A randomised trial to investigate whether giving more blood transfusions to people undergoing surgery for hip fracture improves their outcomes

ISRCTN	ISRCTN28818784
DOI	https://doi.org/10.1186/ISRCTN28818784
IRAS number	308830, 299977
Secondary identifying numbers	CPMS 52646, IRAS 299977 (Scotland), IRAS 308830 (England and Wales), AC21119

Submission date: 28/04/2022
Registration date: 03/05/2022
Last edited: 25/07/2024

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Surgery

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

Background and study aims
Hip fracture is the most common serious injury in older people. More than 95% of patients have surgery. This surgery is often high-risk as patients may be frail and have other health problems including heart disease and anaemia (a low blood count). Patients may be in hospital for a long time and need rehabilitation. Up to 35% of surviving patients do not return to their original residence and have a high rate of increased dependency.
Research suggests that 30-40% of these patients have a blood transfusion around the time of operation. However, doctors are uncertain about what level of anaemia transfusions should be given at. Many current guidelines recommend transfusion at a lower level, but there is research which suggests that this level is too low particularly if the patient has a history of heart disease. In these patients, transfusion at a higher level may be better to prevent complications.

Who can participate?
Older (60 years or older) people with a hip fracture and anaemia

What does the study involve?
Participants will be randomly assigned to either receive blood transfusions at a lower blood count, in line with current guidelines, or a higher level, for the duration of their hospital stay, or 30 days, whichever is soonest.
Patients will have their blood count checked before and after any blood transfusions and will have additional blood tests (Troponin) and heart tracings (electrocardiographs, (ECG)) to check their heart.
At 30 days we will measure how often post-operative heart attacks and other complications occur, how long patients stay in hospital and mortality rate. At 30 and 120 days we will measure quality of life (assessed by questionnaire).
The study will last for 4 years but each patient will only be active in the study for 120 days. The study results will help doctors looking after people with hip fracture decide when is the best time to give blood transfusions

What are the possible benefits and risks of participating?
Benefits: There are no clear benefits of taking part in the study. Participants in the liberal arm of the study may receive a few additional transfusions than they would have had if they had not participated in the trial and participants in the restrictive arm may receive slightly fewer transfusions. One arm may be beneficial to participants but we do not know which and are conducting the study to try and find out.

Risks: Blood transfusions are generally very safe but they do carry risks. Transfusion reactions can occur but these are rare and usually mild (for example a fever or rash). Transfusions also have an increased risk of infections or pulmonary oedema although these are very rare.

Where is the study run from?
University of Edinburgh (UK)

When is the study starting and how long is it expected to run for?
August 2021 to April 2027

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).

Who is the main contact?
Prof. Michael Gillies, michael.gillies@nhslothian.scot.nhs.uk

Study website

Contact information

Prof Michael Gillies
Scientific

The University of Edinburgh
Dept of Anaesthesia, Critical Care and Pain Medicine
Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom

ORCID ID	0000-0003-1909-0790
Phone	+44 131 242 1642
Email	michael.gillies@nhslothian.scot.nhs.uk

Study information

Study design	Interventional randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Patient information material can be found at https://www.ed.ac.uk/usher/edinburgh-clinical-trials/our-studies/all-current-studies/result-hip/result-hip-study/about-study
Scientific title	The impact of REStrictive versUs Liberal Transfusion strategy on cardiac injury and death in patients undergoing surgery for Hip Fracture (RESULT-Hip)
Study acronym	RESULT Hip Version 1
Study hypothesis	Do patients with hip fracture have better clinical outcomes when a more liberal transfusion practice is used to treatanaemia?
Ethics approval(s)	1. Approved 17/03/2022, Scotland A Research Ethics Committee (2ndFloor, Waverley Gate, 2-4 Waterloo Place, Edinburgh, EH1 3EG, UK; +44 (0)7814 764 241; manx.neill@nhslothian.scot.nhs.uk), ref: 22/SS/0001 2. Approved 18/03/2022, North West- Haydock Research Ethics Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 207 1048032; haydock@rec.hra.nhs.uk), ref: 22/NW/0065
Condition	Blood transfusion for recovery from hip surgery
Intervention	Current interventions as of 17/11/2023: RESULT-Hip is a multicentre randomised trial of the effect of two blood transfusion strategies in patients with hip fractures on cardiac complications. One group of patients will have a restrictive transfusion strategy, which follows published guidelines, and the other a more liberal strategy. This is described more fully below. The study will take place in 30 UK hospitals that look after patients with hip fractures. When a patient is admitted to the hospital after breaking their hip, almost all go on to have surgery to treat this condition. They will be assessed by the clinical team or research team (where part of the clinical team) in the hospital to see if they meet the age inclusion criteria and do not have any exclusion criteria for the study. Those receiving palliative care (i.e. do not have surgery), who have life-threatening haemorrhage at the time of screening, pre-randomisation acute, or suspected acute, coronary syndrome, objection to receiving RBC transfusion or chronic transfusion-dependent anaemia, will be excluded. This can take place from the time the patient enters the hospital and up to and including 7 days post-surgery. If the patient meets the criteria they will be approached by a member of the clinical team or research team (where part of the clinical team) to discuss whether they are interested in taking part in the study. If they are, a member of the research team will take consent from the patient to randomise them to the study if they become anaemic (Hb ≤90 g/L) (considered 'consent in principle' or pre-consent') If the patient lacks mental capacity, then the research team will approach a family member or personal consultee, or professional consultee (if appropriate) to discuss the patient taking part in the study. If the patient (or consultee) consents then if the Hb trigger value (Hb ≤90 g/L) is reached the patient will be randomised to one arm or other of the study. The two arms will have all the same tests done. The difference between the two will be the point at which a blood transfusion is given. In one arm the transfusion will be given when the level of haemoglobin in the blood is ≤ 90g/L. This is called the “liberal” transfusion strategy. The aim will be to keep the haemoglobin in the range 90 - 110g/L. In the other arm the transfusion will be given when the level of haemoglobin in the blood is ≤ 75g/L. This is called the “restrictive” transfusion strategy and is the usual, or standard, level of transfusion in patients undergoing surgery for hip fracture. The aim will be to keep the haemoglobin in the range 75-90 g/L. Participants in both arms of the trial will follow either the restrictive or liberal strategy for the duration of their stay in acute hospital or until 30 days following randomisation whichever is soonest. We will follow up what happens to all the patients on both arms. The main (primary) outcome (we are interested in studying is about damage to the heart (cardiac injury) and death after this emergency surgery. The rate of occurrence of each of these may be different in the two arms of the study. To accurately measure the rate of damage to the heart, participants in both arms of the trial will have some additional tests done specifically for the study. They will have blood samples taken to check for levels of a chemical called troponin. Blood samples for troponin testing will be taken when participants are randomised to the trial and twice more between days 1 and 5 following randomisation. Where possible blood samples will be taken at the same time as routine hospital blood samples to minimise inconvenience to the participant. The blood samples will be frozen at the hospital and later transported to Edinburgh for analysis. Participants will have electrocardiographs (ECG, or heart trace) taken at randomisation and once more during days 2-5 following randomisation. The ECG checks the heart's rhythm and electrical activity. It is a common and painless test carried out by attaching sensors to the participant's chest. We are also interested in how the participant's quality of life is affected by the intervention, and we will ask them to complete a simple quality of life questionnaire (EQ-5D-5L), which takes just a few minutes to complete, at the time they are randomised to the study. We will collect data at 30 days and 120 days after randomisation if the participant is still alive. This will allow us to assess whether the blood transfusion affects time in hospital, recovery, and quality of life after this type of surgery. This will be done by asking the participant to complete the EQ-5D-5L questionnaire again which can be done over the telephone. We will also ask the participant to answer a short questionnaire about their health service usage at both 30 and 120 days. The rest of the data that we need for the study is collected from the participant's medical records. After these final questionnaires, at 120 days, we will not require anything else from the participant. In participants that lack capacity, we will ask the participant's personal consultee to complete the proxy EQ-5D-5L questionnaire at randomisation. We will ask the consultee for permission to contact them at 30 and 120 days (if the participant has not regained capacity) for the completion of the EQ-5D-5L and health resource questionnaires on the participant's behalf. To answer the study question accurately we will need to recruit 1964 patients, they will be split between the two arms of the study. This will allow us to detect a difference in the main outcome. This figure has been calculated using information from our previous pilot study and allows for some patients to drop out of the study. The whole project will take 48 months to complete. However, each patient is only actively involved for 120 days post-randomisation. Process Evaluation We will include a process evaluation of the internal pilot study consistent with MRC guidance. Our objectives are: to establish the extent to which the intervention is implemented as intended during the internal pilot across different sites; to ascertain how feasible and acceptable the intervention is to clinical staff across different sites; to identify any facilitators and barriers to recruitment. The methods used to conduct the PE of the internal pilot will be: During Site Initiation Visit - to identify key research staff, collect baseline data on context and establish the acceptability of study protocol. During the internal pilot - all sites in the internal pilot will be invited to participate in individual interviews. Interviews will be conducted remotely by telephone, or by web-based service. Sampling will be used to ensure a range of participants according to grade, profession and role in the research or clinical teams. Interviews will be recorded, transcribed and analysed to identify common themes. The findings of the process evaluation will be reported to the Trial Management and Trial Steering Groups and will feed into decisions about the on-going progress and management of the trial. Previous interventions: RESULT-Hip is a multicentre randomised trial of the effect of two blood transfusion strategies in patients with hip fractures on cardiac complications. One group of patients will have a restrictive transfusion strategy, which follows published guidelines, and the other a more liberal strategy. This is described more fully below. The study will take place in 30 UK hospitals that look after patients with hip fractures. When a patient is admitted to the hospital after breaking their hip, almost all go on to have surgery to treat this condition. They will be assessed by the clinical team or research team (where part of the clinical team) in the hospital to see if they meet the age inclusion criteria and do not have any exclusion criteria for the study. Those receiving palliative care (i.e. do not have surgery), who have life-threatening haemorrhage at the time of screening, pre-randomisation acute coronary syndrome or objection to receiving RBC transfusion will be excluded. This can take place from the time the patient enters the hospital and up to and including 7 days post-surgery. If the patient meets the criteria they will be approached by a member of the clinical team or research team (where part of the clinical team) to discuss whether they are interested in taking part in the study. If they are, a member of the research team will take consent from the patient to randomise them to the study if they become anaemic (Hb ≤90 g/L) (considered 'consent in principle' or pre-consent') If the patient lacks mental capacity, then the research team will approach a family member or personal consultee, or professional consultee (if appropriate) to discuss the patient taking part in the study. If the patient (or consultee) consents then if the Hb trigger value (Hb ≤90 g/L) is reached the patient will be randomised to one arm or other of the study. The two arms will have all the same tests done. The difference between the two will be the point at which a blood transfusion is given. In one arm the transfusion will be given when the level of haemoglobin in the blood is ≤ 90g/L. This is called the “liberal” transfusion strategy. The aim will be to keep the haemoglobin in the range 90 - 110g/L. In the other arm the transfusion will be given when the level of haemoglobin in the blood is ≤ 75g/L. This is called the “restrictive” transfusion strategy and is the usual, or standard, level of transfusion in patients undergoing surgery for hip fracture. The aim will be to keep the haemoglobin in the range 75-90 g/L. Participants in both arms of the trial will follow either the restrictive or liberal strategy for the duration of their stay in acute hospital or until 30 days following randomisation whichever is soonest. We will follow up what happens to all the patients on both arms. The main (primary) outcome (we are interested in studying is about damage to the heart (cardiac injury) and death after this emergency surgery. The rate of occurrence of each of these may be different in the two arms of the study. To accurately measure the rate of damage to the heart, participants in both arms of the trial will have some additional tests done specifically for the study. They will have blood samples taken to check for levels of a chemical called troponin. Blood samples for troponin testing will be taken when participants are randomised to the trial, on day 1 and once more between days 2 - 5 following randomisation. Where possible blood samples will be taken at the same time as routine hospital blood samples to minimise inconvenience to the participant. The blood samples will be frozen at the hospital and later transported to Edinburgh for analysis. Participants will have electrocardiographs (ECG, or heart trace) taken at randomisation and once more during days 2-5 following randomisation. The ECG checks the heart's rhythm and electrical activity. It is a common and painless test carried out by attaching sensors to the participant's chest. We are also interested in how the participant's quality of life is affected by the intervention, and we will ask them to complete a simple quality of life questionnaire (EQ-5D-5L), which takes just a few minutes to complete, at the time they are randomised to the study. We will collect data at 30 days and 120 days after randomisation if the participant is still alive. This will allow us to assess whether the blood transfusion affects time in hospital, recovery, and quality of life after this type of surgery. This will be done by asking the participant to complete the EQ-5D-5L questionnaire again which can be done over the telephone. We will also ask the participant to answer a short questionnaire about their health service usage at both 30 and 120 days. The rest of the data that we need for the study is collected from the participant's medical records. After these final questionnaires, at 120 days, we will not require anything else from the participant. In participants that lack capacity, we will ask the participant's personal consultee to complete the proxy EQ-5D-5L questionnaire at randomisation. We will ask the consultee for permission to contact them at 30 and 120 days (if the participant has not regained capacity) for the completion of the EQ-5D-5L and health resource questionnaires on the participant's behalf. To answer the study question accurately we will need to recruit 1964 patients, they will be split between the two arms of the study. This will allow us to detect a difference in the main outcome. This figure has been calculated using information from our previous pilot study and allows for some patients to drop out of the study. The whole project will take 48 months to complete. However, each patient is only actively involved for 120 days post-randomisation. Process Evaluation We will include a process evaluation of the internal pilot study consistent with MRC guidance. Our objectives are: to establish the extent to which the intervention is implemented as intended during the internal pilot across different sites; to ascertain how feasible and acceptable the intervention is to clinical staff across different sites; to identify any facilitators and barriers to recruitment. The methods used to conduct the PE of the internal pilot will be: During Site Initiation Visit - to identify key research staff, collect baseline data on context and establish the acceptability of study protocol. During the internal pilot - all sites in the internal pilot will be invited to participate in individual interviews. Interviews will be conducted remotely by telephone, or by web-based service. Sampling will be used to ensure a range of participants according to grade, profession and role in the research or clinical teams. Interviews will be recorded, transcribed and analysed to identify common themes. The findings of the process evaluation will be reported to the Trial Management and Trial Steering Groups and will feed into decisions about the on-going progress and management of the trial.
Intervention type	Other
Primary outcome measure	Death or major cardiac adverse events (MACE) measured using patient records up to 30 days
Secondary outcome measures	Measured using patient records at 30 days: 1. All cause mortality 2. Myocardial injury post randomisation (troponin >99th centile (URL) AND a 20% change from baseline) 3. Individual MACE components 4. Complications (including AKI, delirium, stroke, pulmonary embolus) 5. Proportion of participants transfused 6. Discharge destination 7. Acute hospital length of stay 8. EQ-5D-5L9. Health services resource utilisation (from questionnaires) Additional secondary outcome measures Measured using patient records at 120 days: 1. All cause mortality 2. Discharge destination 3. Acute hospital length of stay 4. unplanned hospital readmissions 5. Mobility 6. Residential status 7. EQ-5D-5L9., Health services resource utilisation (from questionnaire)
Overall study start date	01/08/2021
Overall study end date	30/04/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	60 Years
Sex	Both
Target number of participants	Planned Sample Size: 1964; UK Sample Size: 1964
Participant inclusion criteria	Current participant inclusion criteria as of 17/11/2023: 1. Adults aged 60 years or over 2. Admission to acute unit for operative management of hip fracture For Randomisation: 3. Presence of anaemia (Haemoglobin equal to or less than 90 g/L) at any point between the date of admission to hospital up to and including seven days after surgery Previous participant inclusion criteria: 1. Adults aged 60 years or over 2. Admission to hospital for operative management of hip fracture For Randomisation: 3. Presence of anaemia (Haemoglobin equal to or less than 90 g/L) at any point between the date of admission to hospital up to and including seven days after surgery
Participant exclusion criteria	Current participant inclusion criteria as of 17/11/2023: 1. Objection to RBC transfusion 2. Unable to obtain consent (from patient or in accordance with appropriate mental capacity legislation for site) 3. Patients for non-operative management or not expected to survive 48 hours 4. Patients with a new or suspected acute coronary syndrome meeting 4th Universal Definition during current admission 5. Rapid or uncontrolled blood loss resulting in haemodynamic instability 6. Transfusion dependent/chronic anaemias (eg Myelodysplasia or bone marrow failure syndromes) Previous participant inclusion criteria: 1. Objection to RBC transfusion 2. Unable to obtain consent (from patient or in accordance with appropriate mental capacity legislation for site) 3. Patients for non-operative management or not expected to survive 48 hours 4. Patients with a new acute coronary syndrome meeting 4th Universal Definition during current admission 5. Rapid or uncontrolled blood loss resulting in haemodynamic instability
Recruitment start date	01/06/2022
Recruitment end date	30/04/2026

Locations

Countries of recruitment

England
Northern Ireland
Scotland
United Kingdom
Wales

Study participating centres

Royal Infirmary of Edinburgh at Little France

51 Little France Crescent
Old Dalkeith Road
Edinburgh
Lothian
EH16 4SA
United Kingdom

John Radcliffe Hospital

Headley Way
Headington
Oxford
OX3 9DU
United Kingdom

Glasgow Royal Infirmary

84 Castle Street
Glasgow
G4 0SF
United Kingdom

Wishaw General Hospital

50 Netherton Street
Wishaw
ML2 0DP
United Kingdom

Borders General Hospital

Huntlyburn Terrace
Melrose
TD6 9BS
United Kingdom

Rotherham General Hospital

Moorgate Road
Rotherham
S60 2UD
United Kingdom

Southmead Hospital

Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom

Norfolk and Norwich University Hospital

Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom

Leicester Royal Infirmary

Infirmary Square
Leicester
LE1 5WW
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

University Hospital of North Tees

Hardwick Road
Stockton-on-tees
TS19 8PE
United Kingdom

Dumfries and Galloway Royal Infirmary

Bankend Road
Dumfries
Dumfries and Galloway
DG1 4AP
United Kingdom

Victoria Hospital

Hayfield Road
Kirkcaldy
KY25AH
United Kingdom

The James Cook University Hospital

Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Horton General Hospital

81a Oxford Road
Banbury
OX16 9AL
United Kingdom

Hereford County Hospital

Stonebow Road
Hereford
HR1 2BN
United Kingdom

Royal Albert Edward Infirmary

Wigan Lane
Wigan
WN1 2NN
United Kingdom

Ipswich Hospital

Heath Road
Ipswich
IP4 5PD
United Kingdom

East Surrey Hospital

Canada Avenue
Redhill
RH1 5RH
United Kingdom

Worcestershire Royal Hospital

Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Aberdeen Royal Infirmary

Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

North Devon District Hospital

Raleigh Park
Barnstaple
EX31 4JB
United Kingdom

Darlington Memorial Hospital

Hollyhurst Road
Darlington
DL3 6HX
United Kingdom

Royal Devon and Exeter Hospital

Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

University Hospital of North Durham Cdc

University Hospital of North Durham
North Road
Durham
DH1 5TW
United Kingdom

Southport and Formby District General Hospital

Town Lane
Southport
PR8 6PN
United Kingdom

Stoke Mandeville Hospital

Mandeville Road
Aylesbury
HP21 8AL
United Kingdom

Royal Victoria Hospital

Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom

Sponsor information

University of Edinburgh and NHS Lothian Health Board
University/education

The University of Edinburgh
Usher Building
5-7 Little France Road
Edinburgh Bioquarter Gate 3
Edinburgh
EH6 4UX
Scotland
United Kingdom

Phone	+44 131 2423326
Email	resgov@accord.scot
Website	https://www.accord.ed.ac.uk

Funders

Funder type

Government

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC)

No information available

National Institute for Health Research
Government organisation / National government

Alternative name(s): National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
Location: United Kingdom

Results and Publications

Intention to publish date	30/06/2027
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal
IPD sharing plan	The current data sharing plans for this study are unknown and will be available at a later date

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
HRA research summary			26/07/2023	No	No
Protocol file	version 3	15/09/2022	17/11/2023	No	No
Protocol file	version 4	03/05/2023	25/07/2024	No	No

Additional files

ISRCTN28818784_Protocol_v3_15sep2022.pdf
ISRCTN28818784 RESULT-HIP_Protocol_V4_03May2023.pdf

Editorial Notes

25/07/2024: The following changes were made to the trial record:
1. Uploaded protocol v4.0 (not peer-reviewed) as an additional file.
2. The sponsor address was changed.
3. The study participating centres Queens Medical Centre and Royal Victoria Hospital (Belfast) were removed and Royal Devon and Exeter Hospital, University Hospital of North Durham Cdc, Southport and Formby District General Hospital, Stoke Mandeville Hospital, Royal Victoria Hospital (Newcastle) were added.
24/07/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 31/07/2024 to 30/04/2026.
2. The overall study end date was changed from 31/07/2025 to 30/04/2027.
3. The intention to publish date was changed from 30/09/2025 to 30/06/2027.
17/11/2023: The following changes have been made:
1. Study website added.
2. Protocol (not peer-reviewed) uploaded.
3. A link was added to the patient information sheets.
4. The interventions were changed.
5. The participant inclusion criteria were changed.
6. The participant exclusion criteria were changed.
7. The Royal Victoria Infirmary, Royal Devon and Exeter Hospital, University Hospital of North Durham, and Royal Alexandra Hospital were removed from the study participating centres.
8. The Leicester Royal Infirmary, Southampton General Hospital, University Hospital of North Tees, Dumfries and Galloway Royal Infirmary, Victoria Hospital, James Cook University Hospital, Horton General Hospital, Hereford County Hospital, Royal Albert Edward Infirmary, Ipswich Hospital, East Surrey Hospital, Worcestershire Royal Hospital, Aberdeen Royal Infirmary, North Devon District Hospital and Darlington Memorial Hospital were added as study participating centres.
9. The Sponsor Organisation was changed from Accord (United Kingdom) to the University of Edinburgh and NHS Lothian Health Board.
28/04/2022: Trial's existence confirmed by the National Institute for Health and Care Research (NIHR) (UK).