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Background Randomized clinical trials (RCTs) are occasionally stopped prematurely before reaching their planned sample sizes. It has been suggested that early stopped RCTs are associated with under- and overestimation of the effect estimates. We simulated the effect of hypothetical premature stopping of three large RCTs done in the intensive care unit (ICU) setting. Methods In this post hoc study, we simulated the impact of stopping trials early by calculating mortality effect estimates continuously after the inclusion of each individual patient in three large RCTs, that is the 6S trial on hydroxyethyl starch vs Ringer's acetate in sepsis in ICU, the TRISS trial on lower vs higher haemoglobin threshold for transfusion in septic shock in ICU and the SUP-ICU trial on pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. Results The three trials included a total of 5087 patients; 798 from the 6S trial, 998 from the TRISS trial and 3291 patients from the SUP-ICU trial. The premature mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included. The premature estimates became stable after inclusion of 205 patients (26% of the final sample size) in the 6S trial, 133 patients(13%) in the TRISS trial and 1926 patients(59%) in the SUP-ICU trial. Conclusions In this post hoc study of three international RCTs within intensive care, we found that the simulated interim mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included, but remained instable until the final sample sizes had been included. Thus, this study illustrates the necessity for cautious interpretations of prematurely stopped trials.

Patients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During storage, the RBCs and storage medium undergo changes, which may have clinical consequences. Several trials now have assessed these consequences, and we reviewed the present evidence on the effects of shorter versus longer storage time of transfused RBCs on outcomes in ICU patients. We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials including adult ICU patients transfused with fresher versus older or standard issue blood. We included seven trials with a total of 18,283 randomised ICU patients; two trials of 7504 patients were judged to have low risk of bias. We observed no effects of fresher versus older blood on death (relative risk 1.04, 95% confidence interval (CI) 0.97–1.11; 7349 patients; TSA-adjusted CI 0.93–1.15), adverse events (1.26, 0.76–2.09; 7332 patients; TSA-adjusted CI 0.16–9.87) or post-transfusion infections (1.07, 0.96–1.20; 7332 patients; TSA-adjusted CI 0.90–1.27). The results were unchanged by including trials with high risk of bias. TSA confirmed the results and the required information size was reached for mortality for a relative risk change of 20%. We may be able to reject a clinically meaningful effect of RBC storage time on mortality in transfused adult ICU patients as our trial sequential analyses reject a 10% relative risk change in death when comparing fresher versus older blood for transfusion.

We assessed the predefined long-term outcomes in patients randomised in the Transfusion Requirements in Septic Shock (TRISS) trial. In 32 Scandinavian ICUs, we randomised 1005 patients with septic shock and haemoglobin of 9 g/dl or less to receive single units of leuko-reduced red cells when haemoglobin level was 7 g/dl or less (lower threshold) or 9 g/dl or less (higher threshold) during ICU stay. We assessed mortality rates 1 year after randomisation and again in all patients at time of longest follow-up in the intention-to-treat population (n = 998) and health-related quality of life (HRQoL) 1 year after randomisation in the Danish patients only (n = 777). Mortality rates in the lower- versus higher-threshold group at 1 year were 53.5 % (268/501 patients) versus 54.6 % (271/496) [relative risk 0.97; 95 % confidence interval (CI) 0.85–1.09; P = 0.62]; at longest follow-up (median 21 months), they were 56.7 % (284/501) versus 61.0 % (302/495) (hazard ratio 0.88; 95 % CI 0.75–1.03; P = 0.12). We obtained HRQoL data at 1 year in 629 of the 777 (81 %) Danish patients, and mean differences between the lower- and higher-threshold group in scores of physical HRQoL were 0.4 (95 % CI −2.4 to 3.1; P = 0.79) and in mental HRQoL 0.5 (95 % CI −3.1 to 4.0; P = 0.79). Long-term mortality rates and HRQoL did not differ in patients with septic shock and anaemia who were transfused at a haemoglobin threshold of 7 g/dl versus a threshold of 9 g/dl. We may reject a more than 3 % increased hazard of death in the lower- versus higher-threshold group at the time of longest follow-up.

OBJECTIVETo compare patient outcomes of restrictive versus liberal blood transfusion strategies in patients with cardiovascular disease not undergoing cardiac surgery.DESIGNSystematic review and meta-analysis.DATA SOURCESRandomised controlled trials involving a threshold for red blood cell transfusion in hospital. We searched (to 2 November 2015) CENTRAL, Medline, Embase, CINAHL, PubMed, LILACS, NHSBT Transfusion Evidence Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ISRCTN Register, and EU Clinical Trials Register. Authors were contacted for data whenever possible.TRIAL SELECTIONPublished and unpublished randomised controlled trials comparing a restrictive with liberal transfusion threshold and that included patients with cardiovascular disease.DATA EXTRACTION AND SYNTHESISData extraction was completed in duplicate. Risk of bias was assessed using Cochrane methods. Relative risk ratios with 95% confidence intervals were presented in all meta-analyses. Mantel-Haenszel random effects models were used to pool risk ratios.MAIN OUTCOME MEASURES30 day mortality, and cardiovascular events.RESULTS41 trials were identified; of these, seven included data on patients with cardiovascular disease. Data from a further four trials enrolling patients with cardiovascular disease were obtained from the authors. In total, 11 trials enrolling patients with cardiovascular disease (n= 3033) were included for meta-analysis (restrictive transfusion, n= 1514 patients; liberal transfusion, n= 1519). The pooled risk ratio for the association between transfusion thresholds and 30 day mortality was 1.15 (95% confidence interval 0.88 to 1.50, P= 0.50), with little heterogeneity (I-2= 14%). The risk of acute coronary syndrome in patients managed with restrictive compared with liberal transfusion was increased (nine trials; risk ratio 1.78, 95% confidence interval 1.18 to 2.70, P= 0.01, I-2= 0%).CONCLUSIONSThe results show that it may not be safe to use a restrictive transfusion threshold of less than 80 g/L in patients with ongoing acute coronary syndrome or chronic cardiovascular disease. Effects on mortality and other outcomes are uncertain. These data support the use of a more liberal transfusion threshold (> 80 g/L) for patients with both acute and chronic cardiovascular disease until adequately powered high quality randomised trials have been undertaken in patients with cardiovascular disease.

BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established.METHODS: In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization.RESULTS: We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups.CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).

BACKGROUND: Treating anaemia with red blood cell (RBC) transfusion is frequent, but controversial, in patients with septic shock. Therefore we assessed characteristics and outcome associated with RBC transfusion in this group of high risk patients.METHODS: We did a prospective cohort study at 7 general intensive care units (ICUs) including all adult patients with septic shock in a 5-month period.RESULTS: Ninety-five of the 213 included patients (45%) received median 3 (interquartile range 2-5) RBC units during shock. The median pre-transfusion haemoglobin level was 8.1 (7.4-8.9) g/dl and independent of shock day and bleeding. Patients with cardiovascular disease were transfused at higher haemoglobin levels. Transfused patients had higher Simplified Acute Physiology Score (SAPS) II (56 (45-69) vs. 48 (37-61), p = 0.0005), more bleeding episodes, lower haemoglobin levels days 1 to 5, higher Sepsis-related Organ Failure Assessment (SOFA) scores (days 1 and 5), more days in shock (5 (3-10) vs. 2 (2-4), p = 0.0001), more days in ICU (10 (4-19) vs. 4 (2-8), p = 0.0001) and higher 90-day mortality (66 vs. 43%, p = 0.001). The latter association was lost after adjustment for admission category and SAPS II and SOFA-score on day 1.CONCLUSIONS: The decision to transfuse patients with septic shock was likely affected by disease severity and bleeding, but haemoglobin level was the only measure that consistently differed between transfused and non-transfused patients.

Objective To compare the benefit and harm of restrictive versus liberal transfusion strategies to guide red blood cell transfusions. Design Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. Data sources Cochrane central register of controlled trials, SilverPlatter Medline (1950 to date), SilverPlatter Embase (1980 to date), and Science Citation Index Expanded (1900 to present). Reference lists of identified trials and other systematic reviews were assessed, and authors and experts in transfusion were contacted to identify additional trials. Trial selection Published and unpublished randomised clinical trials that evaluated a restrictive compared with a liberal transfusion strategy in adults or children, irrespective of language, blinding procedure, publication status, or sample size. Data extraction Two authors independently screened titles and abstracts of trials identified, and relevant trials were evaluated in full text for eligibility. Two reviewers then independently extracted data on methods, interventions, outcomes, and risk of bias from included trials. random effects models were used to estimate risk ratios and mean differences with 95% confidence intervals. Results 31 trials totalling 9813 randomised patients were included. The proportion of patients receiving red blood cells (relative risk 0.54, 95% confidence interval 0.47 to 0.63, 8923 patients, 24 trials) and the number of red blood cell units transfused (mean difference −1.43, 95% confidence interval −2.01 to −0.86) were lower with the restrictive compared with liberal transfusion strategies. Restrictive compared with liberal transfusion strategies were not associated with risk of death (0.86, 0.74 to 1.01, 5707 patients, nine lower risk of bias trials), overall morbidity (0.98, 0.85 to 1.12, 4517 patients, six lower risk of bias trials), or fatal or non-fatal myocardial infarction (1.28, 0.66 to 2.49, 4730 patients, seven lower risk of bias trials). Results were not affected by the inclusion of trials with unclear or high risk of bias. Using trial sequential analyses on mortality and myocardial infarction, the required information size was not reached, but a 15% relative risk reduction or increase in overall morbidity with restrictive transfusion strategies could be excluded. Conclusions Compared with liberal strategies, restrictive transfusion strategies were associated with a reduction in the number of red blood cell units transfused and number of patients being transfused, but mortality, overall morbidity, and myocardial infarction seemed to be unaltered. Restrictive transfusion strategies are safe in most clinical settings. Liberal transfusion strategies have not been shown to convey any benefit to patients. Trial registration PROSPERO CRD42013004272.

Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year. The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P ≤0.001 is present at this point. The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated. ClinicalTrials.gov: NCT01485315 . Registration date 30 November 2011. First patient was randomised 3 December 2011.