Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001140640
Ethics application status
Approved
Date submitted
15/09/2023
Date registered
3/11/2023
Date last updated
22/09/2024
Date data sharing statement initially provided
3/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to evaluate a best practice cardiogenic shock care pathway vs standard care on equity and patient outcomes in Cardiogenic Shock:
Scientific title
Evaluation of a Standardised ClinicAl Pathway on Equity and patient outcomes in Cardiogenic Shock: The ESCAPE-CS Trial
Secondary ID [1] 310561 0
None
Universal Trial Number (UTN)
Trial acronym
ESCAPE-CS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiogenic shock 331395 0
Condition category
Condition code
Cardiovascular 328141 328141 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ESCAPE-CS is multicentre, two-phase prospective cohort study, to develop, deploy and assess a multifaceted system of care for cardiogenic shock, beginning at the time of referral. A total of 200 patients will take part in this study, 100 in Phase 1, and 100 in Phase 2, conducted in 7 or more Australian centres. Phase 1, a 12-month ‘usual care’ phase, is followed by Phase 2, a 12-month study intervention phase . The overall duration of involvement for participants is up to 6 months post-cardiac shock event.

As yet there are no standardised protocols for identification and treatment of cardiogenic shock, nor guidelines regarding when to refer a patient with early stages of shock to a specialist centre. The study proposes the delivery of a multifaceted system of care for cardiogenic shock, beginning at the time of referral. The intervention has three components: a streamlined referral system; a multidisciplinary shock team; and protocol-driven care

A streamlined referral system;
The referral system will be modelled on the existing ECMO referral system (available from www.nsw-ecmo.net). Clinical data collected via this referral system will be entered into a Research Electronic Data Capture (REDCap ) database built by an expert team at the NHMRC CTC. Upon entering this data, the referring clinician will be provided with immediate automated feedback including shock severity. The referral will be fielded immediately by an on-call heart failure cardiologist. On-call responsibilities will be shared between the two quaternary study centres (St Vincent’s Hospital, Sydney and Royal Prince Alfred Hospital (RPAH), Sydney), with each centre responsible for fielding referrals from their ‘usual’ referring centres within the study. Confirmation that patient meets study inclusion/exclusion criteria will result in automatic activation of the multidisciplinary shock team

A multidisciplinary shock team
Quaternary referral centres will establish a shock team comprising an intensive care specialist, cardiac surgeon, heart failure cardiologist and interventional cardiologist. All shock team members participate in existing 24/7 on-call rosters, so availability should not be an issue. This team will be activated upon confirmation of CS by the on-call heart failure cardiologist from that quaternary centre. Upon activation, the team will convene, involving the referring clinician, to collectively determine investigations, management and need for transfer. Referrals to other centres via usual pathways, if appropriate, will be made by the shock team.

Protocol-driven care.
Clinical decisions will be made with reference to a standardised protocol guiding the use of invasive investigations and treatments, including the use of mechanical circulatory support devices. Key features of the proposed protocol include:
i. Emphasis on using clinical and haemodynamic data to guide rational use of therapies;
ii. Modular approach to treatment selection, based on local practice patterns, resources, availability and expertise, including choice of mechanical support devices and medications; and
iii. Modular approach to referral, guided by patient needs and utilising established local referral pathways wherever appropriate. Transfer to a quaternary centre is considered when the capabilities of local referral centres and pathways are exceeded.

There will potentially be two pathways for treatment - one for Acute Myocardial Infarction (AMI) and the other for Advanced Heart Failure. Both protocols will recommend treatment with the use of vital signs and treatment that is already part of standard care. These patients will be critically unwell and require 24-hour monitoring, including monitoring of blood pressure, ECG, inotropes infusing, and arterial blood gases. All patients admitted with cardiogenic shock would also receive an initial ultrasound imaging undertaken by an interventional cardiologist or doctors in ICU/ED accredited upon admission to the hospital. The treatment pathway provides guidance on when to transfer to a PCI centre for a right or left heart catheter and potential percutaneous coronary intervention to be done by an interventional cardiologist or if mechanical support is required eg IABP, VA ECMO.

The pathway, is to be finalised based on the findings of Preliminary Phase end-user engagement.

The primary clinical outcome is all-cause 30-day mortality. . The patient will complete the study at day 180 post index admission with the completion of quality of life questionaires. EQ5D and KCCQ12
Intervention code [1] 326958 0
Treatment: Other
Comparator / control treatment
Phase 1 is an observation and prospective collection of data related to ‘usual care’ at 7 centres. In Phase 1, all care will be delivered as per current standards for cardiogenic shock, including a case-by-case decision on when to refer, transfer and/or escalate treatment at the discretion of treating teams.

Usual care’ for cardiogenic shock currently comprises a system without clear protocols directing investigations, management or referral for transfer. There is a protocolised system for the most severe cases of cardiogenic shock – the statewide ECMO retrieval service – however this services only 1% of the total cohort of cardiogenic shock patients. The individual components of cardiogenic shock care currently include pharmacotherapy, revascularisation where indicated, selective use of right heart catheterisation, and selective use of mechanical circulatory support including intra-aortic balloon pump, Impella and/or VA-ECMO. However, the decisions to deploy these treatments are generally made on an adhoc basis, and without the input of a specialist, multidisciplinary shock team.
Control group
Active

Outcomes
Primary outcome [1] 336068 0
30-day all-cause mortality.
Timepoint [1] 336068 0
30 days post-index admission
Secondary outcome [1] 426727 0
Overall survival at 180 days post index admission free of durable mechanical circulatory support or cardiac transplant. The participant will be contacted 180 days post-index admission and asked follow-up questions. Medical records will also be reviewed before contacting the participant, The patient's follow up data will be self reported, collected over the phone using a study specific data collection sheet entered into a eCRF (electronic case report form) REDCap database.
Timepoint [1] 426727 0
180 days post-index admission
Secondary outcome [2] 426728 0
ICU length of stay determined by review of medical records
Timepoint [2] 426728 0
ICU discharge
Secondary outcome [3] 426729 0
Treatment-related major adverse events: Major adverse cardiovascular events (MACE) (death, stroke, acute myocardial infarction or hospitalisation for heart failure) at 30 and 180 days. Determined by review of medical records and the participant will be contacted at 30 and 180 days post-index admission and asked follow-up questions. The patient's follow up data will be self-reported and collected over the phone using a study specific data collection sheet entered into the eCRF REDCap database.
Timepoint [3] 426729 0
30 days and 180 days post-index admission
Secondary outcome [4] 427269 0
Hospital Length Of Stay determined by review of medical records
Timepoint [4] 427269 0
Hospital Discharge
Secondary outcome [5] 427270 0
Destination hospital determined by review of medical records
Timepoint [5] 427270 0
Hospital Discharge
Secondary outcome [6] 427271 0
Health-related Quality Of Life (QOL) using the patient self-reported using the EuroQoL (EQ-5D-5L questionnaire), including the visual analogue scale (VAS). The participant will be contacted at 90 and 180 days post-index admission.
Timepoint [6] 427271 0
90 and 180 days post index admission
Secondary outcome [7] 427272 0
Quantify all healthcare use and costs from index admission to 180 day follow-up. Data linkage from MBS, PBS and databases held by CHeReL.
Timepoint [7] 427272 0
Day 180 post index admission
Secondary outcome [8] 428150 0
Health-related Quality Of Life (QOL) using the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) items questionnaire score. The participant will be contacted at 90 and 180 days post-index admission.
Timepoint [8] 428150 0
90 and 180 days post index admission

Eligibility
Key inclusion criteria
1. Inpatients at least 18 years of age at any location within a participating centre.
2. Diagnosed with CS, defined as:
a. ST elevation myocardial infarction (STEMI) OR current/recent (within 12 months) evidence of left ventricular dysfunction
AND
b. At least 2 of:
i. systolic blood pressure less than or equal to 90mmHg;
ii. use of an inotrope or vasopressor
iii. serum lactate greater than or equal to 3mmol/L.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Terminal non-cardiac condition or advanced care directive rendering advanced cardiac and/or life support therapies inappropriate
2. Inpatients being managed with palliative intent
3. Evidence of established anoxic brain injury
4. Established non-cardiac cause of shock (eg. sepsis, haemorrhagic shock, anaphylactic shock).
5. Patients with an established CS diagnosis transferred from: (i) a non-participating tertiary institution, or (ii) a non-participating institution with an established alternative CS referral pathway.
6. Out-of-hospital cardiac arrest with ongoing cardiopulmonary resuscitation (including ECMO-CPR).

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Previous observational studies examining implementation of cardiogenic shock management pathways demonstrated an absolute risk reduction for mortality of between 20% and 30% compared to historical comparator groups. Assuming a pre-intervention 30-day mortality of 40%,enrolment of 100 patients in the pre- and post-intervention arms will provide 80% power to detect an 18% absolute risk reduction at a 2-sided alpha of 0.05. Given the population covered by the participating sites (approximately 1.4 million people), the known incidence of Acute Myocardial Infarction (AMI) and AMI-related CS in Australia, and the percentage of CS attributable to AMI (approximately 40%), we expect to exceed 100 patients enrolled in each phase of the study.

The primary endpoint will be assessed using Fisher’s exact test, with further analysis to adjust for confounding using multivariable logistic regression adjusting for age. The participant will be contacted at 30 and 180 days post-index admission and asked follow-up questions. Age, Society for Cardiovascular Angiography and Interventions (SCAI) severity, aetiology and geographic location will also be used in pre-specified subgroup analyses, assessing for interaction between these variables and the study intervention. Survival to 180 days free of heart transplantation and durable mechanical support will be assessed using Kaplan-Meier analysis and the log-rank test. MACE at 30 and 180 days will be assessed using Kaplan-Meier analysis and the log-rank test. A two-sided p-value of less than 0.05 will be considered statistically significant.

The ESCAPE-CS trial, aims to evaluate the differences in EQ-5D-5L and KCCQ-12 responses across two study phases (Phase – I and Phase – II). This assessment will be adjusted for key clinical and demographic variables gathered during the trial. Given that the quality-of-life data will be collected at two separate time points and across seven different sites, it's crucial to effectively address both within-patient variations and site-specific clustering effects inherent in this longitudinal dataset. To achieve a robust statistical analysis, we plan to employ either hierarchical mixed-effects modelling or Generalized Estimating Equations (GEE). These methodologies are well-suited for handling the correlated nature of our data. Hierarchical mixed-effects modelling is particularly adept at capturing the nested structure of the data (patients within sites) and allows for both fixed effects (treatment phases and predefined predictors) and random effects (patient-specific and site-specific variations). On the other hand, GEE provides an avenue to estimate population-averaged effects and can be advantageous, especially in the context of potentially missing data, a common occurrence in longitudinal studies. Our statistical modelling approach will incorporate clinically and demographically relevant predictors, selected based on both a priori hypotheses and expert clinical opinion.

The study aims to evaluate the differences in cost categories as well as the total costs across the two study phases. Along with quantifying healthcare resource use and costs, data analysis will involve descriptive statistics assessing proportions and means. Hypothesis testing with two-sample Student t tests will be used to detect differences in mean values and will be reported with standard deviations. Chi-square and Fisher’s exact test will be used to detect differences in proportions. The assessment will also involve adjusting for key clinical and demographic variables gathered during the trial. The choice of statistical modelling will be contingent upon data normality and skewness, ensuring that the most suitable method will be applied for precise and reliable cost analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2024
Actual
9/05/2024
Date of last participant enrolment
Anticipated
1/05/2026
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
200
Accrual to date
34
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25515 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 25516 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 25517 0
Concord Repatriation Hospital - Concord
Recruitment hospital [4] 25518 0
Canterbury Hospital - Campsie
Recruitment hospital [5] 25519 0
Orange Health Service - Orange
Recruitment hospital [6] 25520 0
Dubbo Base Hospital - Dubbo
Recruitment hospital [7] 25521 0
Wagga Wagga Base Hospital - Wagga Wagga
Recruitment postcode(s) [1] 41335 0
2050 - Camperdown
Recruitment postcode(s) [2] 41336 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 41337 0
2139 - Concord
Recruitment postcode(s) [4] 41338 0
2194 - Campsie
Recruitment postcode(s) [5] 41339 0
2800 - Orange
Recruitment postcode(s) [6] 41340 0
2830 - Dubbo
Recruitment postcode(s) [7] 41341 0
2650 - Wagga Wagga

Funding & Sponsors
Funding source category [1] 314765 0
Government body
Name [1] 314765 0
Australian Department of Health and Aged Care, Medical Research Future Fund
Country [1] 314765 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre, Medical Foundation Building, 92-94 Parramatta Road, Camperdown, NSW 2050
Country
Australia
Secondary sponsor category [1] 316750 0
None
Name [1] 316750 0
Address [1] 316750 0
Country [1] 316750 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313773 0
Sydney Local Health District Ethics Review Committee, RPAH Zone
Ethics committee address [1] 313773 0
Ethics committee country [1] 313773 0
Australia
Date submitted for ethics approval [1] 313773 0
29/08/2023
Approval date [1] 313773 0
19/10/2023
Ethics approval number [1] 313773 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129318 0
Dr Pankaj Jain
Address 129318 0
Royal Prince Alfred Hospital, Sydney Local Health District, Missenden Rd, Camperdown, NSW, 2050
Country 129318 0
Australia
Phone 129318 0
+61 413355041
Fax 129318 0
Email 129318 0
[email protected]
Contact person for public queries
Name 129319 0
Pankaj Jain
Address 129319 0
Royal Prince Alfred Hospital, Sydney Local Health District, Missenden Rd, Camperdown, NSW, 2050
Country 129319 0
Australia
Phone 129319 0
+61 413355041
Fax 129319 0
Email 129319 0
[email protected]
Contact person for scientific queries
Name 129320 0
Pankaj Jain
Address 129320 0
Royal Prince Alfred Hospital, Sydney Local Health District, Missenden Rd, Camperdown, NSW, 2050
Country 129320 0
Australia
Phone 129320 0
+61 413355041
Fax 129320 0
Email 129320 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
Individual participant data will not be shared. A summary of the study data will be published in a peer reviewed journal.


What supporting documents are/will be available?

No Supporting Document Provided



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.