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Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

ABSTRACT: BACKGROUND:Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy. METHODS:The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (? 70?years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ?9?g/dl during surgery or within 3?days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb???9?g/dl with a target range for the post-transfusion Hb level of 9-10.5?g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb???7.5?g/dl with a target range for the post-transfusion Hb level of 7.5-9?g/dl). The intervention per patient will be followed until hospital discharge or up to 30?days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90?days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect. DISCUSSION:The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90?days after surgery. TRIAL REGISTRATION:ClinicalTrials.gov (identifier: NCT03369210 ).

SUBMITTER: Meybohm P

PROVIDER: S-EPMC6360712 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

Meybohm Patrick P Lindau Simone S Treskatsch Sascha S Francis Roland R Spies Claudia C Velten Markus M Wittmann Maria M Gueresir Erdem E Stoppe Christian C Kowark Ana A Coburn Mark M Selleng Sixten S Baschin Marcel M Jenichen Gregor G Meersch Melanie M Ermert Thomas T Zarbock Alexander A Kranke Peter P Kredel Markus M Helf Antonia A Laufenberg-Feldmann Rita R Ferner Marion M Wittenmeier Eva E Gürtler Karl-Heinz KH Kienbaum Peter P de Abreu Marcel Gama MG Sander Michael M Bauer Michael M Seyfried Timo T Gruenewald Matthias M Choorapoikayil Suma S Mueller Markus M MM Seifried Erhard E Brosteanu Oana O Bogatsch Holger H Hasenclever Dirk D Zacharowski Kai K

Trials 20190204 1

<h4>Background</h4>Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restri ...[more]

PMID: 30717805

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Project description:BackgroundA strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level.MethodsIn this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days.ResultsA total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49).ConclusionsIn patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Project description:ObjectiveTo compare the benefit and harm of restrictive versus liberal transfusion strategies to guide red blood cell transfusions.DesignSystematic review with meta-analyses and trial sequential analyses of randomised clinical trials.Data sourcesCochrane 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 selectionPublished 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 extractionTwo 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.Results31 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.ConclusionsCompared 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 registrationPROSPERO CRD42013004272.

Project description:ImportanceThe optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear.ObjectiveTo determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy.Design, setting, and participantsOpen-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019.InterventionsPatients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy.Main outcomes and measuresThe primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome.ResultsAmong 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups.Conclusions and relevanceAmong patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm.Trial registrationClinicalTrials.gov Identifier: NCT02648113.

Project description:BackgroundBone marrow failure disorders include a heterogenous group of disorders, of which myelodysplastic syndrome (MDS), forms the largest subgroup. MDS is predominantly a disease of the elderly, with many elderly people managed conservatively with regular allogeneic red blood cell (RBC) transfusions to treat their anaemia. However, RBC transfusions are not without risk. Despite regular transfusions playing a central role in treating such patients, the optimal RBC transfusion strategy (restrictive versus liberal) is currently unclear.ObjectivesTo assess the efficacy and safety of a restrictive versus liberal red blood cell transfusion strategy for patients with myelodysplasia, acquired aplastic anaemia, and other inherited bone marrow failure disorders.Search methodsWe searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 4), Ovid MEDLINE (from 1946), Ovid EMBASE (from 1974), EBSCO CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 26th May 2015.Selection criteriaRCTs including patients with long-term bone marrow failure disorders that require allogeneic blood transfusion, who are not being actively treated with a haematopoietic stem cell transplant, or intensive chemotherapy.Data collection and analysisWe used standard Cochrane review methodology. One author initially screened all references, and excluded any that were clearly irrelevant or duplicates. Two authors then independently screened all abstracts of articles, identified by the review search strategy, for relevancy. Two authors independently assessed the full text of all potentially relevant articles for eligibility, completed the data extraction and assessed the studies for risk of bias using The Cochrane Collaboration's 'Risk of bias' tool.Main resultsWe included one trial (13 participants) and identified three ongoing trials that assess RBC transfusion strategies in people with MDS.The quality of the evidence was very low across different outcomes according to GRADE methodology.The one included study randomised participants to a restrictive [haemoglobin (Hb) transfusion trigger < 72 g/L, 8 participants] or liberal [Hb trigger < 96 g/L, 5 participants] transfusion policy. There was insufficient evidence to determine a difference in all-cause mortality (1 RCT; 13 participants; RR 0.13, 95% CI 0.01 to 2.32; very low quality evidence). There was insufficient evidence to determine a difference in the number of red blood cell transfusions (1 RCT; 13 participants; 1.8 units per patient per month in the liberal group, compared to 0.8 in the restrictive arm, no standard deviation was reported; very low quality evidence). There were no anaemia-related complications reported (cardiac failure) and no reported effect on activity levels (no statistics provided). The study did not report: mortality due to bleeding/infection/transfusion reactions or iron overload, quality of life, frequency and length of hospital admissions, serious infections (requiring admission to hospital), or serious bleeding (e.g. WHO/CTCAE grade 3 (or equivalent) or above).Authors' conclusionsThis review indicates that there is currently a lack of evidence for the recommendation of a particular transfusion strategy for bone marrow failure patients undergoing supportive treatment only. The one RCT included in this review was only published as an abstract and contained only 13 participants. Further randomised trials with robust methodology are required to develop the optimal transfusion strategy for such patients, particularly as the incidence of the main group of bone marrow failure disorders, MDS, rises with an ageing population.

Project description:BackgroundHeart failure related to cardiac siderosis remains a major cause of death in transfusion dependent anaemias. Replacement fibrosis has been reported as causative of heart failure in siderotic cardiomyopathy in historical reports, but these findings do not accord with the reversible nature of siderotic heart failure achievable with intensive iron chelation.MethodsTen whole human hearts (9 beta-thalassemia major, 1 sideroblastic anaemia) were examined for iron loading and fibrosis (replacement and interstitial). Five had died from heart failure, 4 had cardiac transplantation for heart failure, and 1 had no heart failure (death from a stroke). Heart samples iron content was measured using atomic emission spectroscopy. Interstitial fibrosis was quantified by computer using picrosirius red (PSR) staining and expressed as collagen volume fraction (CVF) with normal value for left ventricle <3%.ResultsThe 9 hearts affected by heart failure had severe iron loading with very low T2* of 5.0 ± 2.0 ms (iron concentration 8.5 ± 7.0 mg/g dw) and diffuse granular myocardial iron deposition. In none of the 10 hearts was significant macroscopic replacement fibrosis present. In only 2 hearts was interstitial fibrosis present, but with low CVF: in one patient with no cardiac siderosis (death by stroke, CVF 5.9%) and in a heart failure patient (CVF 2%). In the remaining 8 patients, no interstitial fibrosis was seen despite all having severe cardiac siderosis and heart failure (CVF 1.86% ±0.87%).ConclusionReplacement cardiac fibrosis was not seen in the 9 post-mortem hearts from patients with severe cardiac siderosis and heart failure leading to death or transplantation, which contrasts markedly to historical reports. Minor interstitial fibrosis was also unusual and very limited in extent. These findings accord with the potential for reversibility of heart failure seen in iron overload cardiomyopathy.Trial registrationClinicalTrials.gov Identifier: NCT00520559.

Project description:Blood transfusion might affect long-term mortality by changing immune function and thus potentially increasing the risk of subsequent infections and cancer recurrence. Compared with a restrictive transfusion strategy, a more liberal strategy could reduce cardiac complications by lowering myocardial damage, thereby reducing future deaths from cardiovascular disease. We aimed to establish the effect of a liberal transfusion strategy on long-term survival compared with a restrictive transfusion strategy.In the randomised controlled FOCUS trial, adult patients aged 50 years and older, with a history of or risk factors for cardiovascular disease, and with postoperative haemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture, were eligible for enrolment. Patients were recruited from 47 participating hospitals in the USA and Canada, and eligible participants were randomly allocated in a 1:1 ratio by a central telephone system to either liberal transfusion in which they received blood transfusion to maintain haemoglobin level at 100 g/L or higher, or restrictive transfusion in which they received blood transfusion when haemoglobin level was lower than 80 g/L or if they had symptoms of anaemia. In this study, we analysed the long-term mortality of patients assigned to the two transfusion strategies, which was a secondary outcome of the FOCUS trial. Long-term mortality was established by linking the study participants to national death registries in the USA and Canada. Treatment assignment was not masked, but investigators who ascertained mortality and cause of death were masked to group assignment. Analyses were by intention to treat. The FOCUS trial is registered with ClinicalTrials.gov, number NCT00071032.Between July 19, 2004, and Feb 28, 2009, 2016 patients were enrolled and randomly assigned to the two treatment groups: 1007 to the liberal transfusion strategy and 1009 to the restrictive transfusion strategy. The median duration of follow-up was 3·1 years (IQR 2·4-4·1 years), during which 841 (42%) patients died. Long-term mortality did not differ significantly between the liberal transfusion strategy (432 deaths) and the restrictive transfusion strategy (409 deaths) (hazard ratio 1·09 [95% CI 0·95-1·25]; p=0·21).Liberal blood transfusion did not affect mortality compared with a restrictive transfusion strategy in a high-risk group of elderly patients with underlying cardiovascular disease or risk factors. The underlying causes of death did not differ between the trial groups. These findings do not support hypotheses that blood transfusion leads to long-term immunosuppression that is severe enough to affect long-term mortality rate by more than 20-25% or cause of death.National Heart, Lung, and Blood Institute.

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Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

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Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

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