Stopping perioperative angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers in major noncardiac surgery
| ISRCTN | ISRCTN17251494 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17251494 |
| EudraCT/CTIS number | 2016-004141-90 |
| Secondary identifying numbers | ReDA Ref: 11368 |
- Submission date
- 18/05/2017
- Registration date
- 29/05/2017
- Last edited
- 12/12/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Surgery
Plain English Summary
Background and study aims:
Many patients after major surgery have detectable levels of a natural marker for injury to the heart which is linked to delayed recovery, infections and/or death. This may occur as a result of prolonged stress to the body following surgery. Around 40% of surgical patients most at risk of these complications after surgery are prescribed angiotensin converting enzyme inhibitors (ACE-I) or angiotensin-II receptor blockers (ARB). These drugs are used to treat a range of long term conditions, including high blood pressure, kidney disease and heart failure. However, the same drugs are frequently stopped before surgery in the widely-held belief that this prevents low blood pressure during or after surgery. Doctors are uncertain whether these drugs should be stopped or continued. Some clinical research suggests that stopping ACE-I and/or ARB just before surgery could lead to complications after surgery. The aim of this study is to find out whether continuing or temporarily stopping these drugs reduces injury to the heart, and other complications, after major planned surgery.
Who can participate?
Adults aged 60 years and over who are undergoing major surgery and are currently on angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers therapy.
What does the study involve?
Before surgery, participants are randomly allocated to one of two groups. Those in the first group stop taking their regular angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker. Those in the second group continue as normal to take their medications after surgery. Participants then undergo their surgery as normal. Blood samples collected as part of standard care are collected and patients have their heart rate and blood pressure measured just before surgery and after surgery, to see whether stopping/continuing medication drugs makes any difference. Those who stop taking the drugs restart treatment around 24-48 hours after waking up from the operation. These drugs are continued or restarted as there are no signs that this may affect blood pressure or kidney function. After the first two days, participants are visited by the researchers to follow their recovery, reviewing medical notes until they leave hospital. Participants are also contacted by telephone in one month and again six months later to ask some simple questions about their wellbeing. The phone call lasts for around five minutes.
What are the possible benefits and risks of participating?
There are no notable benefits involved with participating. The risks of this trial are very small. Many surgeons/anaesthetists instruct patients to stop these drugs, while many advise to continue them. This reflects the uncertainty as to what doctors should actually do. Early studies suggest that continuing these drugs may benefit many patients in this trial. There is a very small risk of high or low blood pressure for some patients. For this reason, patients will be closely monitored throughout the study period and, if necessary, the research team will make adjustments to patients’ treatment to make ensure they are safe.
Where is the study run from?
Royal London Hospital (UK)
When is study starting and how long is it expected to run for?
July 2016 to June 2022 (updated 26/05/2022, previously: March 2022; updated 31/03/2021, previously: January 2021; updated 19/07/2019, previously: July 2020)
Who is funding the study?
British Oxygen Company Research Chair Award in Anaesthesia (UK)
Who is the main contact?
Dr Priyanthi Dias
p.dias@qmul.ac.uk
Contact information
Public
Adult Critical Care Research
Room 14 Central Tower
The Royal London Hospital
Whitechapel
London
E1 1BB
United Kingdom
 ORCID ID |
0000-0003-0565-5164 |
|---|---|
| Phone | +44 20 3594 0352 |
| admin@spacetrial.org |
Study information
| Study design | Open multi-centre randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN17251494_PIS_08May17_V3.0.docx |
| Scientific title | Stopping Perioperative Angiotensin II Converting Enzyme inhibitors and/or angiotensin receptor blockers in major non-cardiac surgery (SPACE): A phase III, mechanistic, randomised controlled trial |
| Study acronym | SPACE |
| Study hypothesis | The aim of this study is to determine whether continuing angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers reduces the risk of myocardial injury, identified using high-sensitivity plasma troponin measurement during the first 48 hours after surgery. |
| Ethics approval(s) | London - City & East Research Ethics Committee London, 31/03/2017, ref: 16/LO/1495 |
| Condition | Patients undergoing major surgery requiring general anaesthesia |
| Intervention | Following provision of informed consent, participants will be randomly allocated to one of two groups (1:1) using a computer generated dynamic procedure (minimisation) with a random component. Minimisation will be performed by trial centre, angiotensin converting enzyme-inhibitor and/or angiotensin receptor blocker category and surgical procedure. The trial intervention period will commence 48 hours before surgery and continue for at least 48 hours after surgery. After randomisation, participants will received a patient advice letter confirming their treatment group allocation, to stopping or continuing their angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers. Participants will also be reminded by telephone call and/or text message, or in person if they are in hospital. If the patients are not in hospital, they will receive a telephone call and/or text message or visit the day before surgery. Angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers will be continued or discontinued as per treatment group allocation and this will continue until 48 hours after the end of surgery. Since angiotensin II converting enzyme inhibitors and angiotensin receptor blockers have differing durations of action, participants will receive drug-specific instructions as to when to stop. When the angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers duration of action is equal to, or more than, 24 hours, the drug will be stopped 48 hours prior to surgery. All other angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers will be stopped on the day before surgery. Participants will be followed up on days 1, 2 and 3 after surgery and at 30 days after randomisation. The end of the study is defined as the point when the last patient has completed 30-day follow-up. To minimise bias, follow-up data will be collected by a study team member who is blinded to the primary outcome result. Similarly, investigators will review a participant’s medical record (paper or electronic) after surgery, unaware of the primary outcome result (which is measured after the end of the trial). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Any drug listed either as an angiotensin ii converting enzyme inhibitor or angiotensin receptor blocker. |
| Primary outcome measure | Troponin-T levels will be measured in blood samples collected immediately before the induction of anaesthesia, and then at 24 and 48 hours after surgery. |
| Secondary outcome measures | 1. Highest level of Troponin-T is assessed on plasma high sensitivity Troponin-T, measured within 48 hours of surgery (continuous variable) 2. Infection of Clavien-Dindo grade II or greater, assessed using a patient medical note review and telephone interview, within 30 days from randomisation 3. Myocardial infarction assessed by patient medical note review and telephone interview, within 30 days from randomisation 4. Acute heart failure assessed using a patient medical note review and telephone interview within 30 days from randomisation 5. Stroke within 30 days from randomisation assessed using a patient medical note review and telephone interview Process measures: 1. Duration of hospital stay (number of days from randomisation until hospital discharge) assessed by a review of the patient's medical records 2. Number of critical care free days*, assessed by a review of the patient's medical records, up to 30 days from randomisation *A critical care free day is defined as a day in which the patient is alive and is not in a level 2 or level 3 critical care bed. |
| Overall study start date | 01/07/2016 |
| Overall study end date | 30/06/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 260 (130 per arm) |
| Total final enrolment | 260 |
| Participant inclusion criteria | 1. Informed consent (no incapacitated or vulnerable adult or minors will be included) 2. Currently taking angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers therapy 3. Age 60 years and over 4. Patients undergoing major surgery (major joint replacement/ vascular/ gastrointestinal) requiring general anesthesia that is expected to take longer than 120 minutes 5. American Society of Anesthesiologists grade 3 or above |
| Participant exclusion criteria | 1. Current participation in any other trials 2. Recent myocardial infarction (within 3 months) 3. Any condition, which in the opinion of the treating clinician would result in the patient being harmed by the cessation of the angiotensin II converting enzyme inhibitors and/or angiotensin receptor blockers therapy |
| Recruitment start date | 01/06/2017 |
| Recruitment end date | 31/01/2022 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Adult Critical Care Unit Research Offices
4th Floor Adult Critical Care Unit Research Office 14
Whitechapel Road
London
E1 1FR
United Kingdom
Sponsor information
University/education
Joint Research Management Office
5 Walden Street
London
E1 2EF
England
United Kingdom
| Phone | +44 20 7882 7250 |
|---|---|
| sponsorsrep@bartshealth.nhs.uk | |
| Website | http://bartshealth.nhs.uk/research/about-us/contact-us/ |
"ROR" |
https://ror.org/026zzn846 |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 30/06/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a peer reviewed journal, conference presentations and webcasts. Intent to publish the main paper as soon as possible after completion of the trial. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Gareth Ackland, Senior Lecturer, Perioperative Medicine. Translational Medicine & Therapeutics (216B), William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version V3.0 | 08/05/2017 | 13/06/2017 | No | Yes |
| Protocol file | version 2.0 | 14/12/2016 | 16/05/2023 | No | No |
| Protocol file | version 3.0 | 12/05/2017 | 16/05/2023 | No | No |
| Protocol file | version 4.0 | 03/10/2017 | 16/05/2023 | No | No |
| Protocol file | version 5.0 | 21/05/2019 | 16/05/2023 | No | No |
| Protocol file | version 6.0 | 11/03/2020 | 16/05/2023 | No | No |
| Protocol file | version 7.0 | 14/12/2020 | 16/05/2023 | No | No |
| Protocol file | version 8.0 | 28/01/2022 | 16/05/2023 | No | No |
| Statistical Analysis Plan | version 2.0 | 17/03/2022 | 16/05/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 03/11/2023 | 12/12/2023 | Yes | No |
Additional files
- ISRCTN17251494_PIS_08May17_V3.0.docx
- Uploaded 13/06/2017
- ISRCTN17251494_SAP_v2.0_17Mar22.pdf
- ISRCTN17251494_PROTOCOL_v2.0_14Dec16.pdf
- ISRCTN17251494_PROTOCOL_v3.0_12May17.pdf
- ISRCTN17251494_PROTOCOL_v4.0_03Oct17.pdf
- ISRCTN17251494_PROTOCOL_v5.0_21May19.pdf
- ISRCTN17251494_PROTOCOL_v6.0_11Mar20.pdf
- ISRCTN17251494_PROTOCOL_v7.0_14Dec20.pdf
- ISRCTN17251494_PROTOCOL_v8.0_28Jan22.pdf
Editorial Notes
12/12/2023: Publication reference added.
16/05/2023: Statistical analysis plan and protocols uploaded.
28/06/2022: Total final enrolment added.
26/05/2022: The following changes have been made:
1. The overall trial end date has been changed from 03/03/2022 to 30/06/2022 and the plain English summary has been updated to reflect this change.
2. The intention to publish date has been changed from 31/01/2023 to 30/06/2023.
31/03/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2020 to 31/01/2022.
2. The overall end date was changed from 31/01/2021 to 03/03/2022.
3. The intention to publish date was changed from 31/01/2022 to 31/01/2023.
4. The plain English summary was updated to reflect these changes.
19/07/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2019 to 31/12/2020.
2. The overall end date was changed from 01/07/2020 to 31/01/2021.
3. The intention to publish date was changed from 30/06/2020 to 31/01/2022.
4. The plain English summary was updated to reflect these changes.
11/03/2019: Internal review.
22/09/2017: Internal review
13/06/2017: The participant information sheet has been uploaded.
