Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000340831
Ethics application status
Not yet submitted
Date submitted
22/03/2012
Date registered
23/03/2012
Date last updated
23/03/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Can pre-operative Ivabradine and/or Atorvastatin prevent heart injury following surgery for neck of femur fracture in elderly patients?
Scientific title
A randomised controlled trial of Ivabradine and Atorvastatin in emergent orthopaedic lower limb surgery for neck of femur fracture in elderly patients: a mechanistic study of peri-operative myocardial injury and its prevention using computed tomography coronary plaque imaging and novel biomarkers of cardiovascular stress and lipid metabolism
Secondary ID [1] 280187 0
Nil
Universal Trial Number (UTN)
U1111-1129-3244
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coronary artery disease 286116 0
Fractures 286117 0
Peri-operative myocardial injury 286118 0
Condition category
Condition code
Surgery 286312 286312 0 0
Other surgery
Cardiovascular 286340 286340 0 0
Coronary heart disease
Injuries and Accidents 286341 286341 0 0
Fractures

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomised using a computerised block randomisation method with blocks of variable sizes to ensure ‘true’ randomisation and equal numbers in each treatment group. Patients will be randomized to one of four groups in a 1:1:1:1 ratio.
1) No treatment (control group)
2) Atorvastatin orally 80 mg daily till discharge from acute hospital care (to home / rehab)
3) Ivabradine 5mg orally twice daily till discharge from acute hospital care (to home / rehab)
4) Ivabradine 5 mg orally twice daily and atorvastatin orally 80 mg daily till discharge from acute hospital care (to home / rehab)

Treatment would start on randomization prior to surgery which would be as soon as practicable after admission.
Intervention code [1] 284511 0
Prevention
Intervention code [2] 284512 0
Treatment: Drugs
Comparator / control treatment
No treatment
Control group
Active

Outcomes
Primary outcome [1] 286783 0
The frequency (binary outcome) and magnitude (continuous variable) of new myocardial injury following emergent orthopaedic surgery for lower limb fracture as assessed by troponin I, on a per protocol basis.
Timepoint [1] 286783 0
Day 0
Day 1
Day 2
Day 3
Secondary outcome [1] 296644 0
Myocardial infarction according to the universal definition
Timepoint [1] 296644 0
Day 3
Secondary outcome [2] 296645 0
Mean HR over 48 hours Holter monitoring postoperatively
Timepoint [2] 296645 0
48 hours
Secondary outcome [3] 296646 0
Incidence and duration of AF over 48 Holter monitoring postoperatively
Timepoint [3] 296646 0
48 hours
Secondary outcome [4] 296647 0
Serum assays of NT-proBNP, MR-proANP, MR-proADM and CT-proET-1. Samples would be stored at negative 80 degrees prior to testing at external laboratory.
Timepoint [4] 296647 0
Days 0,1,2,3
Secondary outcome [5] 296648 0
Serum assays of sPLA2 and Lp-PLA2 mass and activity
Timepoint [5] 296648 0
Days 0,1
Secondary outcome [6] 296649 0
Platelet activation as measured by VerifyNow P2Y12 assay.
Timepoint [6] 296649 0
Preoperative (day 0)
Secondary outcome [7] 296650 0
Death
Timepoint [7] 296650 0
In hospital
30 days
12 months
Secondary outcome [8] 296651 0
Stroke
Timepoint [8] 296651 0
In hospital
30 days
12 months
Secondary outcome [9] 296652 0
Symptomatic bradycardia or heart block requiring cessation of ivabradine
Timepoint [9] 296652 0
In hospital
Secondary outcome [10] 296653 0
Liver enzyme elevation > 3 times the upper limits of normal
Timepoint [10] 296653 0
In Hospital

Eligibility
Key inclusion criteria
1) Age greater than 60 years
2) Neck of femur fracture with planned surgical treatment within 48 hours
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Current ivabradine use
2) Patients who do not undergo surgical treatment for lower limb fracture for any reason. If such patients were initially enrolled they will be excluded from the analysis, i.e per protocol analysis.
3) Heart rate < 65bpm prior to randomisation
4) Known liver disease or liver enzymes > 3 times the higher limits of normal
5) Pre-operative troponin elevation
6) Artificial pacemakers, sick sinus syndrome or complete heart block
7) Concomittant CYP3A4 inhibitors – ketoconazole, macrolides, cyclosporin, gestodene, antiretrovirals

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)
Patients will be randomised using a computerised block randomisation method with blocks of variable sizes to ensure ‘true’ randomisation and equal numbers in each treatment group using sealed opaque envelopes. Patients will be randomized to one of four groups in a 1:1:1:1 ratio
1) No treatment (control group)
2) Atorvastatin 80 mg daily
3) Ivabradine twice daily (as per protocol)
4) Ivabradine twice daily (as per protocol) and atorvastatin 80 mg daily
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised block randomisation method with blocks of variable sizes to ensure ‘true’ randomisation and equal numbers in each treatment group using sealed opaque envelopes.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/04/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 284936 0
Hospital
Name [1] 284936 0
Northern hospital
Country [1] 284936 0
Australia
Primary sponsor type
Hospital
Name
Northern hospital
Address
Cardiology Department
The Northern hospital
185 Cooper Street
Epping vic 3076
Country
Australia
Secondary sponsor category [1] 283822 0
None
Name [1] 283822 0
Address [1] 283822 0
Country [1] 283822 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 286945 0
The Northern Health Ethics Committee
Ethics committee address [1] 286945 0
185 Cooper street
Epping Vic 3076
Ethics committee country [1] 286945 0
Australia
Date submitted for ethics approval [1] 286945 0
27/03/2011
Approval date [1] 286945 0
Ethics approval number [1] 286945 0

Summary
Brief summary
In patients undergoing urgent orthopaedic surgery , Heart muscle damage around the time of surgery(perioperative myocardial Injury-PMI) can occure in 52.9% of patients shown in a study conducted in the northern hospital. The majority of these patients were asymptomatic, with only 9.8% of patients meeting the universal definition criteria for myocardial infarction (heart attack). One year mortality was dramatically increased across the board in those with any troponin(a blood test showing heart muscle damage) elevation (37% versus 2.1%)after the surgery.
The exact mechanisms of PMI are not well understood, however two broad theories are postulated; myocardial(heart muscle) stress and cholestrol plaque rupture. Prevention of myocardial stress and/or plaque rupture may reduce the incidence of PMI and have been the subject of multiple studies.

This study is going to assess if Ivabradine(a medication lowers the heart rate without affecting the blood pressure) will reduce the rate and magnitude of PMI following emergent lower limb orthopaedic surgery by reducing heart rate and attenuating catecholamine(stress hormons) induced tachycardia(fast heart rate) after operation and to assess if it will correlate with a reduction in biomarkers of cardiovascular stress(blood tests) as measured by NT-proBNP, MR-proANP, MR-proADM and CT-proET-1 and if it will reduce the incidence and burden of atrial fibrillation after the surgery.

Also this study is going to assess if Atorvastatin(a medication lowers the cholestrol and inflamatiom) will reduce the rate and magnitude of PMI following emergent lower limb orthopaedic surgery and if it will correlate with a reduction in sPLA2 and Lp-PLA2 mass and activity(markers of cholesterol plaque burden and inflammation ).

Also we will assess if that patients with higher measures of platelet function(aggregation and reactivity) before and after surgery will have an increased incidence and magnitude of PMI and if patients with a higher burden of atherosclerotic(chorestrol plaque) disease as measured by CT coronary calcium scores( a ct scan messuring amount of calcium in arteries supplying blood to the heart) will have a higher incidence and magnitidue of PMI.

And finally to assess if that the benefit from reduction in the incidence and magnitude of PMI by Ivabradine and Atorvastatin is derived primarily in patients with greater atherosclerotic (cholesterol Plaque) burden as measured by higher CT coronary calcium scores.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33954 0
Address 33954 0
Country 33954 0
Phone 33954 0
Fax 33954 0
Email 33954 0
Contact person for public queries
Name 17201 0
A/Prof William Van Gaal
Address 17201 0
Director of Cardiology
Northern hospital
185 Cooper Street
Epping Vic 3076
Country 17201 0
Australia
Phone 17201 0
+61384058154
Fax 17201 0
+61384058405
Email 17201 0
[email protected]
Contact person for scientific queries
Name 8129 0
A/Prof William Van Gaal
Address 8129 0
Director of Cardiology
Northern hospital
185 Cooper Street
Epping Vic 3076
Country 8129 0
Australia
Phone 8129 0
+61384058154
Fax 8129 0
+61384058405
Email 8129 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



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