Preoperative focused echocardiography on patients with fractured neck of femur. ECHONOF-III trial: study protocol for a multicenter randomized controlled trial

Abstract

Background

Hip fractures are common in older people and are associated with high perioperative mortality. Prompt surgical intervention within the first 48 h of fraction reduces complications; however, surgical urgency often precludes a comprehensive preoperative cardiac evaluation. Preliminary data suggests that performing a focused cardiac ultrasound (FCU) before surgery may reduce postoperative complications. We therefore propose to test the primary hypothesis that FCU reduces a 30-day composite of mortality and serious complications.

Methods

We plan a definitive multicenter pragmatic randomized trial that will enroll 2000 adults with hip fractures. Participants will be randomized before surgery to either receive FCU as part of their preoperative assessment or to routine care without FCU. FCU is a brief, 10-min, goal-directed echocardiography performed at the patient’s bedside. FCU will be conducted by physicians trained in FCU and the information gathered will be shared immediately with all clinicians involved in the patient’s care (anesthesiologists, orthopedic surgeons, geriatricians). The primary outcome will be a 30-day composite of all-cause mortality, hospital readmission, acute kidney injury, cardiac failure, and myocardial injury after noncardiac surgery. Secondary and exploratory outcomes include hospital length of stay, days to return to original residence, postoperative recovery, and quality of life. Additionally, a health cost analysis will be conducted to weigh costs against benefits.

Discussion

Our large RCT aims to determine whether preoperative focused ultrasound examinations of hip fracture patients reduce serious postoperative complications, improves the quality of recovery, improves life quality, and is cost-effective.

Trial registration

Registration number: ACTRN12622001546741. Date registered 14/12/2022.

Administrative information

Title {1}	Preoperative focused echocardiography on patients with fractured neck of femur. ECHONOF-III trial: study protocol for a multicenter randomized controlled trial
Trial registration {2a and 2b}	Trial registered in the Australian and New Zealand Clinical Trials Registry (ANZCTR) Registration number: ACTRN12622001546741
Protocol version {3}	Protocol number: MHREC 2022.071 Version: 4.1
Funding {4}	Funded by a government body. The Department of Health and Aged Care, Medical Research Future Fund
Author details {5a}	1. Ximena Cid-Serra Email: x.cidserra@unimelb.edu.au Affiliations: Department of Surgery, The University of Melbourne, Melbourne, Australia Department of General Medicine, The Royal Melbourne Hospital, Melbourne, Australia 2. Alistair Royse—cardiothoracic surgeon Department of Surgery, The University of Melbourne, Melbourne, Australia 3. Andrea Bowyer—anesthesiologist Department of Surgery, The University of Melbourne, Melbourne, Australia Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Australia 4. A/Prof David Canty—anesthesiologist Department of Surgery, The University of Melbourne, Melbourne, Australia Department of Medicine and Nursing, Monash University 5. Prof Daniel Sessler—anesthesiologist Clinical and Outcomes Research, Center for Outcomes Research and Department of Anaesthesiology, UTHealth, Houston 6. Sandy Clarke-Errey—statistician Department of Mathematics and Statistics, The University of Melbourne, Melbourne, Australia 7. Andre Denault—intensive care specialist Montreal Heart Institute and University of Montreal 8. Dina LoGiudice FRACP PhD—geriatrician Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Australia Department of Aged Care, Royal Park Campus, Royal Melbourne Hospital, Australia 9. Guy Ludbrook—anesthesiologist and health economics expert Department of Anaesthesia, Royal Adelaide Hospital; Discipline of Acute Care Medicine, University of Adelaide 10. D-Yin Lin—anesthesiologist Flinders University, Flinders Medical Centre, Australia 11. Yang Yang—intensive care specialist Western Health, Victoria Heart Hospital, University of Melbourne, Monash University, Australia 12. Kavi Haji—intensive care specialist Intensive Care Unit, Frankston Hospital, Peninsula Health, Australia 13. Lisa Zucherrelli—anesthesiologist Department of Anaesthesia, Joondalup Health Campus, Australia 14. Andrew J Palmer—anesthesiologist Menzies Institute for Medical Research, The University of Tasmania, Australia 15. Benjamin Piper—anesthesiologist Department of Anaesthesia, John Hunter Hospital University of Newcastle, conjoint senior lecturer 16. Thar Nyan Lwin—anesthesiologist Department of Anaesthesia and Perfusion Services, The Prince Charles Hospital, Queensland, Australia Faculty of Medicine, University of Queensland, Queensland, Australia 17. Stefan Dieleman—anesthesiologist Department of Anaesthesia, Westmead Hospital; Western Sydney University 18. David Eccleston—cardiothoracic surgeon University of Melbourne Dept of Cardiology, Royal Melbourne Hospital 19. Alwin Chuan FANZCA PhD—anesthesiologist Department of Anaesthesia, Liverpool Hospital, University of NSW, Australia 20. Richard Cooper—anesthesiologist Mackay Base Hospital, Australia 21. Gregory Henderson—anesthesiologist Grampians Health, Australia 22. Prof Colin Royse (principal investigator) Department of Surgery, The University of Melbourne, Melbourne, Australia Center for Outcomes Research, UTHealth, Houston, TX, USA
Name and contact information for the trial sponsor {5b}	Contact information: Jacqui Waterkeyn Director Office for Research Melbourne Health Sponsor@mh.org.au  + 613 93,427,348
Role of sponsor {5c}	The sponsor and funders were not involved in the study design and will not be involved in data collection, data analysis, or the drafting of the final report

Introduction

Background and rationale {6a}

Hip fractures, often resulting from falls, are a prevalent and serious medical problem among frail and elderly individuals, with cases expected to reach 4.5 million per year globally by 2050 [1]. Despite advancements in healthcare, outcomes for hip fracture patients remain poor, characterized by high mortality rates and significant long-term care needs related to the high prevalence of medical comorbidities, advanced age, and frailty [2]. Successful hip surgery may continue to negatively impacts patients and potentially places a substantial burden on their families, communities, and healthcare systems, leading to increased costs and resource demands. Although urgent surgery is crucial for restoring independence and mobility, it is among the highest-risk medical procedures. Approximately 10% of patients die within 30 days of surgery, and 26% within a year [3]. Factors such as older age, male gender, and comorbidities have been recognized to increase mortality risk [4]. Many of the adverse outcomes are attributable to underlying cardiac and respiratory diseases, which are often undiagnosed at the time of surgery [5].

Focused echocardiography or focused cardiac ultrasound (FCU) is an abbreviated form of transthoracic echocardiography that may detect significant heart disease. It is simple to perform, taking only 5–10 min, and can be performed at the bedside by any trained practitioner. FCU accurately evaluates conditions like heart failure, aortic stenosis, and pulmonary hypertension, which are independent risk factors for postoperative death. By identifying heart disease and shock states accurately, medical teams can manage patients more effectively, maximizing safety and optimizing outcomes [6].

In a randomized pilot study involving 100 patients with hip fractures, the use of FCU led to a 39% reduction in a composite outcome of death, acute kidney injury, stroke, myocardial infarction, pulmonary embolism, or cardiac arrest within 30 days post-surgery [7, 8]. Despite its potential, the widespread adoption of FCU faces challenges due to the significant costs of equipment and training and the lack of definitive evidence showing improved patient outcomes. Therefore, a large pragmatic randomized trial is necessary.

This clinical trial will involve 2000 participants across 12 sites, following a similar protocol as the pilot study. It aims to evaluate whether adding an FCU prior to surgery in patients with fractured neck of femur reduces the incidence of a 30-day composite outcome of all-cause mortality, hospital readmission, acute kidney injury, cardiac failure, or myocardial injury in noncardiac surgery.

Objectives {7}

The study aims to determine whether routine FCU before hip fracture surgery leads to a reduced composite outcome of all-cause mortality, cardiac failure, myocardial injury in noncardiac surgery, acute kidney injury, or hospital readmission at 30 days post-surgery in hip fracture patients compared to patients who do not receive preoperative FCU (the current standard of care).

The secondary objectives of this trial are to evaluate the effect of preoperative FCU in patients with hip fracture on postoperative recovery and to assess the cost-effectiveness of this intervention.

Trial design {8}

This is a parallel group, pragmatic, randomized controlled multicenter trial in which patients with hip fractures are randomly allocated to receive or not receive preoperative FCU in a 1:1 allocation before hip fracture surgery.

Methods: participants, interventions, and outcomes

Study setting {9}

This study is conducted in Australian hospitals that commonly perform hip fracture surgeries and are integral to the established Australian hip fracture care pathway. 

Primary hospital: The Royal Melbourne Hospital, Melbourne Health.

Other participating hospitals:

1. Liverpool Hospital, New South Wales

2. Royal Adelaide Hospital, South Australia

3. Flinders Medical Centre, South Australia

4. Western Health, Victoria

5. Peninsula Health (Frankston Hospital), Victoria

6. Joondalup Health Campus, Western Australia

7. Mackay Hospital, Queensland

8. Grampians Health, Ballarat

9. The Prince Charles Hospital

10. John Hunter Hospital

Eligibility criteria {10}

Inclusion criteria

Adults presenting with isolated, primary, non-metastatic hip fracture, where surgery is expected within 48 h after hospital admission.

Eligibility is determined according to the initial clinical expectation at the time of admission. Patients who are anticipated to undergo surgery within 48 h, but whose procedures are subsequently delayed remain eligible for inclusion.

Exclusion criteria

Exclusion criteria include prior hip surgery on the affected side, likely metastatic cancer, where survival is unlikely in the 24 h from admission, or who have had an echocardiography or FCU in the last 30 days before the admission.

Who will take informed consent? {26a}

Participant consent will be obtained as the primary method of consent. For participants unable to provide their own consent, in-person or telephone consent will be sought from relatives or individuals with authorized medical treatment decision-maker.

If the patient can provide consent, a research nurse will approach them directly, explain the study, provide a hard copy of the Participant Information and Consent Form (PICF), and obtain written consent.

If the patient is unable to consent, the research nurse will identify the authorized person responsible for providing consent, typically the same individual who would consent for the patient’s surgery. If this person is present, the researcher will inform them in person; if they are not present, the researcher will attempt to contact them via telephone, using pre-approved telephone scripts. In these instances, verbal consent will be accepted, witnessed by a third party who is not involved in the research project, with written consent obtained at a later time when feasible.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Not applicable as this protocol does not involve acquiring data or biological specimens for ancillary studies.

Interventions

Explanation for the choice of comparators {6b}

The control group represents the current standard of care. The preoperative assessment is conducted based on medical history, physical examination, blood investigations, and electrocardiogram (ECG). However, the current standard of care does not involve a routine focused cardiac ultrasound.

Intervention description {11a}

In addition to clinical evaluation, participants randomized to the FCU group will receive a preoperative FCU performed at the patient’s bedside prior to surgery following the University of Melbourne iHeartScan protocol [9]. The clinician who performs the FCU will be qualified to the equivalent of a University Graduate Certificate in Clinical Ultrasound and be specifically trained in the iHeartScan protocol. This protocol relies on 2D imaging and Color Flow Doppler for all cardiac assessments, and it is the same protocol used in the pilot study upon which this trial is based. The following cardiac variables are evaluated: size and systolic function of the left and right ventricle; interatrial septum movement; hemodynamically significant regurgitation or stenosis of the cardiac valves (typically moderate to severe stenosis or regurgitation); presence or absence of pericardial effusion; diameter and collapsibility of the inferior vena cava; and a final comment of the hemodynamic state [10]. In line with a pragmatic trial, any qualified member of the treating team may perform the FCU using the ultrasound machine available at their center and will complete a written iHeartScan report summarizing the main findings. The information will be available to all members of the treating team before and after surgery, including surgeons, anesthesiologists, intensivists, internal medicine physicians, ortho-geriatricians, and emergency medicine physicians.

Criteria for discontinuing or modifying allocated interventions {11b}

In the FCU group, the ultrasound examination will be discontinued at any time if it is causing discomfort or pain or upon the participant’s request.

Participants in the control group will not routinely receive an FCU. However, in cases of clinical deterioration or hemodynamic instability, there is no restriction for the anesthesiologist, or any other clinician involved in patient care to perform an FCU if deemed necessary.

These instances will be recorded but not reported as protocol deviations. Participants will remain in the study, and the data will be analyzed using an intention-to-treat approach.

Strategies to improve adherence to interventions {11c}

Drawing from previous experiences, we have devised several strategies to enhance recruitment and adherence to the intervention.

1. Keep medical teams informed and actively engaged in this trial through presentations at their meeting and providing written information about it.

2. Work closely with the treating anesthesiologists to maximize the benefits of FCU when performed and to ensure that FCU is not conducted during surgery on stable patients in the control group, thereby maintaining the integrity of the study

3. One major risk identified is the unavailability of a certified practitioner to perform the FCU when a patient is allocated to the FCU group. To mitigate this, we only recruit and randomize patients after confirming that the practitioner who will perform the ultrasound is available if the patient is allocated to the intervention group.

Relevant concomitant care permitted or prohibited during the trial {11d}

This is a pragmatic study. No concomitant care or investigations are prohibited. If deemed necessary by the treating team, a comprehensive echocardiography can be requested for patients in both groups.

Provisions for post-trial care {30}

There is no payment provided to participants for their involvement in this trial. While participants will not receive direct compensation, this research may contribute to advancements in patient care that will benefit the wider community in the long term. The protocol does not include provisions for ancillary care or compensation for trial-related harms.

Outcomes {12}

Primary outcome

The primary outcome is a 30-day composite outcome of the incidence of at least one of the following: all-cause mortality, hospital readmission, acute kidney injury, decompensated heart failure, and myocardial injury in noncardiac surgery. The occurrence of this composite outcome will be compared between the FCU and control groups using an average relative effect test.

Specific definitions for primary outcome:

• Mortality: death from any cause within 30 days after surgery.

• Myocardial injury in noncardiac surgery (MINS): Occurrence of a troponin rise that meets the pre-specified criteria for myocardial injury within the first 72 h after surgery, irrespective of symptoms or ECG changes, and in the absence of an overt precipitating non-ischemic cause (e.g., pulmonary embolism) [11]. This trial uses troponin thresholds showing prognostic value in the perioperative setting. Specific cTn assays include:

  • ◦ Non–high-sensitivity fourth-generation troponin T ≥30 ng/L (Roche fourth-generation Elecsys TnT assay).
  • ◦ High-sensitivity troponin T of 20 to <65 ng/L with an absolute change of ≥5 ng/L.
  • ◦ High-sensitivity troponin T concentration ≥65 ng/L (Roche Elecsys high-sensitivity troponin T assay).
  • ◦ For patients with abnormal baseline troponin values, myocardial injury is considered acute if there is a ≥20% rise of cTnI or cTnT after noncardiac surgery, an absolute increase in high-sensitivity cTnT of ≥14 ng/L above preoperative values, or an increase in high-sensitivity cTnT ≥5 ng/L above the prior concentration with a peak high-sensitivity cTnT >20 ng/L.

• Hospital readmission: Readmission to the hospital for any cause within 30 days after surgery.

• Acute kidney injury: Serum creatinine (Cr) 1.5–1.9 times baseline value within 7 days, or ≥ 27 mmol/L (0.3 mg/dL) increase within 48 h, or urine output ≤ 0.5 mL/kg/h for 6–12 h. When baseline creatinine is not available, the creatinine on admission will be considered the baseline for defining this outcome.

• Decompensated heart failure: Diagnosis requires both clinical signs (e.g., raised jugular venous pressure, respiratory rales, crepitations, or presence of S3) and radiographic evidence (e.g., vascular redistribution, interstitial pulmonary edema, or frank alveolar pulmonary edema).

Data related to the primary outcome will be collected by designated research nurses through hospital visits, review of hospital records and database, and by telephone, and verified against the death register and through the patient’s family doctor or hospital records if required. Supportive documentation and test results will be collected for all events and reviewed by the endpoint adjudication committee. The primary outcome data will be verified by two independent reviewers blinded to allocation. In instances where there is a disagreement between the two adjudicators, a third adjudicator will arbitrate the decision.

Secondary outcomes

1-year composite outcome incidence: The incidence of the composite outcome (all-cause mortality, hospital readmission, acute kidney injury, decompensated heart failure, and myocardial injury in noncardiac surgery) at 1-year post-surgery in both groups.

Time until death or end of follow-up: The average number of days from surgery to death or end of follow-up, whichever occurs first, will be compared between groups.

Days Alive and at Home at Day 30 (DAH30): The average number of days patients are alive and back to their usual residence within 30 days after surgery will be compared between groups.

Hospital length of stay: The number of days from hospital admission to hospital discharge will be compared between groups.

In-hospital infection incidence: The incidence of reported in-hospital infections, including hospital-acquired pneumonia, surgical site infections (superficial and deep), and urinary tract infections, will be compared between groups.

In-hospital respiratory pathology: The incidence of imaging-diagnosed respiratory pathology while patients are in the hospital will be compared between groups. Lung imaging includes chest X-ray, CT chest scan, or lung ultrasound, and pathologies include pleural effusion, atelectasis, consolidation, or pneumothorax.

Other outcomes

Destination post discharge: The proportion of patients in both groups discharged to the previous place of residence, rehabilitation center, new aged care facility, and other.

Length of stay in rehabilitation hospital: The average number of days from admission to rehabilitation hospital to discharge will be compared between groups.

Polypharmacy: The proportion of participants taking five or more medications will be compared between groups at day 30 post-surgery.

Frailty: Measured using the Clinical Frailty Scale preoperatively, at 30 days, and 1 year post-surgery. Mean scores at these three time points will be compared between groups.

Quality of recovery: Measured using the Postoperative Quality of Recovery Scale (PostopQRS), a validated multidimensional scale assessing physiological, cognitive, activities of daily living, emotive, and nociceptive (including pain) domains. This will be performed preoperatively, on day 1, days 3–5, at 30 days, and at 1 year. The proportion of complete postoperative recovery (return to baseline) at each timepoint will be compared between groups.

Independent living: Assessed using the Lawton and Brody Instrumental Activities of Daily Living (IADL) Scale, performed before surgery, at 30 days, and at 1 year. This scale assesses the skills necessary to live independently in the community. Mean scores will be compared between groups.

Qualitative assessment of personal impact: This will be assessed using the PROMEQ survey scale. It will be conducted before surgery, at 30 days, and at 1 year.

Health economic analysis: Additional costs of routine FCU will be balanced against other costs due to changes in the duration of hospital stay, type of ward, and medical resource consumption due to improved survival. Consent will be sought to obtain the total costs of care in each group over the study period. Healthcare resource consumption, including hospitalizations, general practice and specialist consultations, investigations, and medications, will be obtained. Units of healthcare resources consumed will be combined with Australian unit costs derived from the Pharmaceutical Benefits Scheme, Medicare, and the Australian Refined Diagnosis Related Groups (AR-DRGs). Additional costs of the intervention will be accounted for. Health utility, a summary measure of the quality of life, will be measured using the EQ-5D-5L, a standard, internationally validated instrument with Australian population norms. The EQ-5D-5L will be administered in written (or verbal) form (takes less than 1 min to complete) at baseline as part of the preoperative patient assessment and at 30 days and 12 months as part of the follow-up.

Participant timeline {13}

A comprehensive summary of the timeline for this trial, detailing the key milestones and events throughout the study period, is summarized in Table 1.

Table 1.

Participant timeline

Assessment/procedure	Screening	Preop	Day 1	Day 2	Days 3–5	Day 30	1 year
Informed consent	X
Demographic and baseline information	X
PostopQRS survey	X		X		X	X	X
Clinical frailty score	X					X	X
Lawton Brody IADL	X					X	X
EQ-5D-5L scale	X					X	X
PROMEQ scale	X					X	X
Focused cardiac ultrasound		X
Troponin (blood test)		X	X	X
Clinical outcomes (death, heart failure, acute kidney injury) and length of stay in hospital and other health facilities						X	X
Australian unit costs derived from the PBS, Medicare, and A-DRGs						X	X

This table outlines the schedule for assessments and procedures across study phases: screening, preoperative (Preop), day 1, day 2, days 3–5, day 30, and 1 year after surgery. PostopQRS, Postoperative Quality of Recovery Scale; IADL, Instrumental Activities of Daily Living; EQ-5D-5L, EuroQol 5-Dimension 5-Level scale; PBS, Pharmaceutical Benefits Scheme; A-DRGs, Australian Refined Diagnosis Related Groups.

Sample size {14}

Sample size determination was performed by a consulting statistician at the University of Melbourne. Estimates are based on our pilot data with a control group incidence of the primary outcome of 23.5% and a relative effect size of 39.6%. We will choose a conservative but clinically important relative effect size of 25%. For a two-tailed design, with an alpha of 0.05 and power of 0.9, a sample size of 984 participants per group will be required. A single-blinded interim analysis will be conducted after 50% of patients have been recruited according to the method of O’Brien and Fleming. The trial will be stopped if the primary outcome measure is different at p < 0.0026. To allow for this interim analysis, the sample size will be increased to 992, which will be rounded to 1000 participants in each group.

Recruitment {15}

Eligible patients will be identified from hospital admission records or the emergency booking theater system. The research staff will screen them for eligibility, and then they will be approached to explain the study and obtain consent. Following consent, they will be randomized to the standard of care or standard of care plus FCU groups.

Assignment of interventions: allocation

Sequence generation {16a}

Randomization will be managed by a clinical research organization (CRO): the Neuroscience Trials Australia (NTA). Randomization codes will be stratified by type of surgery (prosthesis—hemiarthroplasty vs osteosynthesis—femoral nail) and by the tertiary or secondary hospital in uneven blocks using a web-based automatic enrollment system at participating institutions to facilitate recruitment across time zones and out-of-hours cases. The use of uneven blocks for each stratum ensures a close balance of numbers in each group at any time during the trial.

Concealment mechanism {16b}

The allocation sequence will be concealed by the web-based enrollment system.

Implementation {16c}

The web-based enrollment system generates and conceals the allocation sequence. At each center, a research nurse coordinator or medical researcher is responsible for approaching suitable candidates, obtaining informed consent, and enrolling them in the study. Once participants have consented, they use the web-based enrollment system in REDCap to allocate them to either the intervention or control group.

Assignment of interventions: blinding

Who will be blinded {17a}

Due to the nature of the intervention, participants and care providers are not blinded to group allocation. As the inclusion of the FCU in the clinical records is essential for all members of the treating team to access it, and in accordance with a pragmatic trial, the research staff who will collect outcome data cannot be blinded.

However, the members of the Endpoints Adjudication Committee and the Data Safety Monitoring Board (DSMB) will be blinded. They will receive the list of participants and their data without information on group allocation, allowing them to perform a blind analysis.

Procedure for unblinding if needed {17b}

Not applicable as neither the participants nor the clinicians are blinded.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Data will be collected by research nurses through hospital visits, review of hospital records and databases, and by telephone. This data will be verified against the death register and through the patient’s general practitioner (or family doctor) or hospital records if required.

Supportive documentation and test results will be collected for all events and reviewed by the endpoint adjudication committee. Data will be stored in the REDCap electronic Case Report Form (eCRF) and the PostopQRS web database, both used in multiple studies at Melbourne Health. Data will be re-identifiable to allow for multiple follow-up points and endpoint verification. However, all data will be de-identified for analysis and presentation, including publication.

Types of data collected:

• I.Demographic information: Obtained by a researcher directly from the patient and hospital records at the time of recruitment.
• II.Postoperative outcome data: Obtained by a researcher from routinely collected blood tests, X-rays, ECGs, medical notes, and discharge summaries. Results are stored in the REDCap database.
• III.
  Surveys: This trial includes five surveys assessing patient’s baseline functional status, quality of recovery, and quality of life: (1) PostopQRS, (2) clinical frailty score, (3) Lawton Brady IADL, (4) EQ-5D-5L scale, and (5) PROMEQ. All of them have been extensively validated and used in previous research projects. Despite some overlap in the information requested, participants receive all five surveys to ensure each tool is used for its validated purpose. These five surveys are performed at baseline, day 30, and 1-year post-surgery. PostopQRS has two additional time points (day 1 and days 3–5). These surveys will be conducted in person by one of the research nurses while the participant remains in the hospital and over the phone after they have been discharged. On average, it takes 15 min to complete all of them.

  1. PostopQRS is a digital measurement tool designed for the assessment of postoperative recovery. It evaluates multiple recovery domains, including physiologic, nociceptive, functional, cognitive, and emotional aspects, as well as the overall patient perspective. This comprehensive tool captures the effects of surgery from both clinician and patient viewpoints, providing a holistic understanding of recovery. By employing repeated measures, PostopQRS allows for continuous assessment over time, from immediate post-surgery recovery to long-term follow-up [12].
  2. Clinical frailty score is a judgment-based tool used to assess the level of frailty in individuals, particularly older adults. It evaluates specific domains such as comorbidity, function, and cognition to generate a score ranging from 1 to 9, where 1 indicates “very fit” and 9 indicates “terminally ill” [13].
  3. Lawton Brody Instrumental Activities of Daily Living (IADL) Scale is a tool used to assess an individual’s ability to perform complex daily tasks necessary for independent living. Unlike basic activities of daily living (ADLs), which include fundamental self-care tasks, the IADL scale evaluates more advanced activities such as using the telephone, shopping, food preparation, housekeeping, laundry, transportation, medication management, and handling finances. This scale is particularly useful in identifying early signs of functional decline in older adults and guiding care planning and interventions [14].
  4. EQ-5D-5L is a standardized instrument developed by the EuroQol Group to measure health-related quality of life. It consists of two main components: the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ VAS records the patient’s self-rated health. This tool is widely used health economics to provide a comprehensive picture of a patient’s health from both clinical and patient perspectives [15].
  5. PROMEQ capabilities is part of the Inclusive Promotion of Health and Wellbeing (PROMEQ) research project. The survey collected data on mental and physical well-being, use of social and health services, and overall life satisfaction. It was designed to assess the effectiveness of different interventions and support the development of strategies to improve the quality of life for older adults [16].
• IV.Perioperative investigations: All investigations, except for serum troponin measurements, are part of standard patient care. Results will be gathered from medical records.
• V.Additional blood test (for MINS): Troponin levels are collected at the time of surgery and on days 1 and 2 post-surgery, added to existing blood collections where possible. The research nurse organizes sample collection. Results are stored in the REDCap database.
• VI.Focused cardiac ultrasound reports are uploaded to the REDCap database.
• VII.Follow-up: There are no home visits or requirements for patients to return to the hospital for follow-up surveys, which will be conducted via telephone. One-year clinical outcome data will be gathered from medical records and direct communication with participants and their family doctor.
• VIII.For the health economics analysis, data on participants’ costs incurred through the Pharmaceutical Benefits Scheme, Medicare, and Australian Refined Diagnosis Related Groups will be collected. Participants have provided explicit written consent to access this government database information.

Plans to promote participant retention and complete follow-up {18b}

Most of the required information is gathered while the patient is in the hospital or immediately after discharge. However, we anticipate some participants might be lost to follow-up after 30 days. Therefore, patient selection is crucial; we prioritize those keen on participating, avoiding persistent efforts to convince reluctant individuals. We clearly explain the time commitment and data involved in the surveys, which is usually the main source of potential missing data. After hospital discharge, surveys are performed over the phone to reduce potential data loss, as participants do not need to come back to the hospital. The rest of the clinical outcomes are collected from medical records.

Data management {19}

The trial management group, NTA, will establish a centralized REDCap electronic Case Report Form (eCRF) database, accessible only to researchers with password-protected access.

Data will be collected locally by the researchers at each participating institution and uploaded to the REDCap database, hosted on the Florey Institute of Neuroscience server. Only de-identified data will be entered into the database, with re-identification capabilities retained solely by the respective sites. Each site will have access only to its data. The NTA clinical trial monitor will review and query data within the database as part of the source verification process.

For primary outcome data, there is an additional verification step. Once uploaded to REDCap, the clinical information defining the primary outcome will be checked by two independent data reviewers. They will confirm data entry accuracy, review medical records, and ensure supporting documents are included.

PostopQRS data will be entered into a specific registry on the PostopQRS.com website, a multiuser platform accessible only to registered users with permissions. The site is hosted by Dataphiles Limited, a UK-based company compliant with NHS data policies. All data entered the registry will be de-identified.

Each trial site will undergo formal initiation and training managed by NTA supplemented with face-to-face visits or webinars. The investigator must ensure participant privacy is maintained. Participants will be identified by a participant number or initials on eCRFs or other documents submitted to the sponsor. Documents not submitted to the sponsor, such as signed informed consent forms, will be kept confidential by the investigator. Authorized representatives of the sponsor, regulatory authorities, and IECs may review the participant’s medical records directly related to the study, as outlined in the informed consent documents.

A comprehensive data management plan will be completed before data collection and analysis. Paper records will be stored in locked cabinets and offices, accessible only to investigators, and maintained for at least 15 years. Destruction of paper records will be conducted via secure document destruction methods. Electronic files will be stored on password-protected, secure servers at each institution and deleted after a minimum of 25 years.

Confidentiality {27}

Personal information about potential and enrolled participants will be maintained with strict confidentiality measures. Only de-identified data will be entered into the database, which is accessible exclusively to researchers with password-protected access. For research purposes, only group data will be analyzed, presented at scientific meetings, and published in journals. Paper records will be securely stored in locked cabinets and offices, accessible only to investigators. These records will be destroyed using secure document destruction methods after 15 years. Electronic files will be stored on password-protected, secure servers at each institution and will be deleted after a minimum of 25 years.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Not applicable as there is no plan of future use of biological specimen in ancillary studies.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The statistical methods have been constructed by a team statistician and in consultation with the senior statistician of the Outcomes Research Division of the Cleveland Clinic, OH, USA (A/Prof Mascher).

Primary outcome analysis: Intention to treat analysis will be performed. The primary composite outcome will be compared between FCU and control groups using a distinct effect generalized estimating equation (GEE) model, specifically, an average relative effect test to determine the common treatment effect across the six components. The heterogeneity of the treatment effects across components will be formally assessed by component interaction test in the GEE. This approach considers the different frequencies of each component, reducing the risk of a single component dominating the composite outcome.

Secondary outcome analysis: All secondary outcomes will be compared between the two groups, with methodology depending on outcome type. The same GEE model used for the 30-day composite will be repeated at 1 year, Kaplan–Meier survival analysis will be used for the time to event data, and comparison of proportions will be used for event data.

Interim analyses {21b}

A single-blinded interim analysis will be conducted by the DSMB after 50% of patients have been recruited according to the method of O’Brien and Fleming. The trial will be stopped if the primary outcome measure is different at p < 0.0026.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Subgroup analysis: Subgroup analyses will assess the treatment-by-subgroup interaction within the GEE model framework for the following three factors, which are considered important contributors to the heterogeneity of treatment effect: (1) age 65–75 versus age > 75 years; (2) presence of cardiac symptoms versus asymptomatic; and (3) living at home versus aged care facility, (4) hospitals, (5) type of surgical implant (hemiarthroplasty versus femoral nail).

Health economic analysis will be performed by our team health economist. Additional costs of routine FCU will be balanced against other costs due to changes in the duration of hospital stay, type of ward, and medical resource consumption due to improved survival. Consent will be sought to obtain the total costs of care in each group over the study period. Healthcare resource consumption in each group, including hospitalizations, general practice and specialist consultations, investigations, and medications, will be obtained. Units of healthcare resources consumed will be combined with Australian unit costs derived from the Pharmaceutical Benefit Scheme, Medicare, and the AR-DRGs. Additional costs of the intervention will be accounted for. Additionally, health utility, a summary measure of quality of life, will be measured using the EQ-5D-5L, a standard, internationally validated instrument with Australian population norms. The EQ-5D-5L will be administered in written form (takes < 1 min to complete) at baseline as part of the preoperative patient assessment and at 30 days and 12 months as part of the patient follow-up assessment. Health utility differences between each group, combined with survival differences, will allow the calculation of quality-adjusted life expectancy and, thus, incremental costs per quality-adjusted life years (QALYs) gained. It is hypothesized that the additional costs of intervention will be partially or fully offset by reductions in the cost of hospitalization. Changes in QALYs will be balanced against differences in total costs for each group, enabling assessment of the incremental cost-effectiveness of the intervention versus the current standard of care for the study period. In addition, a Markov simulation model will be developed using TreeAge Decision Analysis software to project trial results to patient lifetimes. Univariate sensitivity analysis will be performed to identify parameters with the greatest impact on projected costs and clinical outcomes. Probabilistic sensitivity analysis, involving simultaneous sampling for distributions of key parameters, will be used to account for uncertainty in multiple parameters.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Stringent efforts will be made to avoid missing data through careful follow-up at multiple time points by research staff and frequent data quality assessment, noting any reasons given for loss to follow-up where available. If only a few component values are missing, and this appears to be balanced between the randomized groups, the main analysis will assume the major event for missing components did not happen. Depending on the extent and nature of the missingness, multiple imputation may also be employed to handle missing data, using a separate imputation model for each treatment group.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

The complete protocol and statistical analysis will be made publicly available upon the publication of the main results in a peer-reviewed medical journal. Access to anonymized participant-level data will be provided, subject to approval by the ethics committee.

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

The trial is managed by the University of Melbourne. The coordinating center is led by the chief investigator (CR), research coordinator, and trial manager.

The Trial Steering Committee consists of the chief investigator (CR), the site principal investigators (PIs), and the clinical trialist (AB). Its role is to oversee the trial and periodically review its progress.

A CRO, the NTA, conducts regular communication between sites and the coordinating team. Its responsibilities include site coordination and activation, ensuring data integrity, reporting adverse clinical events, general trial management, and site closeout.

Composition of the data monitoring committee, its role and reporting structure {21a}

An independent DSMB comprising a statistician, clinical monitor, clinician, and a member of the Melbourne Health Ethics Committee oversees trial safety and data integrity. The DSMB will perform an interim blind analysis when 50% of recruitment is achieved.

An Endpoint Verification Committee will be established for the primary endpoint. Two individuals will verify each patient’s data, with a third adjudicator involved if there is a discrepancy between the first two verifications. Similar to the DSMB, members of this committee will not be PIs, nor will they be involved in any recruitment or data management activities.

Adverse event reporting and harms {22}

Adverse events are monitored by our CRO and reported to the coordinating team and the chief principal investigator. In accordance with regulatory guidelines and site policy, adverse events may also be reported to the trial sponsor or the reviewing ethics committee.

Frequency and plans for auditing trial conduct {23}

A monitoring and auditing plan has been developed by the chief investigator team and the CRO. The frequency of onsite monitoring typically depends on the site’s recruitment status, with additional onsite monitoring possibly required if serious adverse events are reported at the site. Remote monitoring and online database data entry auditing are conducted on an ad hoc basis and are performed by the CRO.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Any changes to the study documents will be communicated promptly to all involved sites. Updated documents (usually provided in both clean and tracked versions), along with the ethics approval letter and any relevant documents, will be shared with the sites.

Dissemination plans {31a}

Results will be disseminated through presentations at medical conferences and aiming for at least two major publications in peer-reviewed medical journals. One publication will report the primary outcome and 30-day clinical endpoints, while the other will focus on the 1-year outcomes and health economics.

Discussion

Patients presenting with hip fractures are typically elderly and frail. In addition to osteoporosis and risk factors for falls, many of these patients have cardiovascular diseases that influence their prognosis [3, 4, 17]. This trial aims to establish proof of concept regarding the benefits of using FCU in the preoperative assessment of patients with hip fractures, with the potential for broader application to perioperative settings in general.

The addition of FCU has demonstrated the provision of relevant clinical information to anesthesiologists, leading to changes in management during surgery and the immediate postoperative period. These changes include adjustments in fluid management, the need for inotropes, and the determination of the post-surgery destination unit [6, 18]. By influencing the clinician’s decision-making process and management plan, FCU may improve clinical outcomes, as suggested by our pilot data. For this intervention to have a significant impact, decision-making doctors need to be familiar with this technique. Fortunately, it is feasible to conduct such a study in Australia, as FCU has been used by anesthesiologists for over 15 years, with approximately 3500 Australian anesthesiologists trained in this tool.

Furthermore, in this trial, we ensure that the information gathered through FCU is also available to all clinicians involved in patient care and integrated into their assessments. We believe that this approach will enhance its impact on the long-term outcomes. For instance, if FCU identifies heart failure with reduced ejection fraction (HFrEF), the patient may be placed on HFrEF medical treatment by the geriatrician or physician involved in their postoperative care, benefiting from the proven mortality and outcome improvements associated with these medications. Similarly, if significant aortic stenosis is detected and the patient is a candidate for transcatheter aortic valve implantation or aortic valve replacement surgery, appropriate assessment and organization can be undertaken.

This trial faces several challenges inherent to conducting a multicenter study. Coordinating and ensuring adherence to the protocol require rigorous supervision and efficient communication. Once sites are initiated after a brief initial stage, we have observed exceptional acceptance and compliance from participants, their families, and their medical teams. This makes us optimistic about achieving our recruitment goals.

Trial status

Protocol number MHREC 2022.071 version: 4.1 date: 28/07/2023.

Recruitment began in March 2023.

Ten sites have been initiated, and 540 participants have been recruited to date.

The estimated date of completing recruitment is March 2027.

Abbreviations

CRO

Contract research organization

DAH30

Days Alive and at Home at Day 30

DSMB

Data Safety Monitoring Board

ECG

Electrocardiogram

eCRF

Electronic Case Report Form

FCU

Focused cardiac ultrasound

GP

General practitioner (family doctor)

MINS

Myocardial injury in noncardiac surgery

NTA

The Neuroscience Trials Australia (a contract research organization)

PI

Principal investigator

Authors’ contributions {31b}

CR is the chief investigator; he conceived the study and developed the proposal. XCS contributed to the study design, study conduct, data analysis, and drafting of this manuscript. AR, AB, and DS are the lead trial methodologists. DC contributed to the study design and the grant application. SCE contributed to the statistical analysis. AD, DLG, and DE contributed to the study design. AP and GL performed the health economics analysis. AC, DYI, TNL, YY, KH, LZ, RC, GH, SD, and BP substantially contributed to the study’s conduct, data analysis, and will be involved in the study report. All authors read and approved the final manuscript.

Funding {4}

This project has been awarded a grant of 3.6 million AUD from the Medical Research Future Fund. This government funding body did not participate in the design of the study and will not be involved in the collection, analysis, or interpretation of data, nor in writing the final manuscript.

Data availability {29}

All data sets will be password protected. Each principal investigator will have direct access to their own site’s data sets. Only the chief investigator (CR) and the DSMB have access to the full trial dataset to ensure that an individual study site does not disclose the overall results prior to the main publication.

Declarations

Ethics approval and consent to participate {24}

Protocol number MHREC 2022.071 version: 4.1. Approved by the Royal Melbourne Hospital Human Research Ethics Committee.

Consent for publication {32}

Willing to provide a participant model consent form on request.

Competing interests {28}

The author declare that they have no competing interests.