Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001634460p
Ethics application status
Submitted, not yet approved
Date submitted
18/11/2016
Date registered
25/11/2016
Date last updated
25/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Ivabradine in the Prevention of Cardiac Injury in patients undergoing major Orthopaedic surgery.
Scientific title
Ivabradine in the Prevention of Peri-operative Myocardial Injury in patients undergoing major Orthopaedic surgery,
Secondary ID [1] 290571 0
None
Universal Trial Number (UTN)
U1111-1190-0434
Trial acronym
IPMI
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Cardiac injury 301024 0
Mortality 301025 0
Orthopaedic Surgery 301026 0
Condition category
Condition code
Cardiovascular 300818 300818 0 0
Other cardiovascular diseases
Injuries and Accidents 300848 300848 0 0
Fractures

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients undergoing major Orthopaedic Surgery will be randomised to receive Ivabradine (Arm 1) above standard of care, or no intervention (Arm 2: usual standard of care).

Ivabradine will be dosed at 5mg, orally, twice a day for patients with initial heart rate of 60-90 beats per minute (at randomisation), OR 7.5mg orally twice a day for heart rates of >90 beats per minute.

First dose of medication will commence between 2 - 48 hours prior to surgery, and continue for a total of 7 days. Once a patient is scheduled for major orthopaedic surgery (with an estimate of date and time), information regarding trial will be provided. Once informed consent is obtained, randomisation will take place and first dose of medication commenced immediately after randomisation. If surgery is expected to be delayed by more than 48 hours, the patient will be withdrawn from study, as it does not fit with the intended study population (requiring emergent surgery). If surgery is expected to take place within 2 hours of study medication becoming available to the patient, the patient will be withdrawn as well, as it is considered too short a period for the medication to reach effect pre-operatively.

All patients will be interviewed at 30 days, and compliance will be assessed accordingly.
Intervention code [1] 296438 0
Prevention
Comparator / control treatment
Control group will receive standard of care (without any additional intervention). Standard of care consists of routine monitoring of heart rate and blood pressure. Clinically significant tachycardia (rates above 100 bpm), bradycardia (rates below 50 bpm), and hypotension (systolic blood pressure below 90 mmHg and symptomatic) will be thoroughly investigated and treated, by the discretion of the attending clinician.
Control group
Active

Outcomes
Primary outcome [1] 300242 0
Peri-operative myocardial injury (PMI) after undergoing major orthopaedic surgery. PMI is defined by troponin I levels above 0.04 mcg/L (if baseline was 0.04 mcg/L or less), or rise in blood levels of troponin I above 20% (if baseline was above 0.04 mcg/L).

Troponin I levels will be measured from bloods samples, collected at randomisation, and days 1, 2 and 3 post-operatively.
Timepoint [1] 300242 0
Post-operative days 1, 2, of 3.
Secondary outcome [1] 329474 0
Clinically significant hypotension, defined by symptomatic systolic blood pressure below 90 mmHg requiring active intervention, such as intravenous fluids or vasopressors, at the discretion of the treating clinician.

This outcome will be assessed from the review of medical records, based on daily blood pressure charts, as well as clinical notes from the attending physician.
Timepoint [1] 329474 0
Post-operative days 1, 2, and 3.
Secondary outcome [2] 329475 0
Mortality
Timepoint [2] 329475 0
30-day and 1 year.

Eligibility
Key inclusion criteria
Patients above the age of 60 undergoing major Orthopaedic surgery (related to long bones, such as femur fractures), who understand and willing to comply with study activities.
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Bradycardia (heart rates below 60 beats per minute)
Current Ivabradine (study intervention drug) use
Patient's with pacemaker

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



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary outcome of PMI will be calculated and reported by cumulative incidence, and compared between the treatment arms for significant differences. Study end point analysis will be conducted on an intention-to-treat principle, as well as the per-protocol basis.

All time-to-event outcomes (such as mortality, myocardial infarction and stroke) will be calculated from the date of randomisation to the date of first documented event, and examined by time-to-event survival analysis (log rank test), and presented in a Kaplan-Meier curve. Cox Proportional Hazard models will be used to examine a range of covariates and their possible interactions.

Descriptive statistics will be presented as counts and percentage frequencies, mean +/- standard deviation (SD) or median with inter-quartile range (IQR) to summarise patient characteristics and outcomes. Categorical variables will be evaluated using the Chi-square test or Fishers Exact test on occasions of frequencies of less than 5. Continuous variables will be analysed with logistic regression. Multivariate logistic regression will be used to identify significant correlations, with only variables having a p-value of <0.1 on univariate analysis being included in the multivariate analysis. A two-tailed p-value of 0.05 was considered indicative of statistical significance.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2016
Actual
Date of last participant enrolment
Anticipated
30/06/2018
Actual
Date of last data collection
Anticipated
30/06/2019
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6954 0
The Northern Hospital - Epping
Recruitment postcode(s) [1] 14644 0
3076 - Epping

Funding & Sponsors
Funding source category [1] 295007 0
Hospital
Name [1] 295007 0
Department of Cardiology, Northern Hospital
Country [1] 295007 0
Australia
Primary sponsor type
Hospital
Name
Department of Cardiology, Northern Hospital
Address
185 Cooper Street, Epping VIC 3076.
Country
Australia
Secondary sponsor category [1] 293825 0
None
Name [1] 293825 0
Address [1] 293825 0
Country [1] 293825 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 296360 0
Northern Health Human Reseach Ethics Committee
Ethics committee address [1] 296360 0
185 Cooper Street Epping 3076 VIC
Ethics committee country [1] 296360 0
Australia
Date submitted for ethics approval [1] 296360 0
25/10/2016
Approval date [1] 296360 0
Ethics approval number [1] 296360 0

Summary
Brief summary
During or after a major operation (such as bones or joints operations, also known as orthopaedic operations), our body increases its heart rate as a response to the stress of the surgery. As the heart pumps faster to manage the stress, it can sometimes damage itself in the process. As previous study observed that up to 52% of patients undergoing major orthopaedic operations demonstrated some evidence of injury to the heart, and these patients have poorer clinical outcomes.

This has led to previous studies examining the benefits of heart rate lowering agents to prevent damage to the heart after surgery, to improve clinical outcomes. Unfortunately, many heart rate lowering agents have a common side effect of lowering the blood pressure as well. Hence, whilst these trials demonstrated promising benefit in reducing damage to the heart, they caused significant problems with low blood pressure.

Ivabradine is an agent that reduces heart rate, but does not drop blood pressure. It is currently approved for use in Australia for another condition called chronic heart failure. But given its unique properties, we postulate that it can reduce damage to the heart after a major operation as well, without the negative effect of causing low blood pressure. As a result, this trial was conceived to examine this effect.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1240 1240 0 0
/AnzctrAttachments/371881-IPMI_Study Protocol.pdf (Protocol)
Attachments [2] 1241 1241 0 0
/AnzctrAttachments/371881-IPMI_PICF.pdf (Participant information/consent)

Contacts
Principal investigator
Name 70582 0
A/Prof William van Gaal
Address 70582 0
Department of Cardiology
The Northern Hospital
185 Cooper Street, Epping, VIC 3076
Country 70582 0
Australia
Phone 70582 0
+61384058000
Fax 70582 0
Email 70582 0
[email protected]
Contact person for public queries
Name 70583 0
Dr Dominic Chow
Address 70583 0
Department of Cardiology
The Northern Hospital
185 Cooper Street, Epping, VIC 3076
Country 70583 0
Australia
Phone 70583 0
+61384058000
Fax 70583 0
Email 70583 0
[email protected]
Contact person for scientific queries
Name 70584 0
Dr Dominic Chow
Address 70584 0
Department of Cardiology
The Northern Hospital
185 Cooper Street, Epping, VIC 3076
Country 70584 0
Australia
Phone 70584 0
+61384058000
Fax 70584 0
Email 70584 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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