LVAD Versus GDMT in Ambulatory Advanced Heart Failure Patients

End-stage Heart Failure Clinical Trial

— AMBU-VAD  

Official title:

Left Ventricular Assist Device (LVAD) Versus Guideline Recommended Medical Therapy in Ambulatory Advanced Heart Failure Patients (GDMT)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04768322
• Other study ID #: 69HCL20_0072
• Secondary ID: ID-RCB
• Status: Recruiting
• Phase: N/A
• Start date: February 24, 2021
• Est. completion date: February 2027

Study information

• Verified date: August 2023
• Source: Hospices Civils de Lyon
• Contact: Guillaume BAUDRY, Dr
• Phone: 383157331
• Email: g.baudry[@]chru-nancy.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Heart failure is a severe disease affecting approximately 1-2% of the adult population in developed countries and around 26 million people worldwide. Up to 10% of these patients are in advanced stage heart failure, which is defined by a significant morbimortality and considerable medical expenses. Despite advances in its medical management, advanced (or end stage) heart failure is characterized by refractoriness to conventional therapies including guideline-directed pharmacological and non-surgical device treatments. These patients remain severely symptomatic (NYHA IV) and have objective signs of congestion or low cardiac output. Left ventricular assist devices (LVADs) have been used in patients with heart failure with reduced ejection fraction for almost 20 years either as an alternative or a bridge to heart transplantation. LVADs improve heart failure symptoms and survival at the cost of increased rates of infection, stroke and bleeding. Despite the lack of evidence, LVAD implantation in ambulatory patients is not rare, with INTERMACS profiles ≥4 patients representing 15.7% of the overall population implanted between 2012 and 2016. The aim of this study is to investigate the efficacy and safety of left ventricular assist devices compared to traditional HF medical treatment alone in a population of ambulatory advanced heart failure patients. Secondary objectives are to better identify subgroups of patients that would benefit the most from the implantation of an LVAD as well as to assess the optimal timing of intervention.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 92
• Est. completion date: February 2027
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. All patients =18 years,

2. End-stage heart failure, evaluated by the local Heart Team, defined as:

• Left ventricular ejection fraction = 35% within 1 week prior to randomization and
• Cardiac Index < 2.2 L/min/m² by hemodynamic use within 1 month prior to randomization or VO2 max < 14 ml/kg/min (or <50% of predicted VO2max) within 1 month prior to randomization OR low 6-min walking test (< 420 m) within 1 month prior to randomization or = 2 hospitalizations for heart failure in the past year and
• NYHA III-IV (INTERMACS profile 4-6) and and
• Receiving medical management with optimal doses of betablockers, Angiotensin-Converting-Enzyme-inhibitors or Angiotensin II Receptor Blockers or angiotensin receptor neprilysin inhibitor (if eligible) and Mineralocorticoid Receptor Antagonists and Sodium-GLucose co-Transporter-2 (SGLT2) inhibitors for at least 45 days if tolerated according to guideline at maximal tolerated dose (if maximal HF drug dosage is not reached the investigators will have to explain reason behind not maximal dosage).
• Receiving Cardiac Resynchronization Therapy and or Implantable Cardioverter Defibrillators if indicated for at least 45 days and
• No mechanical circulatory support or inotrope therapy since > 30 days,

3. Having a health coverage,

4. Signed written informed consent,

5. Patient without any legal protection measure.

Exclusion Criteria:

1. Inotrope dependent patients or existence of ongoing mechanical circulatory support (MCS) in the last 30 days,

2. Right ventricular dysfunction (heart team consensus) with the expected need of Bi-VAD support,

3. Female patients currently pregnant or women of childbearing age who were not using contraception,

4. Active infection,

5. Irreversible end-organ dysfunction prior to LVAD implantation,

6. Contraindication to anti-coagulant or anti-platelet therapies,

7. History of any organ transplant prior to inclusion,

8. Psychiatric disease/disorder, irreversible cognitive dysfunction or psychosocial issues likely to impair compliance,

9. Frailty according to heart team,

10. Platelet count < 100,000 x 103/liter (<100,000/ml)

11. Body Surface Area (BSA) < 1.2 m2,

12. Any condition other than heart failure that could limit survival to less than 24 months,

13. Chronic renal insufficiency (GFR definitely <30 ml/min) or hepatic cirrhosis,

14. Participation in any other interventional clinical investigation.

Related Conditions & MeSH terms

• End-stage Heart Failure
• Heart Failure

Intervention

Device:
• HeartMate 3 TM Left Ventricular Assist System
The HeartMate 3 TM Left Ventricular Assist System will be implanted within 21 days of randomization.

Other:
• Guideline Directed Medical Therapy
Patients randomized in the control group will continue their guideline directed medical therapy which comprises the following stable combination at the maximal tolerated dose of betablockers, Angiotensin-Converting-Enzyme-inhibitors or Angiotensin II Receptor Blockers or Angiotensin receptor Neprilysin inhibitor and Mineralocorticoid Receptor Antagonists and Sodium-GLucose co-Transporter-2 (SGLT2) inhibitors if tolerated.

Locations

Country	Name	City	State
France	Hôpital Pneumologique et Cardiovasculaire Louis Pradel	Bron
France	La Tronche Hospital / CHU Grenoble	La Tronche
France	Arnaud de Villeneuve Hospital / CHU Montpellier	Montpellier
France	CHU Rouen	Rouen
France	CHRU, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu	Vandœuvre-lès-Nancy

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause mortality rate	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Primary	Number of urgent ECMO implantation	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Primary	Number of urgent heart transplantation	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Primary	Number of LVAD implantation	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Primary	Number of unplanned hospitalization for heart failure	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Primary	Quality of life assessed by KCCQ score	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Primary	Distance in meters at 6-min walking test	The composite of 5 clinical endpoints is using a win ratio concept. Mortality has higher priority than Urgent ECMO implantation, urgent heart transplantation or LVAD implantation, unplanned hospitalization for heart failure, improvement of KCCQ by at least 5points, improvement of 6-minute walk test distance by at least 75 meters. Our main approach uses matched pairs of patients. Each pair is 'untied' first on the basis of the most important event (death) and secondly (if necessary) on the lesser event. The numbers of pairs in which the patient on new treatment 'won' and 'lost' are compared to produce the 'win ratio'. The 95% CI and P-value for the win ratio are readily obtained.	Through 24 months when the last subject completes 12 months of follow-up
Secondary	Number of adverse events (AEs)		at 1 month
Secondary	Number of adverse events (AEs)		at 3 months
Secondary	Number of adverse events (AEs)		at 6 months
Secondary	Number of adverse events (AEs)		at 12 months
Secondary	Number of adverse events (AEs)		at 18 months
Secondary	Number of adverse events (AEs)		at 24 months
Secondary	All-cause mortality rate		at 1 month
Secondary	All-cause mortality rate		at 3 months
Secondary	All-cause mortality rate		at 6 months
Secondary	All-cause mortality rate		at 12 months
Secondary	All-cause mortality rate		at 18 months
Secondary	All-cause mortality rate		at 24 months
Secondary	number of ECMO implantation		at 1 month
Secondary	number of ECMO implantation		at 3 months
Secondary	number of ECMO implantation		at 6 months
Secondary	number of ECMO implantation		at 12 months
Secondary	number of ECMO implantation		at 18 months
Secondary	number of ECMO implantation		at 24 months
Secondary	number of urgent heart transplantation		at 1 month
Secondary	number of urgent heart transplantation		at 3 months
Secondary	number of urgent heart transplantation		at 12 months
Secondary	number of urgent heart transplantation		at 18 months
Secondary	number of urgent heart transplantation		at 24 months
Secondary	VAD implantation rate		at 1 month
Secondary	VAD implantation rate		at 3 months
Secondary	VAD implantation rate		at 6 months
Secondary	VAD implantation rate		at 12 months
Secondary	VAD implantation rate		at 18 months
Secondary	VAD implantation rate		at 24 months
Secondary	Unplanned hospitalization for heart failure rate		at 1 month
Secondary	Unplanned hospitalization for heart failure rate		at 3 months
Secondary	Unplanned hospitalization for heart failure rate		at 6 months
Secondary	Unplanned hospitalization for heart failure rate		at 12 months
Secondary	Unplanned hospitalization for heart failure rate		at 18 months
Secondary	Unplanned hospitalization for heart failure rate		at 24 months
Secondary	Recurrent hospitalizations rate	Defined as total number of hospitalizations	at 1 month
Secondary	Recurrent hospitalizations rate	Defined as total number of hospitalizations	at 3 months
Secondary	Recurrent hospitalizations rate	Defined as total number of hospitalizations	at 6 months
Secondary	Recurrent hospitalizations rate	Defined as total number of hospitalizations	at 12 months
Secondary	Recurrent hospitalizations rate	Defined as total number of hospitalizations	at 18 months
Secondary	Recurrent hospitalizations rate	Defined as total number of hospitalizations	at 24 months
Secondary	Number of patients with a persistence of the eligibility to LVAD implantation	In the GDMT group only	at 12 and 24 months
Secondary	Number of patients with a persistence of the eligibility to LVAD implantation	In the GDMT group only	at 12 months
Secondary	Number of days alive out of hospital		at 24 months
Secondary	New York Heart Association (NYHA) status		at inclusion
Secondary	New York Heart Association (NYHA) status		at 1 month
Secondary	New York Heart Association (NYHA) status		at 3 months
Secondary	New York Heart Association (NYHA) status		at 6 months
Secondary	New York Heart Association (NYHA) status		at 12 months
Secondary	New York Heart Association (NYHA) status		at 18 months
Secondary	New York Heart Association (NYHA) status		at 24 months
Secondary	Distance in meters at 6-min walking test		at inclusion
Secondary	Distance in meters at 6-min walking test		at 3 months
Secondary	Distance in meters at 6-min walking test		at 6 months
Secondary	Distance in meters at 6-min walking test		at 12 months
Secondary	Distance in meters at 6-min walking test		at 18 months
Secondary	Distance in meters at 6-min walking test		at 24 months
Secondary	Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score		at inclusion
Secondary	Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score		at 3 months
Secondary	Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score		at 6 months
Secondary	Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score		at 12 months
Secondary	Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score		at 18 months
Secondary	Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score		at 24 months
Secondary	Quality of life assessed by KCCQ score		at inclusion
Secondary	Quality of life assessed by KCCQ score		at 3 months
Secondary	Quality of life assessed by KCCQ score		at 6 months
Secondary	Quality of life assessed by KCCQ score		at 12 months
Secondary	Quality of life assessed by KCCQ score		at 18 months
Secondary	Quality of life assessed by KCCQ score		at 24 months
Secondary	Right ventricular function assessed by echocardiographic parameters		at inclusion
Secondary	Right ventricular function assessed by echocardiographic parameters		at 3 months
Secondary	Right ventricular function assessed by echocardiographic parameters		at 6 months
Secondary	Right ventricular function assessed by echocardiographic parameters		at 12 months
Secondary	Right ventricular function assessed by echocardiographic parameters		at 18 months
Secondary	Right ventricular function assessed by echocardiographic parameters		at 24 months
Secondary	Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate		at inclusion
Secondary	Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate		at 3 months
Secondary	Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate		at 6 months
Secondary	Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate		at 12 months
Secondary	Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate		at 18 months
Secondary	Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate		at 24 months
Secondary	Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR)		at inclusion
Secondary	Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR)		at 1 month
Secondary	Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR)		at 6 months
Secondary	Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR)		at 12 months
Secondary	Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR)		at 24 months
Secondary	Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6)		at inclusion
Secondary	Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6)		at 1 month
Secondary	Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6)		at 6 months
Secondary	Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6)		at 12 months
Secondary	Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6)		at 24 months
Secondary	Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1)		at inclusion
Secondary	Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1)		at 1 month
Secondary	Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1)		at 3 months
Secondary	Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1)		at 12 months
Secondary	Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1)		at 18 months
Secondary	Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1)		at 24 months