Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000709549
Ethics application status
Approved
Date submitted
27/07/2023
Date registered
6/06/2024
Date last updated
6/06/2024
Date data sharing statement initially provided
6/06/2024
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigating whether bacteria or other organisms are present in the bloodstream at the time of transcatheter aortic valve implantation (TAVI)
Scientific title
Incidence of periprocedural bacteraemia associated with transcatheter aortic valve implantation (TAVI)
Secondary ID [1] 310213 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Aortic stenosis 330890 0
Bacteraemia 330891 0
Infective endocarditis 330892 0
Condition category
Condition code
Infection 327682 327682 0 0
Other infectious diseases
Cardiovascular 330637 330637 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Participants undergoing inpatient transcatheter aortic valve implantation (TAVI) will be sequentially enrolled into the trial. Informed consent will be gained by a study investigator or their delegate.

Participants will have blood cultures collected by the procedural cardiologist or nursing staff at three time points periprocedurally to investigate for bacteraemia. These time points are: 1) at the time of femoral puncture for the TAVI procedure 2) at the time of valve deployment during the TAVI procedure (45-90min post time point 1) 3) the day following the TAVI procedure with routine pathology collection. Blood specimens will be collected through the femoral procedure sheath or arterial line at time points 1 and 2. Time point 3 specimens will be collected via peripheral venipuncture. Participants will be followed up, via review of their electronic medical record, at 12 months post-TAVI to assess for any episodes of infective endocarditis during the study period.

Participants receiving cefazolin as antimicrobial prophylaxis for their procedure will be enrolled in a sub-study investigating periprocedural cefazolin pharmacokinetics and pharmacodynamics. A serum specimen will be collected at the same time points as the above blood culture collections. An additional serum specimen will be collected 4-8 hours post TAVI procedure.
Intervention code [1] 326602 0
Not applicable
Comparator / control treatment
A comparator group of individuals undergoing coronary angiography via femoral approach will be enrolled. These participants will have blood cultures collected at up to three time points: 1) at time of initial femoral puncture 2) at the conclusion of the angiography procedure (30-90min post time point 1) and 3) the day following the procedure provided the participant is still a hospital inpatient. Participants will be followed up, via review of their electronic medical record, at 12 months post-angiography to assess for any episodes of infective endocarditis during the study period.

Participants in the comparator group will not be eligible for the cefazolin PK/PD sub-study.
Control group
Active

Outcomes
Primary outcome [1] 335483 0
Incidence of periprocedural bacteraemia during TAVI procedures, assessed using culture of blood samples
Timepoint [1] 335483 0
6 days post TAVI procedure
Primary outcome [2] 338382 0
Microbiology of periprocedural bacteraemia during TAVI procedures, assessed using culture of blood samples
Timepoint [2] 338382 0
6 days post TAVI procedure
Secondary outcome [1] 424791 0
For participants administered prophylactic cefazolin, model the likelihood of achieving inhibitory serum cefazolin concentrations periprocedurally against viridans group Streptococci
Timepoint [1] 424791 0
Blood specimens for cefazolin total and unbound levels collected at 4 time points: 1) at time of initial femoral puncture for TAVI procedure 2) at time of TAVI deployment (45-90min post time point 1) 3) 4-8 hours post completion of TAVI procedure 4) day 1 following TAVI procedure. Timing and dose of cefazolin administration will be recorded.
Secondary outcome [2] 424792 0
For participants administered prophylactic cefazolin, model the likelihood of achieving inhibitory serum cefazolin concentrations periprocedurally against Enterococcus faecalis
Timepoint [2] 424792 0
Blood specimens for cefazolin total and unbound levels collected at 4 time points: 1) at time of initial femoral puncture for TAVI procedure 2) at time of TAVI deployment (45-90min post time point 1) 3) 4-8 hours post completion of TAVI procedure 4) day 1 following TAVI procedure. Timing and dose of cefazolin administration will be recorded.
Secondary outcome [3] 436014 0
For participants administered prophylactic cefazolin, model the likelihood of achieving inhibitory serum cefazolin concentrations periprocedurally against Staphylococcus aureus
Timepoint [3] 436014 0
Blood specimens for cefazolin total and unbound levels collected at 4 time points: 1) at time of initial femoral puncture for TAVI procedure 2) at time of TAVI deployment (45-90min post time point 1) 3) 4-8 hours post completion of TAVI procedure 4) day 1 following TAVI procedure. Timing and dose of cefazolin administration will be recorded.
Secondary outcome [4] 436015 0
Subsequent post-TAVI episodes of TAVI infective endocarditis assessed from participant electronic medical records
Timepoint [4] 436015 0
1 year post TAVI procedure

Eligibility
Key inclusion criteria
undergoing a clinically indicated TAVI procedure via a transfemoral approach OR undergoing coronary angiography via a transfemoral approach (comparator group)

able to provide informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
known bacteraemia within 30 days prior to TAVI procedure

receipt of systemic antibiotic therapy within 5 days prior to TAVI procedure (other than procedural prophylaxis)

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Convenience sample
Timing
Prospective
Statistical methods / analysis
Power calculations are not possible for this study given the event rate is unknown. The sample size (60 TAVI recipients and 15 comparators) was chosen for feasibility and based on an estimated event rate.

The primary outcome will be reported with descriptive statistics. If there are sufficient events, the impact of certain procedural and demographic factors will be assessed in univariate and multivariate analysis.

Analysis plan for cefazolin PK/PD sub-study:
Median (IQR) cefazolin concentrations in unbound plasma samples at each time point will be compared to the MIC90 of cefazolin for S. aureus (2mg/L).

Population pharmacokinetic modelling of total and unbound concentrations will be performed using Pmetrics®. Pharmacokinetic parameters (volume of distribution, clearance, and half-lives) will be estimated for individual patients and the patient sample and compared with published data from other patient populations. An attempt will be made to determine any associations with patient or treatment characteristics and pharmacokinetic parameter estimates.

The final population pharmacokinetic model will be used to describe an optimised dosing regimen for this clinical indication. Monte Carlo Simulation (MCS) is a statistical approach whereby a pharmacokinetic model with defined pharmacokinetic parameters and covariates can be used to simulate a larger population group. The probability of target attainment (PTA) for a defined PK-PD index in the simulated population group is then calculated. Furthermore, the fractional target attainment (FTA) or cumulative fraction response (CFR) may be used. Both the CFR and FTA consider the PTA across the spectrum of isolates and can be calculated by multiplying the PTA of each MIC by the fraction of isolates with that MIC. These values are then summed. A PTA or FTA of > 95 % reflects a high likelihood of therapeutic success.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
24/10/2022
Date of last participant enrolment
Anticipated
Actual
20/05/2024
Date of last data collection
Anticipated
20/05/2025
Actual
Sample size
Target
75
Accrual to date
Final
75
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 25283 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 25284 0
Victorian Heart Hospital - Clayton
Recruitment postcode(s) [1] 40956 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 314377 0
Hospital
Name [1] 314377 0
Monash Infectious Diseases - Monash Health
Country [1] 314377 0
Australia
Primary sponsor type
Individual
Name
Dr Christopher Robson
Address
246 Clayton RdClaytonVIC3168
Country
Australia
Secondary sponsor category [1] 316328 0
None
Name [1] 316328 0
Address [1] 316328 0
Country [1] 316328 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313470 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 313470 0
246 Clayton RdClaytonVIC3168
Ethics committee country [1] 313470 0
Australia
Date submitted for ethics approval [1] 313470 0
Approval date [1] 313470 0
23/02/2022
Ethics approval number [1] 313470 0

Summary
Brief summary
Aortic stenosis is a common valvular abnormality in adults. Its incidence increases with age. The only effective treatment options for severe aortic stenosis are surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI). TAVI represents a less invasive alternative to SAVR. In patients with high surgical risk TAVI has been associated with increased 1-year survival compared with SAVR, along with reduced risk of death and hospitalisation compared with conservative management. More recently, TAVI has also been shown to result in significantly lower rates of death, stroke or rehospitalisation compared with SAVR in patients with low surgical risk. As such, we can expect an increase in the number of TAVI procedures in future.

Infective endocarditis is a potential complication following TAVI insertion. The rate of infective endocarditis following TAVI has been variably reported between 1 and 3%, which is similar to the rate of prosthetic valve endocarditis (PVE) following SAVR. However, the microbiology of post-TAVI endocarditis is notably different from PVE or native valve infective endocarditis, with a predominance of Enterococci. The reasons for this difference have not been elucidated but may relate to the transfemoral approach utilised for the majority of TAVIs. This raises the possibility of periprocedural bacteraemia and subsequent seeding of the newly placed valve prosthesis. To date there have been no studies investigating the rate of periprocedural bacteraemia in patients undergoing TAVI.

There is a paucity of literature surrounding antibiotic prophylaxis for TAVI procedures. The European Society of Cardiology guidelines advise that antibiotic prophylaxis should be considered in patients undergoing TAVI but give no recommendation as to the agent or duration. Cefazolin is frequently used as prophylaxis for cardiothoracic surgery and a number of institutions have extrapolated this to TAVI prophylaxis. However, little is known about the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics including cefazolin in the TAVI population, in whom there are presumably dramatic changes in haemodynamics and organ perfusion periprocedurally. Furthermore, the predominance of Enterococci in post-TAVI endocarditis would suggest that cephalosporins are a suboptimal prophylactic antibiotic.

In this study, we aim to explore the incidence of periprocedural bacteraemia in patients undergoing TAVI as a possible explanation for the unique microbiological profile of infective endocarditis in this group. Additionally, we will examine demographic and procedural data for associations with any observed bacteraemia. Given the unique haemodynamic changes observed during TAVI procedures we will also examine the PK profile of prophylactic antibiotics and correlate this with any observed bacteraemia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128278 0
Dr Christopher Robson
Address 128278 0
Monash Health 246 Clayton Rd Clayton VIC 3168
Country 128278 0
Australia
Phone 128278 0
+61 395944564
Fax 128278 0
Email 128278 0
christopher.robson@monashhealth.org
Contact person for public queries
Name 128279 0
Dr Christopher Robson
Address 128279 0
Monash Health 246 Clayton Rd Clayton VIC 3168
Country 128279 0
Australia
Phone 128279 0
+61 395944564
Fax 128279 0
Email 128279 0
christopher.robson@monashhealth.org
Contact person for scientific queries
Name 128280 0
Dr Christopher Robson
Address 128280 0
Monash Health 246 Clayton Rd Clayton VIC 3168
Country 128280 0
Australia
Phone 128280 0
+61 395944564
Fax 128280 0
Email 128280 0
christopher.robson@monashhealth.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.