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Trial registered on ANZCTR


Registration number
ACTRN12622001412729p
Ethics application status
Submitted, not yet approved
Date submitted
19/10/2022
Date registered
4/11/2022
Date last updated
4/11/2022
Date data sharing statement initially provided
4/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The associations of pneumonia with cardiac injury and new-onset heart failure
Scientific title
The associations of PNEUmonia with Myocardial fibrOsis and new-onset Heart Failure (PNEUMO-HF)
Secondary ID [1] 308127 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PNEUMO-HF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Community-acquired pneumonia 327840 0
New-onset chronic heart failure 327841 0
Myocardial fibrosis 327842 0
Condition category
Condition code
Respiratory 324917 324917 0 0
Other respiratory disorders / diseases
Cardiovascular 324918 324918 0 0
Other cardiovascular diseases
Infection 325087 325087 0 0
Other infectious diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This observational study will recruit adult participants hospitalised due to community-acquired pneumonia who do not have exclusion criteria.

Enrolled participants will undergo a single cardiac magnetic resonance imaging (CMR) during convalescence (2-4 weeks after discharge from hospital) for assessment of myocardial function and composition. This will be performed using a 1.5T magnet under the supervision of a consultant cardiologist with Level III accreditation of training. The anticipated duration of the imaging procedure is approximately 40 minutes. Gadolinium-based contrast will be administered intravenously at 0.15mmol per kg body weight. Images will be analysed by 2 blinded observers independently, both of whom are consultant cardiologists holding Level 3 accreditation of training in CMR.

The CMR protocol will include:
1. Steady-state-free-precession (SSFP) cine images including the 3 major long axes and short-axis stack for quantification of chamber volumes, stroke volume and ejection fraction.
2. Myocardial oedema assessment by T2-weighted imaging and T2-mapping (qualitative and quantitative assessments respectively).
3. T1 weighted late gadolinium imaging (same planes as SSFP).
4. T1-mapping pre and post contrast for quantification of extra-cellular volume as per the standard protocols prescribed by the Society of Cardiovascular Magnetic Resonance consensus statement (Messroghli et al, JCMR 2017).

Blood samples will also be collected from participants, and will be assessed for biomarkers including C-reactive protein, brain natriuretic peptide and high-sensitivity troponin I. These samples will be collected at admission, peri-discharge, and at the time of the CMR 2-4 weeks post-discharge.

Clinical assessment will also be performed by a study clinician or nurse by telephone interview at 1 year, 2 years and 5 years post index hospitalisation for community-acquired pneumonia. Where a significant clinical event is noted (death, new prescription of a loop-diuretic, hospital admission, emergency department presentation), review of the hospital or primary care notes will be conducted for further clinical details.
Intervention code [1] 324583 0
Early Detection / Screening
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332729 0
Incidence of myocardial fibrosis as detected by gadolinium contrast-enhanced CMR
Timepoint [1] 332729 0
2-4 weeks after discharge from the index hospitalisation for community-acquired pneumonia.
Secondary outcome [1] 414597 0
Incidence of the composite of: new-onset left-ventricular dysfunction (EF<50%), new prescription of loop diuretic, hospitalisation or emergency department presentation for heart failure, and cardiovascular death.

These data will be collected from telephone interview, and where any of the above secondary endpoints is reported these will be further interrogated by review of the hospital medical records and / or primary care physician notes.
Timepoint [1] 414597 0
1yr, 2yrs and 5yrs post the initial admission for community-acquired pneumonia.
Secondary outcome [2] 414894 0
Association of the biomarker high-sensitivity Troponin I (by venous blood sampling) with the composite of myocardial fibrosis and / or new-onset left ventricular dysfunction on the CMR at 2-4 weeks post-discharge. This association will be assessed by the sensitivity and specificity of troponin as a continuous variable, and the positive predictive value of troponin elevation as a binary parameter (as per standard definition of troponin elevation, which is above the 99th percentile upper reference limit for the laboratory).
Timepoint [2] 414894 0
Sampled (i) at admission, (ii) peri-discharge from the hospitalisation for pneumonia, and (iii) at convalescent imaging at 2-4 weeks post-discharge.
Secondary outcome [3] 415047 0
Association of the biomarker brain natriuretic peptide (BNP) on venous blood sampling, with the composite of myocardial fibrosis and / or new-onset left ventricular dysfunction on the CMR at 2-4 weeks post-discharge. This association will be assessed by the sensitivity and specificity of BNP as a continuous variable.
Timepoint [3] 415047 0
Sampled (i) peri-discharge from the hospitalisation for pneumonia, and (ii) at convalescent imaging at 2-4 weeks post-discharge.
Secondary outcome [4] 415048 0
Association of the biomarker pro-calcitonin on venous blood sampling, with the composite of myocardial fibrosis and / or new-onset left ventricular dysfunction on the CMR at 2-4 weeks post-discharge. This association will be assessed by the sensitivity and specificity of pro-calcitonin as a continuous variable.
Timepoint [4] 415048 0
Sampled at admission to hospital with community-acquired pneumonia.
Secondary outcome [5] 415049 0
Association of the biomarker C-reactive protein (CRP) on venous blood sampling, with the composite of myocardial fibrosis and / or new-onset left ventricular dysfunction on the CMR at 2-4 weeks post-discharge. This association will be assessed by the sensitivity and specificity of CRP as a continuous variable.
Timepoint [5] 415049 0
Sampled (i) at admission, (ii) peri-discharge from the hospitalisation for pneumonia, and (iii) at convalescent imaging at 2-4 weeks post-discharge.

Eligibility
Key inclusion criteria
(i) Adults hospitalised with community-acquired pneumonia (meeting American Thoracic Society criteria in terms of clinical presentation and radiological features);
(ii) Capacity to provide written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Viral pneumonia, based on the detection of viral nucleic acid amplification on admission screening for pneumonia pathogens.

Prior clinical history of coronary artery disease, myocarditis, connective tissue disorders, cardiomyopathy, heart failure, or pre-existing requirement for loop diuretics.

Left ventricular ejection fraction <54% (women) or <52% (men) at baseline echocardiogram.

Contraindications to contrast-enhanced CMR including prohibitive implanted ferromagnetic devices, pregnancy, severe claustrophobia, and chronic kidney disease with estimate glomerular filtration rate <=30ml/min/1.73msq.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Incidence of the primary outcome will be descriptive (percentage).

The primary endpoint is the incidence of late gadolinium enhancement consistent with myocardial fibrosis on contrast-enhanced cardiac MRI at 14-28 days. Based on data from our pilot studies, an incidence of myocardial fibrosis of approximately 10% is predicted. Based on this, a sample size of 138 participants is required to ensure the precision of the 95% confidence interval is no more than +/-5 percentage points in absolute terms (e.g. between 5% and 15% for the selected estimate of 10%).

Incidence of the secondary outcome - outcomes for heart failure at 1, 2 and 5 years - will be descriptive (incidence per 100 patient years).

Association of biomarkers with the presence of myocardial fibrosis on convalescent imaging will be by unpaired Student t-test or Mann-Whitney U test (according to normality) in the case of continuous variables. Dichotomous data will be assessed by Fisher's exact test with two-tailed evaluation. Where appropriate, receiver operating characteristic curves will be generated to determine diagnostic thresholds for biomarkers in predicting incidence of myocardial fibrosis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
14/11/2022
Actual
Date of last participant enrolment
Anticipated
31/10/2024
Actual
Date of last data collection
Anticipated
31/10/2029
Actual
Sample size
Target
138
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 23351 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 23352 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [3] 23353 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 23354 0
St John of God Hospital, Murdoch - Murdoch
Recruitment postcode(s) [1] 38726 0
6000 - Perth
Recruitment postcode(s) [2] 38727 0
6009 - Nedlands
Recruitment postcode(s) [3] 38728 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 312384 0
Charities/Societies/Foundations
Name [1] 312384 0
Royal Perth Hospital Research Foundation
Country [1] 312384 0
Australia
Primary sponsor type
Individual
Name
Dr Adil Rajwani
Address
Dept of Cardiology,
Royal Perth Hospital
197 Wellington Street,
Perth 6000
Country
Australia
Secondary sponsor category [1] 313969 0
None
Name [1] 313969 0
Address [1] 313969 0
Country [1] 313969 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311741 0
Royal Perth Hospital Human Research Ethics Committee
Ethics committee address [1] 311741 0
East Metropolitan Health Service
Level 2, Kirkman House
10 Murray Street
Perth Western Australia 6000
Ethics committee country [1] 311741 0
Australia
Date submitted for ethics approval [1] 311741 0
27/09/2022
Approval date [1] 311741 0
Ethics approval number [1] 311741 0

Summary
Brief summary
This is a longitudinal observation study which is evaluating the association of hospitalised community-acquired pneumonia with (i) myocardial fibrosis and with (ii) new-onset left ventricular dysfunction.

An abundance of epidemiological data strongly associates pneumonia and subsequent new-onset heart failure, however the mechanism is unclear. Experimental animal data suggest that bacterial invasion of the myocardium with resulting cardiac fibrosis could be implicated. In a recent exploratory study of 20 adults with bacterial community-acquired pneumonia, highly-selected to ensure no prior history of any heart disease, we reported the highly novel finding of myocardial fibrosis and new-onset left ventricular dysfunction in 30% and 5% respectively (Rajwani et al, Bacterial pneumonia is associated with myocardial fibrosis and new-onset left ventricular dysfunction, JACC Advances 2022, in press).

If this novel finding of a pathophysiological process in the myocardium is replicated in larger studies of pneumonia, this could herald a major paradigm shift in the post-discharge care of pneumonia. In this current larger study, adults free of prior heart disease who are hospitalised with community-acquired pneumonia (except those with positive viral nucleic acid amplification assay at admission) will be recruited. Myocardial function and composition will be assessed during convalescence post-discharge, as well as longer-term clinical outcomes for heart failure. Predictors of myocardial fibrosis will also be evaluated, in order to allow enrichment of future translational studies exploring preventative strategies.
Trial website
Trial related presentations / publications
Public notes
Results of the pilot study evaluating the association of a small highly-select cohort of bacterial community-acquired pneumonia with myocardial injury can be found at: Rajwani et al, Bacterial Pneumonia is Associated With Myocardial Fibrosis and New-Onset Left Ventricular Dysfunction. JACC: Advances 2022.

For the current study, please note that participants with pneumonia due to COVID-19 infection will be excluded.

Contacts
Principal investigator
Name 122206 0
A/Prof Adil Rajwani
Address 122206 0
Dept of Cardiology
Royal Perth Hospital
197 Wellington Street
Perth, WA 6000
Country 122206 0
Australia
Phone 122206 0
+61 8 9224 3617
Fax 122206 0
Email 122206 0
adil.rajwani@health.wa.gov.au
Contact person for public queries
Name 122207 0
A/Prof Adil Rajwani
Address 122207 0
Dept of Cardiology
Royal Perth Hospital
197 Wellington Street
Perth, WA 6000
Country 122207 0
Australia
Phone 122207 0
+61 8 9224 2292
Fax 122207 0
Email 122207 0
adil.rajwani@health.wa.gov.au
Contact person for scientific queries
Name 122208 0
A/Prof Adil Rajwani
Address 122208 0
Dept of Cardiology
Royal Perth Hospital
197 Wellington Street
Perth, WA 6000
Country 122208 0
Australia
Phone 122208 0
+61 8 9224 2292
Fax 122208 0
Email 122208 0
adil.rajwani@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We have not sought consent for this in our ethics application.


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.