Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000764932
Ethics application status
Approved
Date submitted
30/05/2020
Date registered
27/07/2020
Date last updated
21/01/2024
Date data sharing statement initially provided
27/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
What should be the target blood pressure in heart failure patients with an implantable cardioverter defibrillator who already had ventricular tachycardia (VT), so as to prevent future VT and death?
Scientific title
Effect of Aggressive vs. Lenient Blood Pressure Control in Patients with Ventricular Tachycardia (VT) on Future VT and Death
Secondary ID [1] 301410 0
None
Universal Trial Number (UTN)
Trial acronym
REDUCE-VT Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart failure 317685 0
ventricular tachycardia 317686 0
Hypertension 317687 0
Implantable cardioverter defibrillator shocks 317688 0
Condition category
Condition code
Cardiovascular 315763 315763 0 0
Other cardiovascular diseases
Cardiovascular 316085 316085 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We aim to conduct a clinical trial to test whether patients with heart failure who have had sustained VT need lenient or aggressive BP lowering to prevent future VT and death. Patients will either have an existing implantable cardioverter defibrillator or are scheduled to have one immediately as part of their routine clinical care. These patients will be then randomized into 2 arms- aggressive vs. lenient BP reduction. Medications will be adjusted so as to achieve predefined BP targets (systolic BP <120mmHg in aggressive BP reduction arm vs. 120-140mmHg in lenient BP reduction arm). The treatment algorithms for each group have been adapted from the SPRINT trial (NEJM 2015). Patients will be followed up for a minimum of 2 years for the primary outcome of time to recurrent VT or death from any cause.

Lenient BP control arm (systolic BP goal 120-140mmHg) treatment decision tree:

Screening period (4weeks):
• Patient is expected to be on a combination of RAAS inhibitors (ACEI or ARB or ARNI along with an AldA).
• Use of beta-blocker is encouraged, but loop/thiazide diuretics are discouraged. The dose of beta-blocker should be maximized. The loop and thiazide diuretic should either be discontinued or maintained when compelling reason in a least permissible stable dose.
• At least one screening visit is required at the beginning of the 4-week period.
• Expected length of screening visit: 30min.


Run-in period (2 weeks):
• Dose changes to all medications are discouraged.
• Resting blood pressure readings are taken once.
• Exercise stress (Treadmill) test is performed
• At least one run-in visit is required at the beginning of the 2-week period.
• Expected length of run-in visit with stress test: 45min
Resting BP will be estimated by averaging weekly home blood pressure recordings for at least 2 weeks and at least one clinic recording during the run-in period.

Randomization visit:
• Randomization will be performed through a computerized central randomization scheme.
• Resting blood pressure readings are taken once to decide treatment modulation.
• RAAS-inhibitors dose will be adjusted so as to achieve systolic BP 120-140mmHg.
• Expected length of randomization visit: 30min

a) If systolic BP is not in 120-140mmHg range at the initial randomization visit, then titrate, remove or add RAAS inhibitor therapy not already in use as appropriate AND see participant monthly until Systolic BP 120-140mmHg if clinically safe to do so or until clinical decision made that therapy should not be changed further.

b) If systolic BP is 120-140mmHg at the initial randomization visit, RAAS inhibitors are continued as it is, if clinically safe to do so, and patient is transitioned straight to the 3 month follow-up visits.


Follow-up visit:
• After systolic BP has been achieved to 120-140mmHg as above, patient will be followed 3-
monthly to monitor Systolic BP 120-140mmHg at each visit.
• Expected length of each follow-up visit: 30min

a) Continue therapy, unless side effects warrant change in therapy.
b) If systolic BP is not in 120-140mmHg titrate, remove or add RAAS inhibitor therapy not already in use as appropriate, if clinically safe to do so.
c) Monitor every 3-months through follow-up for 2 years.

Each component of the intervention will be administered by the research nurse in consultation with the cardiologist. Adherence to the treatment will be monitored prospectively throughout the trial by patient interview at each study visit, or contacting their pharmacy when compliance is considered doubtful.
Intervention code [1] 317719 0
Prevention
Intervention code [2] 317720 0
Treatment: Drugs
Comparator / control treatment
The only difference between the intervention and control treatments is the aim of systolic BP (120-140mmHg in the lenient arm and <120mmHg in the aggressive arm).

The Aggressive BP control arm (systolic BP goal <120mmHg) treatment decision tree:

Screening period (4weeks):
• Patient is expected to be on a combination of RAAS inhibitors (ACEI or ARB or ARNI along with an AldA).
• Use of beta-blocker is encouraged, but loop/thiazide diuretics are discouraged. The dose of beta-blocker should be maximized. The loop and thiazide diuretic should either be discontinued or maintained when compelling reason in a least permissible stable dose.
• At least one screening visit is required at the beginning of the 4-week period.
• Expected length of screening visit: 30min

Run-in period (2 weeks):
• Dose changes to all medications are discouraged.
• Resting blood pressure readings are taken.
• Exercise stress (Treadmill) test is performed
• At least one run-in visit is required at the beginning of the 2-week period.
• Expected length of run-in visit including stress test: 45min
Resting BP will be estimated by averaging weekly home blood pressure recordings for at least 2 weeks and at least one clinic recording during the run-in period.

Randomization visit:
• Randomization will be performed through a computerized central randomization scheme.
• Resting blood pressure readings are taken once to decide treatment modulation.
• RAAS-inhibitors dose will be adjusted so as to achieve systolic BP <120mmHg.
• Expected length of randomization visit: 30min
a) If systolic BP is not in <120mmHg range at the initial randomization visit, then titrate or add RAAS inhibitor therapy not already in use as appropriate AND see participant monthly until Systolic BP <120mmHg if clinically safe to do so or until clinical decision made that therapy should not be changed further.
b) If systolic BP is <120mmHg at the initial randomization visit, RAAS inhibitors are continued as it is, if clinically safe to do so, and patient is transitioned straight to the 3 month follow-up visits.

Follow-up visit:
• After systolic BP has been achieved to <120mmHg as above, patient will be followed 3-
monthly to monitor Systolic BP <120mmHg at each visit.
• Expected length of each follow-up visit: 30min

a) Continue therapy, unless side effects warrant change in therapy.
b) If systolic BP is not in <120mmHg titrate or add RAAS inhibitor therapy not already in use as appropriate, if clinically safe to do so.
c) Monitor every 3-months through follow-up for 2 years.

Each component of the intervention will be administered by the research nurse in consultation with the cardiologist. Adherence to the treatment will be monitored prospectively throughout the trial by patient interview at each study visit, or contacting their pharmacy when compliance is considered doubtful.
Control group
Active

Outcomes
Primary outcome [1] 323970 0
The primary outcome is a composite of time to recurrence of sustained VT after a 30-day treatment period or death from any cause occurring any time after randomisation. The 30-day treatment period is imposed to exclude VT events that may occur before target BP steady state is achieved.

ICD data will be obtained at baseline and every 3 months thereafter for sustained VT events. Whenever clinical staff will become aware of a death, medical records will be obtained for documentation of events leading to death.
Timepoint [1] 323970 0
VT: At any time after a 30-day treatment period until 2 years post-randomisation.
Death: At any time until 2 years post-randomisation
Secondary outcome [1] 383465 0
Recurrence of sustained VT

ICD data will be obtained at baseline and every 3 months thereafter for sustained VT events.
Timepoint [1] 383465 0
At any time after a 30-day treatment period until 2 years post-randomisation.
Secondary outcome [2] 384238 0
Death from any cause

Whenever clinical staff will become aware of a death, medical records will be obtained for documentation of events leading to death.
Timepoint [2] 384238 0
Any time until 2-years post-randomisation
Secondary outcome [3] 384239 0
Death from cardiovascular cause

Whenever clinical staff will become aware of a death, medical records will be obtained for documentation of events leading to death.
Timepoint [3] 384239 0
Any time until 2-years post-randomisation
Secondary outcome [4] 384240 0
Hospitalization with heart failure

Medical records will be obtained for documentation of event
Timepoint [4] 384240 0
Any time until 2-years post-randomisation
Secondary outcome [5] 384241 0
Combination of primary outcome and heart failure hospitalization
Timepoint [5] 384241 0
Any time until 2-years post-randomisation

Eligibility
Key inclusion criteria
1. Age 18-year to 80-years.
2. Heart failure due to ischemic or non-ischemic etiology of more than 3 months duration.
3. Left ventricular ejection fraction <40%.
4. History of spontaneous sustained VT.
5. Have an implantable cardioverter defibrillator (ICD) or consent to have one.
6. NYHA Class 1 -3.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. VT related hospitalization within the last 3 weeks.
2. VT ablation in last 3 months.
3. Heart failure NYHA Class 4 or heart failure hospitalization within the last 3 weeks.
4. Resting systolic BP < 90mmHg at lowest doses of heart failure medication.
5. History of symptomatic systolic BP drop on standing.
6. Exercise induced systolic BP > 180mmHg or <90mmHg.
7. Known secondary cause of hypertension.
8. eGFR less than 30ml/min.
9. Intolerance to beta-blocker (equivalent to Metoprolol 12.5mg BD) (due to worsening of hypotension or heart failure).
10. Left ventricular ejection fraction <10%.
11. Suspected tachy-cardiomyopathy (arrhythmia as cause of heart failure).
12. Acute coronary event or stroke within the last 3 months.
13. Coronary revascularization within the last 3 months.
14. Expected survival less than 3 years due to terminal non-cardiac illness.
15. Severe pulmonary artery hypertension.
16. Large pericardial effusion.
17. Severe peripheral vascular disease or aortic aneurysm.
18. Non-compliance to medication.
19. Active alcohol or substance abuse.
20. Pregnancy.
21. Morbid obesity (BMI >40).
22. Remote residence out of reach to clinic sites.
23. Dementia or other cognitive impairment in ability to follow the protocol.
24. Current participation in another trial.

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)
Randomization will be performed through a concealed computerized central randomization scheme.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
There is reported wide variability in the composite outcome of recurrent VT and death in heart failure patients with prior VT who have received an ICD and are receiving a combination of anti-arrhythmic drugs and may undergo VT ablation. Three large clinical trials have been conducted over three different decades and report composite rate of all-cause death and VT recurrence between 28 – 37% per year. [AVID trial 1997 (37%), OPTIC study 2006 (35%), VANISH trial 2016 (28%)]. Additionally, aggressive BP reduction with RAAS inhibitors is expected to increase the risk of death by approximately 1.3-fold in heart failure patients (PARADIGM-HF trial 1.3-fold, VAL-HEFT trial 1.4-fold) .

Accordingly, we calculate that enrolling anywhere between 39 to 126 patients in each arm will provide a power of 80% to determine 16-22% greater incidence of primary outcome in the aggressive BP reduction arm at a significance level of 0.05 (two-sided) at a minimum follow-up of 2-years. We aim to enroll approximate 120 patients (60 patients in each arm). Depending on recruitment success and participation of additional sites, maximum of 250 patients can be enrolled.
An interim analysis of VT recurrence rate and death will be performed by an independent data and safety monitoring committee at 6-months intervals (or after enrolment of every 30 patients, whichever is earlier). If VT recurrence and death rate after lenient BP control is >50%, then the trial will be stopped prematurely.
All analyses will be conducted according to the intention-to-treat principle. Survival-analysis techniques will be used to compare the incidence of primary and secondary outcomes between the groups.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 16783 0
The Townsville Hospital - Douglas
Recruitment hospital [2] 26048 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 30406 0
4814 - Douglas
Recruitment postcode(s) [2] 41900 0
4215 - Southport
Recruitment outside Australia
Country [1] 22700 0
Canada
State/province [1] 22700 0
Ontario

Funding & Sponsors
Funding source category [1] 305850 0
Hospital
Name [1] 305850 0
In-kind support only for use of facility and staff-time. Rest of funding is still being explored.
Country [1] 305850 0
Australia
Primary sponsor type
Individual
Name
Sachin Nayyar
Address
1 Hospital Blvd, Southport, QLD 4215
Country
Australia
Secondary sponsor category [1] 306295 0
None
Name [1] 306295 0
Address [1] 306295 0
Country [1] 306295 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306112 0
Townsville Human Research Ethics Committee
Ethics committee address [1] 306112 0
Ethics committee country [1] 306112 0
Australia
Date submitted for ethics approval [1] 306112 0
25/05/2020
Approval date [1] 306112 0
16/10/2020
Ethics approval number [1] 306112 0
HREC/QTHS/63527_Approved

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102750 0
Dr Sachin Nayyar
Address 102750 0
Department of Cardiology, 1 Hospital Blvd, Gold Coast University Hospital, Southport, QLD 4215
Country 102750 0
Australia
Phone 102750 0
+61 56874946
Fax 102750 0
Email 102750 0
[email protected]
Contact person for public queries
Name 102751 0
Sachin Nayyar
Address 102751 0
Department of Cardiology, 1 Hospital Blvd, Gold Coast University Hospital, Southport, QLD 4215
Country 102751 0
Australia
Phone 102751 0
+61 56874946
Fax 102751 0
Email 102751 0
[email protected]
Contact person for scientific queries
Name 102752 0
Sachin Nayyar
Address 102752 0
Department of Cardiology, 100 Angus Smith Drive, Townsville University Hospital, Douglas, QLD 4814
Country 102752 0
Australia
Phone 102752 0
+61 56874946
Fax 102752 0
Email 102752 0
[email protected]

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8351Study protocol  [email protected]
8352Informed consent form  [email protected]



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.