394 patients were potentially eligible for the trial. 145 patients were screened and met all the basic eligibility criteria (37%, 95% CI 32 to 42%). 82 agreed to take part in the trial (57%, 95% CI 48 to 65%). Eight patients were found to be ineligible after consent and 10 were withdrawn. Reasons for withdrawal at this stage included surgeon preference (n = 4), clinical condition of the patient (n = 2) and logistical reasons (n = 5), leaving 63 randomized participants, 31 to standard perfusion and 33 to receive a leukodepletion filters (Fig. 1).
There was one treatment crossover from the leukodepletion filter to the standard filter, as the pump flow was considered too high for the leukodepletion LG-6 filter. This was the only case where un-blinding occurred. One patient did not receive either intervention as the operation was abandoned due to an intra operative finding of a porcelain aorta.
Patient demographics are illustrated in Table 3.
Table 3
Participant characteristics: Overall, characteristics were generally well balanced across the treatment groups.
| | Randomized to leukodepletion filter (n = 32) | Randomized to standard Filter (n = 31) | Overall (n = 63) |
| | n | % | n | % | n | % |
Age (years) | Median (IQR) | 73.5 | (69.6, 77.9) | 72.0 | (61.5, 76.9) | 72.6 | (66.1, 77.7) |
Male | | 21/32 | 66% | 18/31 | 58% | 39/63 | 62% |
Black ethnicity | | 2/32 | 6% | 0/31 | 0% | 2/63 | 3% |
BMI | Median (IQR) | 27.0 | (24.4, 32.3) | 29.7 | (26.0, 34.6) | 27.8 | (25.5, 33.3) |
EuroSCORE | Median (IQR) | 6.0 | (5.0, 7.0) | 6.0 | (3.0, 7.0) | 6.0 | (4.0, 7.0) |
Cleveland CSA-AKI score | Median (IQR) | 2.0 | (1.0, 3.0) | 2.0 | (2.0, 3.0) | 2.0 | (1.0, 3.0) |
ECHO/ANGIOGRAM REPORT | | | | | | | |
LV function | Good (> 50%) | 28/32 | 88% | 26/31 | 84% | 54/63 | 86% |
| Moderate (30–50%) | 4/32 | 13% | 5/31 | 16% | 9/63 | 14% |
Extent of coronary disease | None/not investigated | 22/32 | 69% | 20/31 | 64% | 42/63 | 66% |
| Single | 2/32 | 6% | 5/31 | 16% | 7/63 | 11% |
| Double | 3/32 | 9% | 4/31 | 13% | 7/63 | 11% |
| Triple | 5/32 | 16% | 2/31 | 6% | 7/63 | 11% |
> 50% disease in left main stem | | 2/32 | 6% | 2/31 | 6% | 4/63 | 6% |
The median age of participants was 72.6 years (interquartile range (IQR) 66.1 to 77.7) and 39/63 (62%) were male. The median additive European System for Cardiac Operative Risk Evaluation score (EuroSCORE) was 6.0 (IQR, 4.0 to 7.0) and the median Cleveland AKI severity score was 2.0 (IQR, 1.0 to 3.0). Overall, characteristics were well balanced across the treatment groups. The groups were also equivalent in terms of preoperative co morbidities, ventricular function and the extent of coronary artery disease based on pre-operative angiogram.
The operative data are demonstrated in Table 4. Isolated valve operations accounted for 33/62 (53%) procedures; the remainder included other procedures, mainly valve and coronary artery bypass graft (CABG) (21/62; 34%). The majority of patients had an aortic valve replacement (47/62; 76%). The peri-operative anesthetic management was standardized and bypass data was compatible. The median (IQR) total duration of CPB in minutes for the LG-6 group was 119.0 (97.0, 151.0) versus 124.0 (107.0, 141.0) for the standard filter group.
Table 4
Operative details: The bypass data were compatible.
| | Randomized to leukodepletion filter (n = 32) | Randomized to standard filter (n = 31) | Overall (n = 63) |
OPERATION DETAIL | | n | % | n | % | n | % |
Type of surgery | Valve | 15/31* | 48% | 18/31 | 58% | 33/62 | 53% |
| CABG and valve | 11/31* | 35% | 10/31 | 32% | 21/62 | 34% |
| Valve and other | 5/31* | 16% | 3/31 | 10% | 8/62 | 13% |
Valve replacement | | 26/31* | 84% | 25/31 | 81% | 51/62 | 82% |
Valve repair | | 8/31* | 26% | 7/31 | 23% | 15/62 | 24% |
Valve Replacement Details | Aortic | 23/26 | 88% | 24/25 | 96% | 47/51 | 92% |
| Mitral | 3/26 | 12% | 1/25 | 4% | 4/51 | 8% |
Valve Repair Details | Mitral | 4/8 | 50% | 5/7 | 71% | 9/15 | 60% |
| Tricuspid | 3/8 | 38% | 2/7 | 29% | 5/15 | 33% |
| Pulmonary | 1/8 | 13% | 0/7 | 0% | 1/15 | 7% |
BYPASS DATA | | | | | | | |
Total CPB duration (minutes) | Median (IQR) | 119.0 | (97.0, 151.0) | 124.0 | (107.0, 141.0) | 123.5 | (99.0, 146.0) |
NOTES: |
IQR = interquartile |
Details on missing data (Leukodepletion, Standard): (1, 0). |
*1 patient in the leukodepletion filter group was missing CPB specific data, as this patient was an open and shut case. |
Table 5
Post-Operative primary and secondary outcomes:
| | Randomized to leukodepletion filter (n = 32) | Randomized to standard filter (n = 31) | Overall (n = 63) |
PRIMARY OUTCOME: | | | | |
| | n | % | | n | % | | n | % | (95% CI) |
Any AKI | At any time | 14/32 | 44% | | 7/31 | 23% | | 21/63 | 33% | (0.22, 0.46) |
| Prior to discharge | 14/29 | 48% | | 6/25 | 24% | | 20/54 | 37% | |
| Between discharge and 6 weeks ~ | 0/26 | 0% | | 1/24 | 4% | | 1/50 | 2% | |
Highest AKI stage | Stage 1 | 9/14 | 64% | | 4/6 | 67% | | 13/20 | 65% | |
| Stage 2 | 4/14 | 29% | | 1/6 | 17% | | 5/20 | 25% | |
| Stage 3 | 1/14 | 7% | | 1/6 | 17% | | 2/20 | 10% | |
First instance of AKI | Day 1 | 9/14 | 64% | | 2/6 | 33% | | 11/20 | 55% | |
| Day 2 | 4/14 | 29% | | 3/6 | 50% | | 7/20 | 35% | |
| Day 3 to discharge | 1/14 | 7% | | 1/6 | 17% | | 2/20 | 10% | |
Maximum AKI stage | Day 1 | 6/14 | 43% | | 0/6 | 0% | | 6/20 | 30% | |
| Day 2 | 7/14 | 50% | | 5/6 | 83% | | 12/20 | 60% | |
| Day 3 to discharge | 1/14 | 7% | | 1/6 | 17% | | 2/20 | 10% | |
SECONDARY OUTCOMES: | | | | | | | | | | |
Need for haemodialysis | 1/32 | 3% | | 0/31 | 0% | | 1/63 | 2% | (0.0,0.1) |
In hospital mortality | 2/32 | 6% | | 0/31 | 0% | | 2/63 | 3% | (0.0,0.1) |
Infection complications | 5/32 | 16% | | 4/31 | 13% | | 9/63 | 14% | (0.1,0.3) |
Length of post-operative stay | Median (IQR) days | 7.7 | (5.8,13.9) | | 8.8 | (5.9, 11.7) | | 7.9 | (5.9, 12.0) | |
CICU length of stay | Median (IQR) days | 47.3 | (24.8, 100.0) | | 48.5 | (26.6, 92.8) | | 48.5 | (25.0, 98.3) | |
Ward length of stay | Median (IQR) days | 120.8 | (94.0, 168.8) | | 141.5 | (92.0, 188.4) | | 121.3 | (93.5, 187.0) | |
Figure Legends and Foot Notes: |
Study outcomes are summarized in Table 4.
The incidence of post-operative AKI was reported in 21/63 (33%) participants (95% CI 22 to 46%). The incidence was higher in the leukodepletion filter group (14/32; 44% versus 7/31; 23%, risk difference 21%, 95% CI -2–44%).
Most patients developed stage 1 AKI (13/20; 65%), whereas only 10% were classified with stage 3 AKI. One patient in the leukodepletion filter group required haemodialysis. Diuretic use and fluid balance over the first 5 days were similar in the two groups. Only four patients were not given diuretics during this time.
There was no clear association between the incidence, severity of AKI and the secondary outcome of length of stay observed between the two groups (Table 4).
Hospital stay by highest AKI stage is illustrated in Fig. 2. The median length of stay in intensive care was 47.3 hours in the leukodepletion filter group and 48.5 hours in the standard group. The median overall post-operative hospital stay was 7.7 days and 8.8 days respectively. Two patients in the leukodepletion filter group died during their post-operative stay. This was not directly related to the use of the filter. Infective complications occurred in 9/63 (14%) patients, with a similar incidence in both groups (leukodepletion filter 16%, standard filter 13%).
Biomarker comparisons are summarized in Fig. 3.
The urinary RBP:Cr and KIM-1:Cr ratios were, on average, tended to be higher in the leukodepletion filter group compared to standard filter group (geometric mean ratio (GMR) 1.16, 95% CI 0.80 to 1.69, p = 0.45 and 1.15, 95% CI 0.87 to 1.52, p = 0.35 respectively). A proportion of samples were below the limit of detection for KIM-1:Cr, i.e. below 0.156 ng/ml (46/338 observations, 13.7%). Urinary NGAL and Alb:Cr ratio were, on average, lower in the leukodepletion group (geometric mean ratio (GMR) 0.80, 95% CI 0.54–1.18, p = 0.29 and 0.84, 95% CI 0.51–1.39, p = 0.53). None of the differences were statistically significant. Serum Cystatin C concentration was the only biomarker where the difference between the groups varied significantly with time (p = 0.011). After adjustment for pre-operative AKI severity, the data suggest a possible difference at 48 hours (mean difference 0.11, 95% CI 0.00 to 0.23, p = 0.068) with higher average values in the leukodepletion groups, but not at other times.
Comprehensive resource use data were collected. EQ-5D- 5L scores were missing for ≤ 3 (5%) patients at each time point (patients who died were assigned a score of zero for each time point after death). The mean (SD) EQ-5D single summary index scores for the cohort as a whole were 0.82 (0.15) preoperatively, and 0.72 (0.24), 0.78 (0.22) and 0.85 (0.22) at 5 days, 6 weeks and 12 weeks respectively, indicating that HRQoL improved with time after surgery. The MLHF scores showed a similar pattern.
The overall scores and the scores for both the physical and emotional subscales reduced from 5 days to 12 weeks indicating HRQoL improved over time (mean (SD)): overall score at baseline 37.4 (23.0), 5 days 45.6 (25.1), 6 weeks 29.6 (19.6), 12 weeks 16.2 (16.3). Resource use during follow up was captured for 36/38 (95%) participants at 6 weeks and 57/61 (93%) participants at 3 months.
Overall, 3% of resource use data were missing: 1% for the in-patient period (which had the greatest number of resource use variables), 5% for follow up to 6 weeks, and 8% of follow up data to 3 months. On average, health related quality of life returned to pre-operative levels by 3 months.
A total of 203 adverse events (Supplementary material) were reported in 58 participants in the first 3 months after surgery, 66 of which were classified as serious adverse events (SAE). Forty SAEs were reported in 13 patients in the leucodepletion filter group compared to 26 SAEs in 13 patients in the standard filter group. Of the 203 adverse events reported, 182 were expected complications after cardiac surgery, i.e. they were listed in the study protocol, and 21 were unexpected. Approximately one third of SAEs occurred after hospital discharge; SVT/AF requiring treatment was the most frequently reported SAE, which occurred in 5 participants (8%).