Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001376730
Ethics application status
Approved
Date submitted
10/10/2022
Date registered
26/10/2022
Date last updated
14/01/2024
Date data sharing statement initially provided
26/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of pump speed and a vessel dilating medication on the exercise capacity of patients with left ventricular assist devices (artificial heart pumps)
Scientific title
The effect of pump speed and nitrates on the exercise capacity of left ventricular assist device (LVAD) recipients
Secondary ID [1] 308062 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
heart failure
 327755 0
Condition category
Condition code
Cardiovascular 324826 324826 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pump speed calibration test:
• Estimated duration: 30 minutes, to be performed 1-4 hours prior to the exercise test
• At baseline, a pump speed calibration test will be performed for the assessment of a safe speed increase range, under guidance of transthoracic echocardiography. This step will be performed prior to the exercise protocol.
• Ensure both transthoracic echocardiogram (TTE) machine and echocardiographer are available for this test.
• Record the subject’s height and weight without shoes and wearing light clothing. Place the backpack on the ground or a nearby table or chair, so it is not on the scales
• Direct the subject to lie supine for 10 minutes prior to starting the pump speed calibration study
• Record resting LVAD parameters including pump speed, pump flow, pump power
• Use TTE to estimate left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD).
• Record state of aortic valve (open/closed/intermittent opening), grade of aortic regurgitation, grade of mitral regurgitation, position of interatrial and interventricular septa
• Record mean arterial pressure non-invasively
• Reduce pump speed in 200rpm steps. Wait for 2 minutes after changing the speed to record pump speed, flow, power, LVEDD and LVESD at each level.
• At each step calculate the percentage reduction in pump flow from resting level.
• Stop when pump flow reaches 80% of the resting pump flow or speed reaches 4600rpm or LV dimension increases by more than 10%.
• Increase the speed in 200rpm increments approximately every minute until resting pump speed is re-attained.
• Rest for 5 minutes
• Increase the pump speed in increments of 200rpm. Wait for 2 minutes after changing the speed to record mean arterial pressure, pump speed, flow, power, LVEDD and LVESD at each level.
• Record state of aortic valve (open/closed/intermittent opening), grade of aortic regurgitation, grade of mitral regurgitation
• Stop increasing speed at 9000rpm or if LVEDD on TTE < 80% of resting value, pump flow is equal or greater than 130% of resting value or evidence of left ventricular suck down is seen on echo images/device controller. Record the pump flow at this level.
• The study is performed at rest to incorporate an extra level of safety in avoiding suction, as it is expected right ventricular function should be higher in exercise

Exercise test:
• Subjects will be randomised on the day they come to have their routine right heart catheter study.
• Subjects will have the catheter inserted via the right internal jugular vein.
• Under local anaesthesia insert a Swan-Ganz catheter into the internal jugular vein, positioned with the tip in the pulmonary artery, under fluoroscopy guidance.
• Take 10mL blood samples for brain natriuretic peptide (BNP), lactate and haemoglobin via Swan-Ganz sheath.
• Insertion of arterial line, under local anaesthesia, for accurate measurement of blood pressure and estimate of pulsatility.
• Take resting blood pressure non-invasively using a Doppler flow probe and cuff sphygmomanometry.
• Take a blood sample from the pulmonary artery for oxygen saturation calibration.
• Use TTE to examine the position of the aortic valve, interatrial and interventricular septa. Measure LVEDD and LVESD. Assess for other significant valvular pathology.
• Set up the continuous cardiac output monitor, pulse oximeter and 12-lead ECG so that haemodynamics, cardiac output, oxygen saturation, heart rate and rhythm are measured and recorded continuously throughout.
• Ensure resting values are recorded for haemodynamics (pulmonary artery pressures (PAP), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), cardiac output (CO), cardiac index (CI), TTE, electrocardiogram, oxygen saturation and LVAD parameters.
• With the subjects at rest, data will be recorded with the pump at baseline speed and at maximum pump speed, as determined by the pump speed calibration test. Echo parameters will also be recorded to ensure safety of the speed setting. Pump speed changes will be performed by a trained nurse or cardiologist.
• Subjects will then start to exercise at 15 watts, with half of the cohort exercising at baseline pump speed (Group B) and the other half exercising at maximum determined safe speed (Group A). Cadence should be maintained at 50rpm throughout the test, as much as possible.
• After 1 minute, the speed will be increased to 30 watts and subjects will exercise for another minute.
• Subjects will then enter the submaximal exercise period, where the workload will be maintained at 30W until the end of the test. At this point, the pump speed will be changed as follows: Group A will be changed to baseline pump speed whereas group B will have the pump speed increased to maximum, with both groups exercising for 3 minutes.
• After 3 minutes of submaximal exercise Group A will have the pump speed set to maximum and Group B will change back to baseline speed. Subjects will then exercise for another 3 minutes.
• An extra minute during the exercise protocol will be devoted to performing the aforementioned pump speed adjustments not to affect the pre-specified duration of the submaximal stages.
• In case subjects become fatigued before the end of the submaximal exercise period, they will be allowed to drop the load to 20W. Exercise duration for these subjects will be considered as the amount of exercise performed at 30W.
• At the end of the submaximal exercise duration phase, intra venous (IV) GTN infusion at 83.3 mcg/min (10ml/h) will be started with the purpose of assessing changes in preload/afterload markers and exercise capacity with the drug. After 2 minutes, the infusion will be increased to 166 mcg/min (20ml/h), if the initial dose was well tolerated. If this dose increase is also well tolerated, then the infusion rate will be increased to 322mcg/min (40ml/h) and the subject will exercise for an additional 4 minutes, if tolerated. These doses are based on our routine vasodilatation challenge protocol and are well tolerated by the vast majority of patients. It should be noted that the blood pressure is expected to increase with exercise, thus minimising the possibility of hypotension. GTN initiation or uptitration will only take place for patients with a MAP > 70mmHg. A study nurse will be responsible for administering the drug.
• In total, the maximum possible exercise duration will be 17 minutes.
• A cool down period of 2 minutes cycling without load will then take place.
• Lactate levels will be measured at the end of each submaximal stage (baseline and maximum pump speed), at 2-minute intervals after GTN initiation and at the end of the exercise period, when BNP will also be collected.
• All haemodynamic, ECG and LVAD parameters will be recorded continuously throughout the exercise. PCWP specifically will be measured at baseline, at the end of the warm-up exercise period, at the end of each of the submaximal exercise periods and at the end of the exercise duration period.
• The Borg scale for dyspnoea and fatigue will be assessed at the end of the submaximal exercise stage and at the last minute of exercise.
• Five minutes after the cessation of exercise, blood samples for lactate, haemoglobin and BNP will be taken via the Swan-Ganz sheath after withdrawal of the catheter. Non-invasive, invasive and echocardiographic data will be recorded one last time.
• The total duration of this intervention is estimated to be 45 minutes.
Intervention code [1] 324509 0
Treatment: Drugs
Intervention code [2] 324688 0
Treatment: Devices
Comparator / control treatment
Comparator is the patients' baseline pump speed and the pre intravenous GTN administration time period.
Control group
Active

Outcomes
Primary outcome [1] 332751 0
Change in pulmonary wedge pressure (assessed independently), using right heart catheterisation.
Timepoint [1] 332751 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Primary outcome [2] 332869 0
Change in cardiac output (assessed independently), using right heart catheterisation.
Timepoint [2] 332869 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Primary outcome [3] 332884 0
Exercise duration, timed using a digital stopwatch.
Timepoint [3] 332884 0
Start of exercise until fatigue
Secondary outcome [1] 414596 0
Change in right atrial pressure (assessed independently), determined using right heart catheterisation.
Timepoint [1] 414596 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [2] 414970 0
Change in mean arterial pressure (assessed independently), determined using intra-arterial catheter.
Timepoint [2] 414970 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [3] 414971 0
Change in LVAD pump flow (assessed independently). This parameter is provided by the pump controller.
Timepoint [3] 414971 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [4] 414972 0
Change in LVAD pulsatility index (assessed independently). This parameter is provided by the pump controller.
Timepoint [4] 414972 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [5] 414973 0
Change in pump flow amplitude (assessed independently). This parameter is provided by the SNOOPY device, which is connected to the LVAD.
Timepoint [5] 414973 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [6] 414974 0
Change in right ventricular function, assessed by transthoracic echocardiography
Timepoint [6] 414974 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [7] 414975 0
Change in aortic valve opening, assessed by echocardiography
Timepoint [7] 414975 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [8] 414976 0
Change in the degree of mitral regurgitation, assessed by echocardiography
Timepoint [8] 414976 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [9] 414977 0
Change in left ventricular dimensions, assessed by echocardiography
Timepoint [9] 414977 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [10] 414978 0
Change in inter ventricular septum position, assessed by echocardiography
Timepoint [10] 414978 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [11] 414979 0
Changes in Borg scale of perceived exertion (0-10), using a printed visual scale presented to the patient.
Timepoint [11] 414979 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [12] 414980 0
Change in brain natriuretic peptide levels (BNP), collected in a SST tube (blood sample).
Timepoint [12] 414980 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)
Secondary outcome [13] 414981 0
Change in lactate levels, collected in a Flow tube (blood sample).
Timepoint [13] 414981 0
Pre interventions (pre exercise, all groups at baseline pump speed, no GTN)
After 3 minutes of 30Watts sub maximal exercise (Group A - baseline speed, Group B - maximum pump speed)
After 6 minutes of 30 Watts sub maximal exercise (Group A- maximum speed, Group B - baseline speed)
After IV GTN administration (after 7-8 minutes of sub maximal exercise at 30Watts, Group A- maximum pump speed, Group B - baseline speed)
At the end of the exercise intervention, limited by fatigue (30Watts, Group A- maximum pump speed, Group B - baseline speed)

Eligibility
Key inclusion criteria
• Willingness to give written informed consent and willingness to participate to and comply with the study.
• Age more or equal to 18 or legal guardian has signed consent
• Clinically stable
• Ambulatory
• More than 2 months after pump insertion
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Active infection
• Exercise induced myocardial ischaemia or significant arrhythmias
• Recent acute coronary syndrome (<6 weeks)
• Inability to achieve a significant increase in LVAD flow without risk of suction
• Estimated peak exercise load less than 30 watts
• Regular use of sildenafil

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)
Sealed opaque envelopes, prepared by a researcher not involved with the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated block randomisation. Study investigators are blind to to the block sizes and order.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 0
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sixteen subjects will be recruited. A sample size of 15 subjects will have approximately 80% power to consider a difference in mean pulmonary capillary wedge pressure (PCWP) of 5 mmHg, between groups, statistically significant (p <0.05).

The effect of exercise and pump speed changes and their interaction will be assessed by repeated measures analysis using a linear mixed model. Post hoc significance will be assessed after Bonferroni correction for multiple comparisons. The impact of pump speed alone will be assessed using paired t-tests. Differences in the proportion of subjects with aortic valve opening with exercise were assessed using Chi square test. A p value of < 0.05 will be considered statistically significant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
26/10/2022
Date of last participant enrolment
Anticipated
23/10/2024
Actual
Date of last data collection
Anticipated
20/12/2024
Actual
Sample size
Target
16
Accrual to date
13
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 23350 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 38725 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 312320 0
Charities/Societies/Foundations
Name [1] 312320 0
MCS research trust fund (242058)
Country [1] 312320 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
390 Victoria Street, Darlinghurst. 2010, NSW
Country
Australia
Secondary sponsor category [1] 313968 0
None
Name [1] 313968 0
Address [1] 313968 0
Country [1] 313968 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311687 0
St Vincent's Hosital Sydney Human Ethics Committee
Ethics committee address [1] 311687 0
Ethics committee country [1] 311687 0
Australia
Date submitted for ethics approval [1] 311687 0
26/05/2022
Approval date [1] 311687 0
11/08/2022
Ethics approval number [1] 311687 0
2021/ETH12204

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

Contacts
Principal investigator
Name 121998 0
Prof Christopher Hayward
Address 121998 0
Cardiology Department
St Vincent's Hospital
390 Victoria Street
Darlinghurst, 2010
NSW
Country 121998 0
Australia
Phone 121998 0
+610409575454
Fax 121998 0
Email 121998 0
cshayward@stvincents.com.au
Contact person for public queries
Name 121999 0
Ricardo Deveza e Silva
Address 121999 0
Cardiology Department
St Vincent's Hospital
390 Victoria Street
Darlinghurst, 2010
NSW
Country 121999 0
Australia
Phone 121999 0
+61283823052
Fax 121999 0
Email 121999 0
lvad.rhcstudy@gmail.com
Contact person for scientific queries
Name 122000 0
Ricardo Deveza e Silva
Address 122000 0
Cardiology Department
St Vincent's Hospital
390 Victoria Street
Darlinghurst, 2010
NSW
Country 122000 0
Australia
Phone 122000 0
+61283823052
Fax 122000 0
Email 122000 0
lvad.rhcstudy@gmail.com

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.