin concentration ≥ 7.5 mmol/L (120 g/L) in women and ≥ 8.0 mmol/L (128 g/L) in men.

Exclusion criteria:

  • Malignancy.

  • Serious cardiac arrhythmias.

  • Heart failure.

  • Epilepsy.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: therapeutic erythrocytapheresis (n = 19).

Further details: 350 mL to 800 mL of red blood cells once every 2 weeks.

Group 2: phlebotomy (n = 19).

Further details: 500 mL of whole blood once weekly.

Treatment duration: variable depending upon the iron to be removed.

Outcomes

Mortality, adverse events, and health‐related quality of life.

Notes

We attempted to contact the corresponding author to obtain additional information on risk of bias and outcomes in June 2015. We did not receive any reply.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomly assigned in a 1:1 ratio by an independent person working as quality assurance manager".

Allocation concealment (selection bias)

Low risk

Quote: "patients were randomly assigned in a 1:1 ratio by an independent person working as quality assurance manager".

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "single‐blind".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "single‐blind".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: there were no post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: all important outcomes were reported.

For‐profit bias

Low risk

Quote: "This work was performed with the support of the Sanquin Blood Bank grants 03‐006".

Other bias

Low risk

Comment: no other risk of bias.

Rombout‐Sestrienkova 2016

Methods

Randomised clinical trial.

Participants

Country: Netherlands.

Number randomised: 53.

Post‐randomisation dropouts: 7 (13.2%).

Revised sample size: 46.

Mean age: 55 years.

Number of women: not stated.

Symptomatic: not stated.

Asymptomatic: not stated.

Mean follow‐up period: 1 year (after this there was cross‐over).

Target used for iron reduction: serum ferritin ≤ 50 μg/L.

Inclusion criteria:

  • Homozygous for C282Y mutation.

  • Aged ≥ 18 years.

  • Weight ≥ 50 kg.

  • Currently treated in hospital setting with maintenance phlebotomy therapy for ≥ 6 months.

  • Signed informed consent.

  • Willingness to fill out additional questionnaires at 3 points in time.

Exclusion criteria:

  • Excessive overweight (body mass index > 35 kg/m2).

  • Chelating therapy.

  • Forced dietary regimen.

  • Pregnancy.

  • Malignancy.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: therapeutic erythrocytapheresis (n = 20).

Further details: 350 mL to 800 mL red blood cells; variable frequency depending on serum ferritin level.

Group 2: phlebotomy (n = 26).

Further details: 500 mL per single treatment; variable frequency depending on serum ferritin level.

Treatment duration: 1 year.

Outcomes

None of our outcomes of interest were reported at the end of the first treatment.

Notes

Reasons for post‐randomisation dropouts: not stated clearly.

We attempted to contact the corresponding author in June 2015 to obtain additional information on risk of bias and outcomes. We did not receive any reply.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: this information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: this information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: probably not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Comment: probably not blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: important outcomes such as mortality and complications were not reported.

For‐profit bias

Unclear risk

Comment: this information was not available.

Other bias

Low risk

Comment: no other risk of bias.

Sundic 2014

Methods

Randomised clinical trial.

Participants

Country: Norway.

Number randomised: 62.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 62.

Mean age: 42 years.

Number of women: 6 (9.7%).

Symptomatic: not stated.

Asymptomatic: not stated.

Mean follow‐up period (for all groups): 3 months.

Target used for iron reduction: serum ferritin ≤ 50 μg/L.

Inclusion criteria:

  • Aged ≥ 18 years.

  • No previous treatment for haemochromatosis.

  • Diagnosis of haemochromatosis, defined as: presence of a homozygous genotype for C282Y or H63D or compound heterozygous genotype for C282Y and H63D and serum ferritin > 300 ng/mL or a transferrin saturation > 50% OR heterozygous C282Y genotype and ferritin levels > 500 ng/mL or transferrin saturation > 50%.

Exclusion criteria:

  • Atypical haemochromatosis without any documented genetic aberration or exclusively due to mutations other than C282Y and H63D.

  • Bodyweight < 65 kg.

  • Initial haemoglobin level < 13.5 g/dL.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: therapeutic erythrocytapheresis (n = 30).

Further details: 400 mL per single treatment bi‐weekly*.

Group 2: phlebotomy (n = 32).

Further details: 450 mL per single treatment weekly.

Treatment duration: 12 weeks.

Outcomes

Adverse events.

Notes

We attempted to contact the corresponding author in June 2015 to obtain additional information on risk of bias and outcomes. We did not receive any reply.

* It was unclear whether the authors meant 'bi‐weekly' to be once every two weeks or twice weekly.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomisation procedure was centralised to one of the participating centres, using a randomly generated sequence".

Allocation concealment (selection bias)

Unclear risk

Comment: this information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "different treatment".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: this information was not available.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: there were 6 dropouts/withdrawal but data regarding tolerance reported.

Selective reporting (reporting bias)

High risk

Comment: no data about mortality but just tolerability.

For‐profit bias

Low risk

Quote: "Grants from Helse Vest RHF and Helse Fonna HF (public hospital trusts)".

Other bias

Low risk

Comment: no other risk of bias.

Characteristics of ongoing studies [ordered by study ID]

Jump to:

Ong 2015

Trial name or title

Mi‐iron

Methods

Randomised clinical trial

Participants

Inclusion criteria:

  • Aged 18 to 70 years.

  • HFE p.C282Y homozygous.

  • Serum ferritin between 300 μg/L and 1000 μg/L.

  • Previously or currently raised transferrin saturation.

Exclusion criteria:

  • Hereditary haemochromatosis due to other genotypes.

  • Venesection in the past 2 years for treatment of hereditary haemochromatosis.

  • Other risk factor(s) for liver injury including hepatitis B or C, excess alcohol consumption (> 60 g/day in men, 40 g/day in women), body mass index ≥ 35 kg/m2.

  • Pregnant women.

Interventions

Erythrocytapheresis versus plasmapheresis

Outcomes

Modified Fatigue Impact Scale

Medical Outcomes Study 36‐item short form V.2

Hospital Anxiety and Depression Scale

Arthritis Impact Measurement Scales 2 short form

Starting date

June 2012

Contact information

Martin Delatycki ([email protected])

Notes

HFE = human haemochromatosis protein.

Data and analyses

Open in table viewer
Comparison 1. Therapeutic erythrocytapheresis versus phlebotomy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse events (proportion) Show forest plot

2

100

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.36, 2.43]

Analysis 1.1

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 1 Adverse events (proportion).

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 1 Adverse events (proportion).

2 Adverse events (number) Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Totals not selected

Analysis 1.2

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 2 Adverse events (number).

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 2 Adverse events (number).

3 Health‐related quality of life (EQ‐VAS) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 1.3

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 3 Health‐related quality of life (EQ‐VAS).

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 3 Health‐related quality of life (EQ‐VAS).

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Trial Sequential Analysis of adverse events (proportion) performed using an alpha error of 2.5%, power of 90% (beta error of 10%), relative risk reduction of 20%, control group proportion (Pc) observed in trials (21.6% for proportion of people with adverse events), and observed diversity (0%) shows that the accrued sample size was only a small fraction of the diversity‐adjusted required information size (DARIS) that the boundaries could not be drawn. The Z‐curve (blue line) does not cross the conventional boundaries (dotted green line). There was a high risk of random errors.
Figures and Tables -
Figure 4

Trial Sequential Analysis of adverse events (proportion) performed using an alpha error of 2.5%, power of 90% (beta error of 10%), relative risk reduction of 20%, control group proportion (Pc) observed in trials (21.6% for proportion of people with adverse events), and observed diversity (0%) shows that the accrued sample size was only a small fraction of the diversity‐adjusted required information size (DARIS) that the boundaries could not be drawn. The Z‐curve (blue line) does not cross the conventional boundaries (dotted green line). There was a high risk of random errors.

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 1 Adverse events (proportion).
Figures and Tables -
Analysis 1.1

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 1 Adverse events (proportion).

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 2 Adverse events (number).
Figures and Tables -
Analysis 1.2

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 2 Adverse events (number).

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 3 Health‐related quality of life (EQ‐VAS).
Figures and Tables -
Analysis 1.3

Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 3 Health‐related quality of life (EQ‐VAS).

Summary of findings for the main comparison. Erythrocytapheresis versus phlebotomy for hereditary haemochromatosis

Erythrocytapheresis versus phlebotomy for hereditary haemochromatosis

Patient or population: people with hereditary haemochromatosis
Settings: secondary or tertiary
Intervention: erythrocytapheresis
Comparison: phlebotomy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Phlebotomy

Therapeutic erythrocytapheresis

Long‐term mortality

None of the included trials reported mortality beyond 1 year.

Mortality

Follow‐up period: 8 months

There was no mortality in either group in the short‐term in the 1 trial that reported this information.

38
(1 study)

⊕⊝⊝⊝
Very low1,2

Serious adverse events

Follow‐up period: 8 months

There were no serious adverse events in either group in the 1 trial that reported this information.

38
(1 study)

⊕⊝⊝⊝
Very low1,2

Health‐related quality of life
EQ‐VAS. Scale from: 0 to 100.

Follow‐up period: 8 months

The mean health‐related quality of life in the control groups was
68

The mean health‐related quality of life in the intervention groups was
1 higher
(10.8 lower to 12.8 higher)

38
(1 study)

⊕⊝⊝⊝
Very low1,2

Health‐related quality of life beyond one year

None of the included trials reported health‐related quality of life beyond one year

*The basis for the assumed risk is the mean control group proportion or control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

1 Downgraded one level for risk of bias.
2 Downgraded two levels for imprecision (one level for small sample size and one level for wide confidence intervals).

Figures and Tables -
Summary of findings for the main comparison. Erythrocytapheresis versus phlebotomy for hereditary haemochromatosis
Comparison 1. Therapeutic erythrocytapheresis versus phlebotomy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse events (proportion) Show forest plot

2

100

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.36, 2.43]

2 Adverse events (number) Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Totals not selected

3 Health‐related quality of life (EQ‐VAS) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 1. Therapeutic erythrocytapheresis versus phlebotomy