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Trial registered on ANZCTR


Registration number
ACTRN12621001732875
Ethics application status
Approved
Date submitted
16/08/2021
Date registered
20/12/2021
Date last updated
14/01/2024
Date data sharing statement initially provided
20/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of a combination of beta-blockers, angiotensin receptor blockers, and calcium channel blockers in aortic stenosis
Scientific title
The Effect of a Combination of Beta-blockers, Angiotensin Receptor Blockers, and Calcium Channel Blockers on Clinical Outcomes in Mild or Moderate Aortic Stenosis (the Pressure Reduction in Mild or Moderate Aortic Stenosis trial)
Secondary ID [1] 304786 0
None
Universal Trial Number (UTN)
U1111-1268-0803
Trial acronym
PUMAS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Aortic stenosis 322846 0
Condition category
Condition code
Cardiovascular 320426 320426 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
B: Intervention group
A combination of a beta-blocker (bisoprolol) plus angiotensin receptor blocker (candesartan) plus calcium channel blocker (amlodipine)
Bisoprolol doses - 2.5mg, 5mg, 10mg
Candesartan doses - 8mg, 16mg, 32mg
Amlodipine doses - 2.5mg, 5mg, 10mg

Dose titration will be performed as follows:
• Initially start 8mg candesartan per day.
• Week 2: as long as BP remains >100mmHg, add Bisoprolol 2.5mg daily.
• Week 3: as long as BP remains >100mmHg, add Amlodipine 2.5mg daily.
• Medications will then be titrated in order each week - candesartan 16mg week 4/32mg week 7, bisoprolol 5mg week 5/10mg week 8, amlodipine 5mg week 6/10mg week 9

In case of intolerance to standard titration, a lower rate of dose escalation can be used.

All drugs will be oral tablets given once daily over the length of the study (10 years), and may continue indefinitely following satisfactory evaluation.
Adherence will be monitored by comparison with pharmaceutical dispensing and by questionnaire.
Intervention code [1] 321164 0
Treatment: Drugs
Comparator / control treatment
A: Standard management
Patients will be managed by their health care provider (primarily general practitioner). If the patient has hypertension, standard management of hypertension will be recommended, but will be left to the discretion of the patients’ health care providers. In New Zealand hypertension management is based on both the measured blood pressure, overall cardiovascular risk assessment, and management of other risk factors, according to the guidance provided in:
Ministry of Health. Cardiovascular Disease Risk Assessment and Management for Primary Care. (2018).
Lifestyle advice covering physical activity, eating for a healthy heart, and smoking cessation advice is routinely indicated, followed by treatment of specific risk factors. Choice of antihypertensive therapy is not mandated, although beta-blockers are recommended to be reserved only as second line agents in those without specific indications for their use. At the baseline study visit, patients will be recommended to engage with their healthcare provider to seek appropriate lifestyle advice and cardiovascular risk factor management which will be left to the discretion of the patient’s own general practitioner.
Control group
Active

Outcomes
Primary outcome [1] 328267 0
Composite outcome of any of aortic valve replacement, hospitalisation with heart failure or aortic stenosis, or cardiovascular death. The outcome will be assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [1] 328267 0
The outcome will be assessed annually, for 10 years, with the 5 year assessment as the primary endpoint.
Secondary outcome [1] 398279 0
Valvuloarterial impedence, as measured by echocardiography
Timepoint [1] 398279 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [2] 398280 0
Severity of aortic stenosis, as measured by echocardiography (aortic valve maximum velocity (AV Vmax), aortic valve mean pressure gradient, dimensionless index, categorical aortic stenosis severity class)
Timepoint [2] 398280 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [3] 398281 0
Aortic valve replacement.
The outcome will be assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [3] 398281 0
The outcome will be assessed annually, for 10 years post study enrolment.
Secondary outcome [4] 398282 0
All-cause mortality
Timepoint [4] 398282 0
The outcome will be assessed annually, for 10 years post study enrolment.
Secondary outcome [5] 398283 0
Other major adverse cardiovascular events (specifically myocardial infarction, hospitalisation with unstable angina, stroke), as assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [5] 398283 0
The outcome will be assessed annually, for 10 years post study enrolment.
Secondary outcome [6] 399750 0
Prescription fulfilment, as assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [6] 399750 0
The outcome will be assessed at approximately two years and five years post study enrolment.
Secondary outcome [7] 399751 0
Cardiovascular mortality, as assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [7] 399751 0
The outcome will be assessed annually after, for 10 years post study enrolment.
Secondary outcome [8] 401071 0
Hospitalisation with heart failure or aortic stenosis, as assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [8] 401071 0
The outcome will be assessed annually, for 10 years post study enrolment.
Secondary outcome [9] 401072 0
Patient reported outcome measure: EQ-5D, paper self-report of generic quality of life.
Timepoint [9] 401072 0
Assessed at the two-year study visit, and (if funding allows) at a five-year study visit
Secondary outcome [10] 401073 0
Patient reported outcome measure: KCCQ, paper self-report to measure participant's perception of their health status.
Timepoint [10] 401073 0
Assessed at the two-year study visit, and (if funding allows) at a five-year study visit
Secondary outcome [11] 401074 0
Patient reported outcome measure: SF-12v2, paper self-report to measure participant's health-related quality of life.
Timepoint [11] 401074 0
Assessed at the two-year study visit, and (if funding allows) at a five-year study visit
Secondary outcome [12] 401075 0
Patient reported outcome measure: VALVQ, paper self-report to measure participant's valve-specific quality of life.
Timepoint [12] 401075 0
Assessed at the two-year study visit, and (if funding allows) at a five-year study visit
Secondary outcome [13] 401076 0
Left ventricular global longitudinal strain, as measured by echocardiography
Timepoint [13] 401076 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [14] 401077 0
Left ventricular E/e', as measured by echocardiography
Timepoint [14] 401077 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [15] 401078 0
Left atrial volume, as measured by echocardiography
Timepoint [15] 401078 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [16] 401079 0
Left ventricular mass, as measured using clinical echocardiography
Timepoint [16] 401079 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [17] 401080 0
Left ventricular diastolic dysfunction (categorical), as measured by echocardiography.
Timepoint [17] 401080 0
Approximately annually (or when clinical echocardiography performed) after baseline echocardiography, for a minimum of five years
Secondary outcome [18] 401227 0
Composite outcome of either hospitalisation with heart failure or cardiovascular death
The outcome will be assessed via the electronic health record and/or by data-linkage with Ministry of Health records.
Timepoint [18] 401227 0
The outcome will be assessed annually after aortic valve replacement, for 10 years after study enrolment.

Eligibility
Key inclusion criteria
• Provide signed and dated informed consent form (analogue or digital).
• Willing to comply with all study procedures and be available for the duration of the study.
• Age between 18 and 90 years, inclusive.
• Systolic BP <200 and >100 mmHg.
• Participant has mild to moderate AS as defined by echocardiogram with;
o aortic valve thickening/calcification and
o maximum aortic valve transvalvular velocity 2.5 – 4.0 m/s and
o mean aortic valve transvalvular gradient (AVG) <40mmHg and
o Qualitative restriction to valve opening
• Bicuspid or tricuspid aortic valve is eligible for inclusion.
Minimum age
18 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Major medical comorbidities that, in the opinion of the investigator, would make initiation or adjustment of medications unsafe, or life expectancy is estimated to be less than 5 years.
• Significantly impaired renal function (CKD4 or more significant, i.e. eGFR < 30ml/min/1.73m2).
• Left ventricular ejection fraction < 50%
• Pregnancy
• Already prescribed maximal tolerated doses of any one of the investigational antihypertensive regimes (i.e. maximal tolerated dose of (beta-blocker and angiotensin receptor blocker) or (calcium channel blocker))
• Contraindication to any one of the investigational antihypertensive regimes (i.e. to both beta-blocker and angiotensin receptor blocker, or to calcium channel blocker)
• Cognitive impairment, dementia, or other limitation that would make the study participant unable to follow dose escalation/study protocols.

Study design
Purpose of the study
Treatment
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, with equal distribution across groups, i.e. 1:1 to control (group A):intervention (group B)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary analysis will based on time to event for the primary outcome for the control group (A) vs the intervention group (B) to examine whether antihypertensive therapy is efficacious. For sample size calculations, we used an event rate of 38% at 5 years. Based on this, we would need 263 in each comparator group to detect a 30% reduction in event rate (for 80% power at alpha=0.05) and 610 per comparator group to detect a reduction of 20%. For the primary analysis (group A vs group B) this leads to a sample size of 1220, and we have set a target recruitment of 1250, as loss to follow-up is expected to be minimal as outcomes as assessed via data-linkage.
Formal sample size calculation will be performed at the end of the 2 year Vanguard phase based. Participants in the Vanguard phase will continue into the main study for assessment of the primary and secondary outcomes.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
24/01/2022
Actual
8/09/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1250
Accrual to date
87
Final
Recruitment outside Australia
Country [1] 23970 0
New Zealand
State/province [1] 23970 0
Otago, Southland

Funding & Sponsors
Funding source category [1] 309158 0
Charities/Societies/Foundations
Name [1] 309158 0
Healthcare Otago Trust
Country [1] 309158 0
New Zealand
Funding source category [2] 309159 0
University
Name [2] 309159 0
University of Otago
Country [2] 309159 0
New Zealand
Funding source category [3] 310292 0
Government body
Name [3] 310292 0
Health Research Council
Country [3] 310292 0
New Zealand
Funding source category [4] 310403 0
Government body
Name [4] 310403 0
Lottery Health Research
Country [4] 310403 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Research and Enterprise
University of Otago
PO Box 56
Dunedin 9016
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310114 0
None
Name [1] 310114 0
Address [1] 310114 0
Country [1] 310114 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309022 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 309022 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 309022 0
New Zealand
Date submitted for ethics approval [1] 309022 0
20/08/2021
Approval date [1] 309022 0
09/12/2021
Ethics approval number [1] 309022 0
21/NTA/164

Summary
Brief summary
Due to a progressive build-up of calcium, aortic stenosis (AS) restricts movement of the valve leaflets, increasing the workload of the heart. Over time this causes scarring and reduces the ability of the heart to function, and without treatment leads to heart failure and death. Currently there are no medications to slow the progression of AS and treatment is based on careful observation to time heart valve replacement, which is an expensive and sometimes risky procedure. High blood pressure is associated with more rapid progression of AS and scarring of the heart muscle. It is unknown whether lowering blood pressure changes outcomes related to aortic valve disease. Even after aortic valve replacement, scar tissue remains and can increase the risk of heart failure and death. This study aims to analyse the efficacy of medications to reduce the workload on the heart, starting when AS is in a mild to moderate stage. We will examine the progression of AS and changes in the heart muscle over time, to see if reducing the workload on the heart will slow the development and progression of problems related to AS.
Trial website
Trial related presentations / publications
Public notes
The initial phase of the trial is an internal feasibility or vanguard phase, of approximately 200 participants. Using the information from this, we will derive more formal sample size calculations for the main trial. Those in the vanguard phase will continue for outcome assessment in the main trial.

Contacts
Principal investigator
Name 112678 0
Dr Sean Coffey
Address 112678 0
Department of Medicine
Dunedin School of Medicine, PO Box 56
University of Otago
Dunedin 9054
Country 112678 0
New Zealand
Phone 112678 0
+64 34740999
Fax 112678 0
Email 112678 0
[email protected]
Contact person for public queries
Name 112679 0
Katherine Sneddon
Address 112679 0
Department of Cardiology
Dunedin Hospital
201 Great King Street
Dunedin 9016
Country 112679 0
New Zealand
Phone 112679 0
+64 34740999
Fax 112679 0
Email 112679 0
[email protected]
Contact person for scientific queries
Name 112680 0
Peter McLeod
Address 112680 0
Department of Medicine
Dunedin School of Medicine, PO Box 9056
University of Otago
Dunedin 9054
Country 112680 0
New Zealand
Phone 112680 0
+64 3 4740999
Fax 112680 0
Email 112680 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Non-identifiable participant information of published results.
When will data be available (start and end dates)?
Data will be available within 12 months of publication of primary trial results, and for a minimum of 10 years.
Available to whom?
Anyone
Available for what types of analyses?
For any analyses
How or where can data be obtained?
Unrestricted access via vivli.org (providing funding is obtained to pay for this).


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.