Interventions for hereditary haemochromatosis

Elena Buzzetti; Maria Kalafateli; Douglas Thorburn; Brian R Davidson; Emmanuel Tsochatzis; Kurinchi Selvan Gurusamy

doi:10.1002/14651858.CD011647.pub2

Intervenciones para la hemocromatosis hereditaria

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Referencias

Referencias de los estudios incluidos en esta revisión

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estudios en curso
otras referencias

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.

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.

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.

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.

Referencias de los estudios en curso

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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.

Referencias adicionales

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Adams PC, Barton JC. Haemochromatosis. Lancet 2007;370(9602):1855‐60.

Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron‐overload‐related disease in HFE hereditary hemochromatosis. New England Journal of Medicine 2008;358(3):221‐30.

Assi TB, Baz E. Current applications of therapeutic phlebotomy. Blood Transfusion 2014;12(Suppl 1):s75‐83.

Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.) 2011;54(1):328‐43.

Bardou‐Jacquet E, Brissot P. Diagnostic evaluation of hereditary hemochromatosis (HFE and non‐HFE). Hematology/Oncology Clinics of North America 2014;28(4):625‐35.

Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G → A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359(9302):211‐8.

Bradley LA, Haddow JE, Palomaki GE. Population screening for haemochromatosis: a unifying analysis of published intervention trials. Journal of Medical Screening 1996;3(4):178‐84.

Cancado R, Melo MR, de Moraes Bastos R, Santos PC, Guerra‐Shinohara EM, Ballas SK, et al. Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1‐year Phase 2 study. European Journal of Haematology 2015;95(6):545‐50.

Cassanelli S, Pignatti E, Montosi G, Garuti C, Mariano M, Campioli D, et al. Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy. Journal of Hepatology 2001;34(4):523‐8.

Chaimani A, Salanti G. Using network meta‐analysis to evaluate the existence of small‐study effects in a network of interventions. Research Synthesis Methods 2012;3(2):161‐76.

Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta‐analysis in STATA. PloS one 2013;8(10):e76654.

Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza‐Jeric K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Annals of Internal Medicine 2013;158(3):200‐7.

de Graaff B, Neil A, Sanderson K, Si L, Yee KC, Palmer AJ. A systematic review and narrative synthesis of health economic studies conducted for hereditary haemochromatosis. Applied Health Economics and Health Policy 2015;13(5):469‐83.

Del Re AC, Spielmans GI, Flückiger C, Wampold BE. Efficacy of new generation antidepressants: differences seem illusory. PLoS One 2013;8(6):e63509.

DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341‐50.

DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐88.

Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta‐analysis. Statistics in Medicine 2010;29(7‐8):932‐44.

Dias S, Sutton AJ, Welton NJ, Ades AE. NICE DSU Technical Support Document 3: heterogeneity: subgroups, meta‐regression, bias and bias‐adjustment, September 2011 (last updated April 2012). www.nicedsu.org.uk/TSD3%20Heterogeneity.final%20report.08.05.12.pdf (accessed 27 March 2014).

Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU Technical Support Document 1: introduction to evidence synthesis for decision making, April 2011 (last updated April 2012). www.nicedsu.org.uk/TSD1%20Introduction.final.08.05.12.pdf (accessed 27 March 2014).

Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU Technical Support Document 2: a generalised linear modelling framework for pairwise and network meta‐analysis of randomised controlled trials, August 2011 (last updated April 2014). www.nicedsu.org.uk/TSD2%20General%20meta%20analysis%20corrected%2015April2014.pdf (accessed 8 October 2014).

Dias S, Welton NJ, Sutton AJ, Caldwell DM, Lu G, Ades AE. NICE DSU Technical Support Document 4: inconsistency in networks of evidence based on randomised controlled trials, May 2011 (last updated April 2014). www.nicedsu.org.uk/TSD4%20Inconsistency.final.15April2014.pdf (accessed 8 October 2014).

European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. Journal of Hepatology 2010;53(1):3‐22.

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315(7109):629‐34.

Ellervik C, Birgens H, Tybjaerg‐Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta‐analyses including 66,000 cases and 226,000 controls. Hepatology 2007;46(4):1071‐80.

EuroQol. About EQ‐5D, 2014. www.euroqol.org/about‐eq‐5d.html (accessed 8 October 2014).

Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I‐like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics 1996;13(4):399‐408.

Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato‐Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)). 2015, Issue 11. Art. No.: LIVER.

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction ‐ GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383‐94.

Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org.

Higgins JPT, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta‐analysis: Concepts and models for multi‐arm studies. Research Synthesis Methods 2012;3(2):98‐110.

International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1, Pennsylvania: Barnett International/PAREXEL, 1997.

Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta‐analytic methods. BMC Medical Research Methodology 2014;14(1):120.

Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9.

Lu G, Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. Journal of the American Statistical Association 2006;101(474):447‐59.

Lucotte G, Dieterlen F. A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?. Blood, Cells, Molecules & Diseases 2003;31(2):262‐7.

Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2017, Issue 2. [DOI: 10.1002/14651858.MR000033.pub3]

Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta‐analysis. Statistics in Medicine 2001;20(4):641‐54.

Sweetman S, editor. Martindale: the complete drug reference (online version), 37th edition, 2011. www.pharmpress.com/product/MC_MART/martindale‐the‐complete‐drug‐reference (accessed 23 September 2014).

Mercier G, Bathelier C, Lucotte G. Frequency of the C282Y mutation of hemochromatosis in five French populations. Blood, Cells, Molecules & Diseases 1998;24(2):165‐6.

Mills EJ, Ioannidis JP, Thorlund K, Schünemann HJ, Puhan MA, Guyatt GH. How to use an article reporting a multiple treatment comparison meta‐analysis. JAMA 2012;308(12):1246‐53.

Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13.

Newell DJ. Intention‐to‐treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837‐41.

Members of OpenBUGS Project Management Group. OpenBUGS. Version 3.2.3. Members of OpenBUGS Project Management Group, 2014.

Pennell DJ, Porter JB, Piga A, Lai Y, El‐Beshlawy A, Belhoul KM, et al. A 1‐year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta‐thalassemia major (CORDELIA). Blood 2014;123(10):1447‐54.

Pietrangelo A. Hereditary hemochromatosis ‐ a new look at an old disease. New England Journal of Medicine 2004;350(23):2383‐97.

Puhan MA, Schünemann HJ, Murad MH, Li T, Brignardello‐Petersen R, Singh JA, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta‐analysis. BMJ (Clinical Research Ed.) 2014;349:g5630.

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Ropero P, Briceno O, Mateo M, Polo M, Mora A, Gonzalez FA, et al. Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain). Annals of Hematology 2006;85(5):323‐6.

Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603.

Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple‐treatment meta‐analysis: an overview and tutorial. Journal of Clinical Epidemiology 2011;64(2):163‐71.

Salanti G. Indirect and mixed‐treatment comparison, network, or multiple‐treatments meta‐analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Research Synthesis Methods 2012;3(2):80‐97.

Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized controlled trials: combined analysis of meta‐epidemiological studies. Health Technology Assessment 2012;16(35):1‐82.

Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized controlled trials. Annals of Internal Medicine 2012;157(6):429‐38.

Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians. Annals of Internal Medicine 2005;143(7):522‐36.

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12.

Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ (Clinical Research Ed.) 2010;340:c332.

Severini TA. Bayesian interval estimates which are also confidence intervals. Journal of the Royal Statistical Society. Series B (Methodological) 1993;55(2):533‐40.

StataCorp LP. Stata/SE 14.2 for Windows[64‐bit x86‐64]. Version 14. College Station: StataCorp LP, 2017.

Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillan GM, Bowman BA, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 2001;285(17):2216‐22.

Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for trial sequential analysis (TSA). Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark. 2011. p. 1‐115. Available from www.ctu.dk/tsa.

Thorlund K, Mills EJ. Sample size and power considerations in network meta‐analysis. Systematic Reviews 2012;1:41.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen. TSA version 0.9. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, 2011.

Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JP. Predicting the extent of heterogeneity in meta‐analysis, using empirical data from the Cochrane Database of Systematic Reviews. International Journal of Epidemiology 2012;41(3):818‐27.

van Bokhoven MA, van Deursen CT, Swinkels DW. Diagnosis and management of hereditary haemochromatosis. BMJ (Clinical Research Ed.) 2011;342:c7251.

van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta‐analysis. Research Synthesis Methods 2012;3(4):285‐99.

Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. British Journal of Haematology 2007;136(3):501‐8.

Voicu PM, Cojocariu C, Petrescu‐Danila E, Covic M, Stanciu C, Rusu M. Prevalence of HFE (hemochromatosis) gene mutations C282Y and H63D in a Romanian population. Blood, Cells, Molecules & Diseases 2009;42(1):14‐5.

Ware JE. SF‐36® health survey update, 2014. www.sf‐36.org/tools/sf36.shtml (accessed on 8 October 2014).

Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta‐analysis. Journal of Clinical Epidemiology 2008;61(1):64‐75.

Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Annals of Internal Medicine 2006;145(3):209‐23.

Wojcik JP, Speechley MR, Kertesz AE, Chakrabarti S, Adams PC. Natural history of C282Y homozygotes for hemochromatosis. Canadian Journal of Gastroenterology 2002;16(5):297‐302.

Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336(7644):601‐5.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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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]

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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]
Open in figure viewer Analysis 1.1 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
Open in figure viewer Analysis 1.2 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
Open in figure viewer Analysis 1.3 Comparison 1 Therapeutic erythrocytapheresis versus phlebotomy, Outcome 3 Health‐related quality of life (EQ‐VAS).

Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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

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.

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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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 low^1,2
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 low^1,2
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 low^1,2
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).

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

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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

Comparison 1. Therapeutic erythrocytapheresis versus phlebotomy

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Referencias

Referencias de los estudios incluidos en esta revisión

Rombout‐Sestrienkova 2012 {published data only}

Rombout‐Sestrienkova 2016 {published data only}

Sundic 2014 {published data only}

Referencias de los estudios en curso

Ong 2015 {published data only}

Referencias adicionales

Adams 2007

Allen 2008

Assi 2014

Bacon 2011

Bardou‐Jacquet 2014

Beutler 2002

Bradley 1996

Cancado 2015

Cassanelli 2001

Chaimani 2012

Chaimani 2013

Chan 2013

de Graaff 2015

Del Re 2013

DeMets 1987

DerSimonian 1986

Dias 2010

Dias 2012a

Dias 2012b

Dias 2014a

Dias 2014b

EASL 2010

Egger 1997

Ellervik 2007

EuroQol 2014

Feder 1996

Gluud 2015

Guyatt 2011

Higgins 2011

Higgins 2012

ICH‐GCP 1997

Jakobsen 2014

Kjaergard 2001

Lu 2006

Lucotte 2003

Lundh 2017

Macaskill 2001

Martindale 2011

Mercier 1998

Mills 2012

Moher 1998

Newell 1992

OpenBUGS 3.2.3 [Computer program]

Pennell 2014

Pietrangelo 2004

Puhan 2014

RevMan 2014 [Computer program]

Ropero 2006

Royle 2003

Salanti 2011

Salanti 2012

Savović 2012a

Savović 2012b

Schmitt 2005

Schulz 1995

Schulz 2010

Severini 1993

Stata/SE 14.2 [Computer program]

Steinberg 2001

Thorlund 2011

Thorlund 2012

TSA 2011 [Computer program]

Turner 2012

van Bokhoven 2011

van Valkenhoef 2012

Vichinsky 2007

Voicu 2009

Ware 2014

Wetterslev 2008

Whitlock 2006