Abstract

BACKGROUND The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. METHODS The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. FINDINGS Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1.1 years (IQR 0.7-1.3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0.11 units per year (95% CI 0.04-0.17; p=0.0003) in men and 0.06 units per year (0.01-0.11; p=0.0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0.23 units per year (0.21-0.25) in men and 0.14 units per year (0.12-0.15) in women (both p<0.0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1.19 [95% CI 1.15-1.22] in men and 1.10 [1.06-1.14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval -0.84 g/L [95% CI -0.99 to -0.70] in men and -0.45 g/L [-0.59 to -0.31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval -6.5% [95% CI -7.6 to -5.5] in men and -5.3% [-6.5 to -4.2] in women; all p<0.0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0.0001). INTERPRETATION During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. FUNDING NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.

Abstract

BACKGROUND Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. METHODS In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. FINDINGS 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99.5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1.69 units (95% CI 1.59-1.80; approximately 795 mL) in the 8-week group and by 0.79 units (0.69-0.88; approximately 370 mL) in the 10-week group (p<0.0001 for both). In women, compared with the 16-week group, it increased by 0.84 units (95% CI 0.76-0.91; approximately 395 mL) in the 12-week group and by 0.46 units (0.39-0.53; approximately 215 mL) in the 14-week group (p<0.0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0.0001 for each) than those observed in the standard frequency groups. INTERPRETATION Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. FUNDING NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.

Abstract

BACKGROUND The interpretation of trial results can be helped by understanding how generalisable they are to the target population for which inferences are intended. INTERVAL, a large pragmatic randomised trial of blood donors in England, is assessing the effectiveness and safety of reducing inter-donation intervals. The trial recruited mainly from the blood service's static centres, which collect only about 10 % of whole-blood donations. Hence, the extent to which the trial's participants are representative of the general blood donor population is uncertain. We compare these groups in detail. METHODS We present the CONSORT flowchart from participant invitation to randomisation in INTERVAL. We compare the characteristics of those eligible and consenting to participate in INTERVAL with the general donor population, using the national blood supply 'PULSE' database for the period of recruitment. We compare the characteristics of specific groups of trial participants recruited from different sources, as well as those who were randomised versus those not randomised. RESULTS From a total of 540,459 invitations, 48,725 donors were eligible and consented to participate in INTERVAL. The proportion of such donors varied from 1-22 % depending on the source of recruitment. The characteristics of those consenting were similar to those of the general population of 1.3 million donors in terms of ethnicity, blood group distribution and recent deferral rates from blood donation due to low haemoglobin. However, INTERVAL participants included more men (50 % versus 44 %), were slightly older (mean age 43.1 versus 42.3 years), included fewer new donors (3 % versus 22 %) and had given more donations over the previous 2 years (mean 3.3 versus 2.2) than the general donor population. Of the consenting participants, 45,263 (93 %) donors were randomised. Compared to those not randomised, the randomised donors showed qualitatively similar differences to those described above. CONCLUSIONS There was broad similarity of participants in INTERVAL with the general blood donor population of England, notwithstanding some differences in age, sex and donation history. Any heterogeneity of the trial's results according to these characteristics will need to be studied to ensure its generalisability to the general donor population. TRIAL REGISTRATION Current Controlled Trials ISRCTN24760606 . Registered on 25 January 2012.

Abstract

BACKGROUND Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors. METHODS/DESIGN INTERVAL is a randomised trial of whole blood donors enrolled from all 25 static centres of NHS Blood and Transplant. Recruitment of about 50,000 male and female donors started in June 2012 and was completed in June 2014. Men have been randomly assigned to standard 12-week versus 10-week versus 8-week inter-donation intervals, while women have been assigned to standard 16-week versus 14-week versus 12-week inter-donation intervals. Sex-specific comparisons will be made by intention-to-treat analysis of outcomes assessed after two years of intervention. The primary outcome is the number of blood donations made. A key secondary outcome is donor quality of life, assessed using the Short Form Health Survey. Additional secondary endpoints include the number of 'deferrals' due to low haemoglobin (and other factors), iron status, cognitive function, physical activity, and donor attitudes. A comprehensive health economic analysis will be undertaken. DISCUSSION The INTERVAL trial should yield novel information about the effect of inter-donation intervals on blood supply, acceptability, and donors' physical and mental well-being. The study will generate scientific evidence to help formulate blood collection policies in England and elsewhere. TRIAL REGISTRATION Current Controlled Trials ISRCTN24760606, 25 January 2012.

Abstract

OBJECTIVE The acute administration of high-dose erythropoietin (EPO) on reperfusing ischaemic myocardium has been reported to halve myocardial infarct (MI) size in preclinical studies, but its effect in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention (PPCI) remains unknown. We investigated whether high-dose EPO administered as an adjunct to PPCI reduces MI size. DESIGN Double-blinded, randomised, placebo-controlled. SETTING Single tertiary cardiac centre. PATIENTS Fifty-one ST elevation myocardial infarction patients undergoing PPCI. INTERVENTIONS Patients were randomly assigned to receive either a single intravenous bolus of EPO (50,000 IU) prior to PPCI with a further bolus given 24 h later (n=26) or placebo (n=25). MAIN OUTCOME MEASURES MI size measured by 24 h area under the curve troponin T and cardiac magnetic resonance imaging performed on day 2 and at 4 months. RESULTS EPO treatment failed to reduce MI size (troponin T area under the curve: 114.6+/-78 ug/ml EPO vs 100.8+/-68 ug/ml placebo; infarct mass by cardiac magnetic resonance: 33+/-16 g EPO vs 25+/-16 g placebo; both p>0.05). Unexpectedly, EPO treatment doubled the incidence of microvascular obstruction (82% EPO vs 47% placebo; p=0.02) and significantly increased indexed left ventricular (LV) end-diastolic volumes (84+/-10 ml/m(2) EPO vs 73+/-13 ml/m(2) placebo; p=0.003), indexed LV end-systolic volumes (41+/-9 ml/m(2) EPO vs 35+/-11 ml/m(2) placebo; p=0.035) and indexed myocardial mass (89+/-16 g/m(2) EPO vs 79+/-11 g/m(2) placebo; p=0.03). At 4 months, there were no significant differences between groups. CONCLUSIONS High-dose EPO administered as an adjunct to PPCI failed to reduce MI size. In fact, EPO treatment was associated with an increased incidence of microvascular obstruction, LV dilatation and increased LV mass. Clinical Trial Registration Information http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=4058 Unique Identifier=Study ID 4058.

Abstract

BACKGROUND Intravenous immunoglobulin (IVIG) is a fractionated blood product whose off-label use for treating a variety of conditions, including spontaneous recurrent miscarriage, has continued to grow in recent years. Its high costs and short supply necessitate improved guidance on its appropriate applications. OBJECTIVE We conducted a systematic review of randomised controlled trials evaluating IVIG for treatment of spontaneous recurrent miscarriage. SEARCH STRATEGY A systematic search strategy was applied to Medline (1966 to June 2005) and the Cochrane Register of Controlled Trials (June 2005). SELECTION CRITERIA We included all randomised controlled trials comparing all dosages of IVIG to placebo or an active control. DATA COLLECTION AND ANALYSIS Two investigators independently extracted data using a standardised data collection form. Measures of effect were derived for each trial independently, and studies were pooled based on clinical and methodologic appropriateness. MAIN RESULTS We identified eight trials involving 442 women that evaluated IVIG therapy used to treat recurrent miscarriage. Overall, IVIG did not significantly increase the odds ratio (OR) of live birth when compared with placebo for treatment of recurrent miscarriage (OR 1.28, 95% CI 0.78-2.10). There was, however, a significant increase in live births following IVIG use in women with secondary recurrent miscarriage (OR 2.71, 95% CI 1.09-6.73), while those with primary miscarriage did not experience the same benefit (OR 0.66, 95% CI 0.35-1.26). AUTHOR'S CONCLUSIONS IVIG increased the rates of live birth in secondary recurrent miscarriage, but there was insufficient evidence for its use in primary recurrent miscarriage.