Abstract: Three trials with 146 participants met the inclusion criteria of this review. Two parallel group trials with 100 participants provided information on one or more outcomes. The remaining trial was a cross-over trial, with no usable data for analysis. All the trials were at high risk of bias. Overall, all the evidence was of very low quality. All three trials compared erythrocytapheresis (removal of red cells only, instead of whole blood) versus phlebotomy. Two of the trials shared the same first author. The mean or median age in the three trials ranged from 42 to 55 years. None of the trials reported whether the included participants were symptomatic or asymptomatic or a mixture of both. Two trials were conducted in people who were haemochromatosis treatment-naive. The trial that provided most data for this review excluded people with malignancy, heart failure, and serious cardiac arrhythmias. We found no trials assessing iron-chelating agents. Only one of the trials with 38 participants reported no short-term mortality and no serious adverse events at the end of the short-term follow-up (eight months). Two trials reported the proportion of people with adverse events: 10/49 (20.4%) in the erythrocytapheresis group versus 11/51 (21.6%) in the phlebotomy group. One of these two trials provided data on adverse event rates (42.1 events per 100 participants with erythrocytapheresis versus 52.6 events per 100 participants with phlebotomy). There was no evidence of differences in the proportion of people with adverse events and the number of adverse events (serious and non-serious) between the groups (proportion of people with adverse events: OR 0.93, 95% CI 0.36 to 2.43; participants = 100; trials = 2; number of adverse events: rate ratio 0.80, 95% CI 0.32 to 2.03; participants = 38; trial = 1). There was no difference between the groups regarding short-term health-related quality of life (mean difference (MD) 1.00, 95% CI -10.80 to 12.80; participants = 38; trials = 1). This outcome was measured using EQ-VAS (range: 0 to 100 where a higher score indicates better health-related quality of life). None of the trials reported mortality beyond one year, health-related quality of life beyond one year, liver transplantation, decompensated liver disease, cirrhosis, hepatocellular carcinoma, diabetes, or cardiovascular complications during the long-term follow-up. The two trials that provided data for this review were funded by parties with no vested interest in the results; the source of funding of the third trial was not reported. There is currently insufficient evidence to determine whether erythrocytapheresis is beneficial or harmful compared with phlebotomy. Phlebotomy has less equipment requirements and remains the treatment of choice in people with hereditary haemochromatosis who require blood letting in some form. However, it should be noted that there is no evidence from randomised clinical trials that blood letting in any form is beneficial in people with hereditary haemochromatosis. Having said this, a trial including no treatment is unlikely to be conducted. Future trials should compare different frequencies of phlebotomy and erythrocytapheresis versus phlebotomy with and without different iron-chelating agents compared with each other, and with placebo. Such trials should include long-term follow-up of participants (e.g. using national record linkage databases) to determine whether treatments are beneficial or harmful in terms of clinical outcomes such as deaths, health-related quality of life, liver damage and its consequences, heart damage and its consequences, and other outcomes that are of importance to people with hereditary haemochromatosis.

Plain-language summary: We identified three trials. Two trials with 100 participants provided information on one or more outcomes (measures of how well the treatments worked). The trials compared phlebotomy (removal of blood or 'blood letting') versus erythrocytapheresis (removal of blood, separation of red cells (which carry oxygen in the blood), and return of the remaining parts of the blood). Two trials were conducted in people who had not undergone previous treatment for haemochromatosis. The trial that provided most data for this review excluded people with cancer, heart failure, and serious irregular heartbeats. Source of funding: the two trials that provided data for this review were funded by parties with no vested interest in the results; the source of funding of the third trial was not reported. There were no deaths or serious complications in the short term in either group in the only trial that reported this information. There was no evidence of any difference in the percentage of people with any complications, the number of complications per person, and short-term health-related quality of life (a measure of a person's satisfaction with their life and health) between the treatments. None of the trials reported deaths beyond one year, health-related quality of life beyond one year, liver transplantation, severe liver damage, liver failure, liver cancer, diabetes, heart failure, or stroke during the long term. There is currently insufficient evidence to determine whether erythrocytapheresis is beneficial or harmful compared with phlebotomy. Erythrocytapheresis requires special equipment, while phlebotomy does not. So, phlebotomy remains the treatment of choice in people with hereditary haemochromatosis even though there is no evidence from randomised clinical trials that blood letting is beneficial. Having said this, a randomised clinical trial including no treatment is unlikely to be conducted. The overall quality of evidence was very low as the trials were at high risk of bias, which means that there is possibility of making wrong conclusions overestimating benefits or underestimating harms of treatments because of the way that the studies were conducted. Further high-quality randomised clinical trials to identify how often blood letting should be performed and those comparing erythrocytapheresis versus blood letting are required. Such trials should include long-term monitoring of participants (perhaps by linking health records in some countries).