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Trial registered on ANZCTR


Registration number
ACTRN12623000848606
Ethics application status
Approved
Date submitted
28/06/2023
Date registered
8/08/2023
Date last updated
14/01/2024
Date data sharing statement initially provided
8/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised trial of blood pressure maintenance using angiotensin II versus noradrenaline in cardiac surgery patients to determine effect on length of hospital stay
Scientific title
A Prospective angiOtensin vs. noRadrenaline Trial for Hypotension management to determine the effect on length Of hospital stay in cardiac Surgery
Secondary ID [1] 309951 0
None
Universal Trial Number (UTN)
U1111-1294-0768
Trial acronym
PORTHOS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiac surgery 330433 0
Hypotension 330434 0
Condition category
Condition code
Anaesthesiology 327277 327277 0 0
Other anaesthesiology
Cardiovascular 327278 327278 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Angiotensin II intravenous infusion titrated to a systemic mean arterial pressure of 70 - 80 mmHg in a dose range of 0-80ng/kg/min starting after induction of anaesthesia and prior to start of surgery and continuing for 48 hours after induction of anaesthesia
Study drug administration adherence as recorded in case report form
Intervention code [1] 326369 0
Treatment: Drugs
Comparator / control treatment
Noradrenaline intravenous infusion titrated to a systemic mean arterial pressure of 70 - 80 mmHg in a dose range of 0-0.4mcg/kg/min starting after induction of anaesthesia and prior to start of surgery and continuing for 48 hours after induction of anaesthesia
Study drug administration adherence as recorded in case report form
Control group
Active

Outcomes
Primary outcome [1] 335152 0
Main study primary outcome:
Duration of hospital stay - defined as length of time from anaesthesia start date/time until hospital discharge date/time (according to medical record)
Timepoint [1] 335152 0
At time of hospital discharge
Secondary outcome [1] 423277 0
Acute kidney injury of any stage as defined by KDIGO criteria, based on serum creatinine only
Timepoint [1] 423277 0
Within 7 days of surgery
Secondary outcome [2] 423278 0
Major adverse kidney events (death, renal replacement therapy, persistent loss of eGFR at discharge > 50%) (data from review of medical record)
Timepoint [2] 423278 0
Within primary hospital stay
Secondary outcome [3] 423279 0
Requirement for renal replacement therapy (data from review of medical record)
Timepoint [3] 423279 0
Within 7 days of surgery
Secondary outcome [4] 423280 0
Duration of stage 2 or 3 acute kidney injury by KDIGO criteria (serum creatinine only)
Timepoint [4] 423280 0
Within primary hospital stay
Secondary outcome [5] 423281 0
New onset atrial fibrillation or flutter (data from review of medical record)
Timepoint [5] 423281 0
Within 7 days of surgery
Secondary outcome [6] 423282 0
Requirement for mechanical cardiovascular support (data from review of medical record)
Timepoint [6] 423282 0
Within 7 days of surgery
Secondary outcome [7] 423283 0
Venous thromboembolism (data from review of medical record)
Timepoint [7] 423283 0
Within 7 days of surgery
Secondary outcome [8] 423284 0
New stroke (data from review of medical record)
Timepoint [8] 423284 0
Within 7 days of surgery
Secondary outcome [9] 423285 0
Use of psychotropic drugs for control of delirium (data from review of medical record)
Timepoint [9] 423285 0
Within 7 days of surgery
Secondary outcome [10] 423286 0
Duration of first intensive care stay after surgery (data from review of medical record)
Timepoint [10] 423286 0
At time of intensive care discharge
Secondary outcome [11] 423287 0
Duration of mechanical ventilation (data from review of medical record)
Timepoint [11] 423287 0
Within first intensive care admission after surgery
Secondary outcome [12] 423288 0
Death
Timepoint [12] 423288 0
Within hospital admission and within 30 days from time of surgery
Secondary outcome [13] 423289 0
Return to operating theatre after primary surgery (data from review of medical record)
Timepoint [13] 423289 0
Within 7 days of surgery
Secondary outcome [14] 423290 0
Postoperative infection (any site) (as recorded in medical record)
Timepoint [14] 423290 0
Within 7 days of surgery

Eligibility
Key inclusion criteria
1. Coronary artery bypass grafting (CABG) surgery, valve repair or replacement (VR) surgery or a combination of CABG and VR surgery
2. Elevated risk of acute kidney injury as predicted by any of the following:
a) Haemoglobin <130g/l
b) Creatinine > 100mmol/l
c) Age > 70 years
d) New York Heart Association classification 4
e) Body Mass Index > 30 kg/m2
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Major aortic surgery, transplant surgery, pulmonary thrombendarterectomy or ventricular assist device surgery
2. Already receiving inotropic or vasopressor support
3. Dialysis dependent, prior renal transplant
4. Pre-existing significant hypertension (systolic blood pressure > 180mm Hg)
5. Significant pulmonary hypertension (estimated systolic pulmonary artery pressure (PAP) > 70mmHg, mean PAP > 40mmHg) AND right ventricular systolic dysfunction (graded more severe than mild)
6. Pregnant or breastfeeding women

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer (REDCap)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation stratified by site in blocks of 2, 4 and 6 (computer generated sequence)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A prior feasibility study showed a mean length of hospital stay of 9.9 days (sd 7) vs 7.1 days (sd 1.9) days in the noradrenaline vs angiotensin II groups (ACTRN12621000195853). This represented a 2.8-day mean difference. To allow for a more conservative estimate of effect, we propose a difference of 1.8 days between the two groups, with the same standard deviations. Based on an independent groups t-test with equal allocation between treatment arms, and assuming homogeneity of variance between arms, and a power of 90% requires a sample size of 346 patients (173 per treatment arm). To compensate for data loss and the effect of skewed data, we will randomize 400 patients.

The above estimates are based on a previous feasibility study. Taking account of the possibility for estimates to differ in this study, we will recalculate the sample size after the first 100 patients to detect the same difference in days length of stay (1.8 days), with the pooled standard deviations updated to use the accumulated data in this study.

A full statistical analysis plan will be published prior to analysis of the data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/01/2024
Actual
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
31/01/2026
Actual
Sample size
Target
400
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 24967 0
The Alfred - Melbourne
Recruitment hospital [2] 24968 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 24969 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [4] 24970 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [5] 24971 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [6] 24972 0
Prince of Wales Hospital - Randwick
Recruitment hospital [7] 24973 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [8] 24975 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 24994 0
Victorian Heart Hospital - Clayton
Recruitment postcode(s) [1] 40620 0
3004 - Melbourne
Recruitment postcode(s) [2] 40621 0
3084 - Heidelberg
Recruitment postcode(s) [3] 40622 0
3220 - Geelong
Recruitment postcode(s) [4] 40623 0
3065 - Fitzroy
Recruitment postcode(s) [5] 40624 0
2050 - Camperdown
Recruitment postcode(s) [6] 40625 0
2031 - Randwick
Recruitment postcode(s) [7] 40626 0
2010 - Darlinghurst
Recruitment postcode(s) [8] 40628 0
5042 - Bedford Park
Recruitment postcode(s) [9] 40651 0
3168 - Clayton
Recruitment outside Australia
Country [1] 25603 0
New Zealand
State/province [1] 25603 0
Wellington

Funding & Sponsors
Funding source category [1] 314128 0
Commercial sector/Industry
Name [1] 314128 0
La Jolla Pharmaceuticals
Country [1] 314128 0
United States of America
Primary sponsor type
Hospital
Name
Alfred Health
Address
55 Commercial Rd, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 316045 0
None
Name [1] 316045 0
Address [1] 316045 0
Country [1] 316045 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313264 0
Alfred HREC
Ethics committee address [1] 313264 0
Alfred Hospital,
55 Commercial Rd,
Melbourne,
VIC 3004
Ethics committee country [1] 313264 0
Australia
Date submitted for ethics approval [1] 313264 0
31/05/2023
Approval date [1] 313264 0
11/07/2023
Ethics approval number [1] 313264 0

Summary
Brief summary
More than 20,000 heart operations are carried out each year in Australia. While most patients survive their surgery, many spend a long period of time in hospital recovering. Delayed recovery may happen as a result of the complexity of the surgery, or due to medical problems that occur after the operation such as irregular heart rhythms, stroke or kidney failure. These medical problems following surgery are known as postoperative complications. Postoperative complications can lead to long-term ill health and loss of independence, as well as prolonging hospital stay. In addition, a longer stay in hospital may expose patients to risks such as infection and predispose to physical deconditioning. Reducing length of stay in hospital is associated with improved recovery from surgery, in addition to reduced healthcare costs.

Previous studies have suggested that a new drug called ‘angiotensin II’ can successfully be used to treat low blood pressure in critically unwell patients. Drugs to preserve blood pressure are also often needed in heart surgery, however there are no large studies that have assessed the effectiveness of angiotensin II in patients during and after heart surgery. We previously carried out a small study that showed that using the drug angiotensin II during and after cardiac surgery is possible (ACTRN12621000195853). This knowledge has allowed us to design a new study to compare the use of angiotensin II to the current standard drug used to treat low blood pressure after heart surgery, called noradrenaline. In our previous research, patients who were given angiotensin II had fewer postoperative complications (although this difference wasn't statistically significant) and shorter lengths of stay in hospital. However, before we can recommend that angiotensin II is better for treatment of low blood pressure during cardiac surgery, we need to confirm these findings in a much larger study to make sure that our previous study findings were not simply the result of chance.

In this study we will assess whether the administration of angiotensin II reduces length of hospital stay compared to noradrenaline.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127530 0
Dr Tim Coulson
Address 127530 0
Department of Anaesthesiology and Perioperative Medicine,
Alfred Health,
55 Commercial Rd,
Melbourne VIC 3004
Country 127530 0
Australia
Phone 127530 0
+61 3 9076 3707
Fax 127530 0
Email 127530 0
[email protected]
Contact person for public queries
Name 127531 0
Tim Coulson
Address 127531 0
Department of Anaesthesiology and Perioperative Medicine,
Alfred Health,
55 Commercial Rd,
Melbourne VIC 3004
Country 127531 0
Australia
Phone 127531 0
+61 3 90762000
Fax 127531 0
Email 127531 0
[email protected]
Contact person for scientific queries
Name 127532 0
Tim Coulson
Address 127532 0
Department of Anaesthesiology and Perioperative Medicine,
Alfred Health,
55 Commercial Rd,
Melbourne VIC 3004
Country 127532 0
Australia
Phone 127532 0
+61 3 90762000
Fax 127532 0
Email 127532 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not part of HREC approval


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19500Study protocol    Will be published after ethics approval
19501Statistical analysis plan    Will be published prior to analysis



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.