Patients

The international trial cohort was recruited between March 2009 and May 2014. The UK cohort was recruited between January 2012 and October 2014. The UK patients recruited after the international trial sample size was achieved (over a period of 6 months) were included in this summary of the UK cohort and the health economic evaluation. There were 293 patients recruited to the UK trial who were included in the main trial analysis, previously published.³¹ In total, 359 patients were recruited in the UK (90% of the revised 400 patient sample size; see Figure 6 for timelines). In total, 354 patients were included in the UK cohort reported here for clinical outcomes (multiple imputation enabled the inclusion of 357 patients in the economic evaluation). These included 58 patients recruited after achievement of the international sample size. In four cases there were no primary outcome data, and in one case a patient withdrew consent.

FIGURE 6

Recruitment accrual over time to the UK ABLE trial. The revised trial target of 400 patients was agreed with the HTA programme when the end date for the international trial was predicted.

In the international trial, 2510 patients underwent randomisation; 80 (3.2%) were withdrawn after randomisation because primary outcome data could not be obtained, leaving 2430 patients (1211 in the group allocated to receive fresh blood and 1219 in the group allocated to receive standard-aged blood) in the intention-to-treat analysis.

Baseline data were available for 2412 of the 2430 patients with primary outcome data. Of these 2430 patients, 94 (3.9%) did not receive any RBC transfusions. The overall rate of loss to follow-up was 3.2% at 90 days.

For the UK, the Consolidated Standards of Reporting Trials (CONSORT) flow diagram describing the trial is shown in Figure 7. In total, 5989 patients received a blood transfusion during the first 7 days of ICU stay. However, of these, 2081 did not meet the other inclusion criteria. Of the 3908 patients who met all inclusion criteria, 2270 were excluded in accordance with the protocol. By far the most common reason for exclusion, in 2021 patients, was the patient having had a transfusion earlier during their hospital stay. This included transfusions undertaken prior to ICU admission, for example to treat haemorrhage or perioperative blood loss. Of the 1638 patients who were eligible for randomisation, a high proportion (n = 1279, 78%) were excluded for a variety of practical reasons that meant that randomisation and group allocation were not feasible. The most common reason was transfusion at night (n = 957). In these situations, delay of transfusion to enable randomisation was not considered clinically appropriate or safe, but the randomisation procedure could not be organised either by clinical research staff or at the blood bank level. In total, 359 patients were randomised in the UK cohort, out of 1638 (22%) eligible patients according to the trial protocol. Five patients were not included in the primary analysis. In four cases, there were no primary outcome data; in one case, a patient withdrew consent. Of these 354 patients, 179 were randomised to the group allocated to receive fresh blood and 175 patients to the group allocated to receive standard-aged blood.

FIGURE 7

The CONSORT flow diagram for the UK ABLE trial. a, No admission data from three sites. N/A, not applicable.

Baseline characteristics of the patients for the ABLE trial UK cohort, and for the overall international trial, are shown in Table 6. Patients had an age and sex profile typical of general ICU populations in the UK. The illness severity, based on APACHE II score and requirement for organ support, was high and the majority had significant levels of organ dysfunction based on the MODS score. Almost all patients were non-elective ICU admissions. The majority had a medical diagnosis, most likely to be consistent with the non-eligibility of patients receiving blood transfusion prior to ICU admission, which will include many surgical and trauma patients. The UK ABLE trial cohort was similar to the international cohort, although there were more elective ICU admissions in the UK ABLE trial cohort.

TABLE 6

Baseline characteristics

Intervention

Table 7 shows the comparison of transfusion practice between the groups, between the UK ABLE trial and the international trial. In the international trial, a total of 5198 RBC units were given to patients in the group allocated to receive fresh blood and 5210 to patients in the group allocated to receive standard-aged blood. The pre-transfusion haemoglobin concentration was similar in the international cohort to the UK ABLE trial and the values indicated a restrictive transfusion practice consistent with current evidence. Patients received a similar number of RBC units in both groups. This was the case for the overall trial, and for the UK cohort. There was excellent separation of storage-age profile, which was similar in the UK to the international cohort. The difference between the distribution of storage age in each group was clinically relevant (see Figure 8; reproduced from full trial data). Protocol compliance was high. The rate of adherence to the transfusion protocol was 95.4% for all red blood cells transfused, with 100% of patients allocated to receive standard-aged blood receiving only standard-issue RBCs and 84.0% of patients allocated to receive fresh blood receiving only red blood cells stored for ≤ 7 days. In the group allocated to receive fresh blood, only 6.6% of the patients received > 1 RBC unit that had been stored for > 7 days, and only 4.6% received > 2 units that had been stored for > 7 days. Most patients in the group allocated to receive fresh blood [238 of 249 patients (95.6%)] who received only one RBC transfusion received exclusively RBC units that had been stored for < 8 days.

TABLE 7

Anaemia and RBC transfusions

FIGURE 8

Distribution of RBC units in accordance with length of storage, as transfused to patients allocated to the fresh blood arm (green bars) and to the standard arm (black bars). Source: Lacroix et al.

Primary outcome

In the international trial, at 90 days after randomisation, 37.0% of patients in the group allocated to receive fresh blood and 35.3% of patients in the group allocated to receive standard-aged blood had died. The unadjusted and adjusted risk differences are shown in Table 8. There was no evidence of any clinically or statistically important difference between the groups. The proportion of patients who died was similar in the UK ABLE trial cohort.

TABLE 8

Primary outcome and secondary outcomes related to death and major illness

Secondary analyses

In the international trial, the survival analysis of the time to death showed a hazard ratio in the group allocated to receive fresh blood, compared with the group allocated to receive standard-aged blood, of 1.1 (95% CI 0.9 to 1.2; p = 0.38). No significant difference in mortality was observed between the groups on the basis of follow-up duration, age, number of units transfused, APACHE II score or admission category. Differences between the groups in the UK ABLE trial cohort were similar to those in the international cohort (see Table 8).

In the international trial, no significant differences were observed with respect to major illnesses, duration of respiratory, haemodynamic or renal support, or length of stay in the ICU or hospital. There were also no differences in reported transfusion reactions. Data were comparable for the UK ABLE trial subgroup (see Table 8).

Data for other secondary outcomes are shown in Table 9. There were no differences between the groups in the international trial, and data were similar for the UK ABLE trial cohort.

TABLE 9

Other secondary outcomes

The per-protocol analysis of the primary outcome, which included only patients who received a transfusion, showed no difference between the groups in the international trial, and data were comparable for the UK ABLE trial cohort. In the sensitivity analysis of the primary outcome, in which outcomes of the patients in the fresh-blood group who received only RBCs that had been stored for ≤ 7 days, were compared with the outcomes in patients in the standard-aged blood group, who received RBCs that had been stored for > 7 days, also showed no differences between the groups. Data are shown in Tables 10 and 11.

TABLE 10

Per-protocol analysis (at least one transfusion). This analysis included only patients who actually received a red blood cell transfusion

TABLE 11

Per-protocol analysis (full compliance). This analysis included only patients in whom there was full compliance with the storage age allocation of the fresh and standard-aged red blood cell groups