LVAD Versus GDMT in Ambulatory Advanced Heart Failure Patients (AMBU-VAD)

• ClinicalTrials.gov Identifier: NCT04768322
• Recruitment Status: Recruiting
• First Posted: February 24, 2021
• Last Update Posted: January 21, 2022
• Sponsor: Hospices Civils de Lyon
• Information provided by (Responsible Party): Hospices Civils de Lyon

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
End-stage Heart Failure	Device: HeartMate 3 TM Left Ventricular Assist System; Other: Guideline Directed Medical Therapy	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Left Ventricular Assist Device (LVAD) Versus Guideline Recommended Medical Therapy in Ambulatory Advanced Heart Failure Patients (GDMT)
• Actual Study Start Date: February 24, 2021
• Estimated Primary Completion Date: February 2024
• Estimated Study Completion Date: February 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Early Left Ventricular Assist Device and Guideline Directed Medical Therapy; The intervention group will receive an early left ventricular assist device implantation (bridge to transplantation, bridge to candidacy or destination therapy) in addition to guideline directed medical therapy within 21 days of randomization.	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 if tolerated.
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 if tolerated.	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 if tolerated.

Outcome Measures

Primary Outcome Measures :

1. All-cause mortality rate [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.
2. Number of urgent ECMO implantation [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.
3. Number of urgent heart transplantation [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.
4. Number of LVAD implantation [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.
5. Number of unplanned hospitalization for heart failure [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.
6. Quality of life assessed by KCCQ score [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.
7. Distance in meters at 6-min walking test [ Time Frame: Through 24 months when the last subject completes 12 months of follow-up ]
   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.

Secondary Outcome Measures :

1. Number of adverse events (AEs) [ Time Frame: at 1 month ]
2. Number of adverse events (AEs) [ Time Frame: at 3 months ]
3. Number of adverse events (AEs) [ Time Frame: at 6 months ]
4. Number of adverse events (AEs) [ Time Frame: at 12 months ]
5. Number of adverse events (AEs) [ Time Frame: at 18 months ]
6. Number of adverse events (AEs) [ Time Frame: at 24 months ]
7. All-cause mortality rate [ Time Frame: at 1 month ]
8. All-cause mortality rate [ Time Frame: at 3 months ]
9. All-cause mortality rate [ Time Frame: at 6 months ]
10. All-cause mortality rate [ Time Frame: at 12 months ]
11. All-cause mortality rate [ Time Frame: at 18 months ]
12. All-cause mortality rate [ Time Frame: at 24 months ]
13. number of ECMO implantation [ Time Frame: at 1 month ]
14. number of ECMO implantation [ Time Frame: at 3 months ]
15. number of ECMO implantation [ Time Frame: at 6 months ]
16. number of ECMO implantation [ Time Frame: at 12 months ]
17. number of ECMO implantation [ Time Frame: at 18 months ]
18. number of ECMO implantation [ Time Frame: at 24 months ]
19. number of urgent heart transplantation [ Time Frame: at 1 month ]
20. number of urgent heart transplantation [ Time Frame: at 3 months ]
21. number of urgent heart transplantation [ Time Frame: at 12 months ]
22. number of urgent heart transplantation [ Time Frame: at 18 months ]
23. number of urgent heart transplantation [ Time Frame: at 24 months ]
24. VAD implantation rate [ Time Frame: at 1 month ]
25. VAD implantation rate [ Time Frame: at 3 months ]
26. VAD implantation rate [ Time Frame: at 6 months ]
27. VAD implantation rate [ Time Frame: at 12 months ]
28. VAD implantation rate [ Time Frame: at 18 months ]
29. VAD implantation rate [ Time Frame: at 24 months ]
30. Unplanned hospitalization for heart failure rate [ Time Frame: at 1 month ]
31. Unplanned hospitalization for heart failure rate [ Time Frame: at 3 months ]
32. Unplanned hospitalization for heart failure rate [ Time Frame: at 6 months ]
33. Unplanned hospitalization for heart failure rate [ Time Frame: at 12 months ]
34. Unplanned hospitalization for heart failure rate [ Time Frame: at 18 months ]
35. Unplanned hospitalization for heart failure rate [ Time Frame: at 24 months ]
36. Recurrent hospitalizations rate [ Time Frame: at 1 month ]
    Defined as total number of hospitalizations
37. Recurrent hospitalizations rate [ Time Frame: at 3 months ]
    Defined as total number of hospitalizations
38. Recurrent hospitalizations rate [ Time Frame: at 6 months ]
    Defined as total number of hospitalizations
39. Recurrent hospitalizations rate [ Time Frame: at 12 months ]
    Defined as total number of hospitalizations
40. Recurrent hospitalizations rate [ Time Frame: at 18 months ]
    Defined as total number of hospitalizations
41. Recurrent hospitalizations rate [ Time Frame: at 24 months ]
    Defined as total number of hospitalizations
42. Number of patients with a persistence of the eligibility to LVAD implantation [ Time Frame: at 12 and 24 months ]
    In the GDMT group only
43. Number of patients with a persistence of the eligibility to LVAD implantation [ Time Frame: at 12 months ]
    In the GDMT group only
44. Number of days alive out of hospital [ Time Frame: at 24 months ]
45. New York Heart Association (NYHA) status [ Time Frame: at inclusion ]
46. New York Heart Association (NYHA) status [ Time Frame: at 1 month ]
47. New York Heart Association (NYHA) status [ Time Frame: at 3 months ]
48. New York Heart Association (NYHA) status [ Time Frame: at 6 months ]
49. New York Heart Association (NYHA) status [ Time Frame: at 12 months ]
50. New York Heart Association (NYHA) status [ Time Frame: at 18 months ]
51. New York Heart Association (NYHA) status [ Time Frame: at 24 months ]
52. Distance in meters at 6-min walking test [ Time Frame: at inclusion ]
53. Distance in meters at 6-min walking test [ Time Frame: at 3 months ]
54. Distance in meters at 6-min walking test [ Time Frame: at 6 months ]
55. Distance in meters at 6-min walking test [ Time Frame: at 12 months ]
56. Distance in meters at 6-min walking test [ Time Frame: at 18 months ]
57. Distance in meters at 6-min walking test [ Time Frame: at 24 months ]
58. Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score [ Time Frame: at inclusion ]
59. Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score [ Time Frame: at 3 months ]
60. Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score [ Time Frame: at 6 months ]
61. Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score [ Time Frame: at 12 months ]
62. Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score [ Time Frame: at 18 months ]
63. Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score [ Time Frame: at 24 months ]
64. Quality of life assessed by KCCQ score [ Time Frame: at inclusion ]
65. Quality of life assessed by KCCQ score [ Time Frame: at 3 months ]
66. Quality of life assessed by KCCQ score [ Time Frame: at 6 months ]
67. Quality of life assessed by KCCQ score [ Time Frame: at 12 months ]
68. Quality of life assessed by KCCQ score [ Time Frame: at 18 months ]
69. Quality of life assessed by KCCQ score [ Time Frame: at 24 months ]
70. Right ventricular function assessed by echocardiographic parameters [ Time Frame: at inclusion ]
71. Right ventricular function assessed by echocardiographic parameters [ Time Frame: at 3 months ]
72. Right ventricular function assessed by echocardiographic parameters [ Time Frame: at 6 months ]
73. Right ventricular function assessed by echocardiographic parameters [ Time Frame: at 12 months ]
74. Right ventricular function assessed by echocardiographic parameters [ Time Frame: at 18 months ]
75. Right ventricular function assessed by echocardiographic parameters [ Time Frame: at 24 months ]
76. Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate [ Time Frame: at inclusion ]
77. Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate [ Time Frame: at 3 months ]
78. Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate [ Time Frame: at 6 months ]
79. Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate [ Time Frame: at 12 months ]
80. Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate [ Time Frame: at 18 months ]
81. Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate [ Time Frame: at 24 months ]
82. Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR) [ Time Frame: at inclusion ]
83. Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR) [ Time Frame: at 1 month ]
84. Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR) [ Time Frame: at 6 months ]
85. Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR) [ Time Frame: at 12 months ]
86. Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR) [ Time Frame: at 24 months ]
87. Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6) [ Time Frame: at inclusion ]
88. Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6) [ Time Frame: at 1 month ]
89. Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6) [ Time Frame: at 6 months ]
90. Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6) [ Time Frame: at 12 months ]
91. Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6) [ Time Frame: at 24 months ]
92. Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) [ Time Frame: at inclusion ]
93. Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) [ Time Frame: at 1 month ]
94. Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) [ Time Frame: at 3 months ]
95. Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) [ Time Frame: at 12 months ]
96. Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) [ Time Frame: at 18 months ]
97. Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) [ Time Frame: at 24 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. All patients ≥18 years,

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

   • Left ventricular ejection fraction ≤ 30% within 1 week prior to randomization and

   • Cardiac Index < 2.2 L/min/m² by hemodynamic use within 1 month prior to randomization and

     • VO2 max < 14 ml/kg/min (or <50% of predicted VO2max) or low 6-min walking test (<300 m) and
     • NYHA III-IV (INTERMACS profile 4-6) or ≥ 2 hospitalizations for heart failure in the past year 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 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.

Contacts and Locations

Contacts

Contact: Guillaume BAUDRY, Dr; 4 72 35 71 46 ext +33; guillaume.baudry@chu-lyon.fr

Contact: Géraldine SAMSON; geraldine.samson@chu-lyon.fr

Locations

France

Hôpital Pneumologique et Cardiovasculaire Louis Pradel; Recruiting

Bron, France

Contact: Guillaume BAUDRY, Dr 4 72 35 71 46 ext +33 guillaume.baudry@chu-lyon.fr

Sponsors and Collaborators

Hospices Civils de Lyon

Investigators

• Principal Investigator: Guillaume BAUDRY, Dr; Hospices Civils de Lyon

More Information

• Responsible Party: Hospices Civils de Lyon
• ClinicalTrials.gov Identifier: NCT04768322
• Other Study ID Numbers: 69HCL20_0072; ID-RCB ( Other Identifier: 2020-A03451-38 )
• First Posted: February 24, 2021
• Last Update Posted: January 21, 2022
• Last Verified: January 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospices Civils de Lyon:

Heart Failure; End-stage; Not inotrope-dependent; Left Ventricular Assist Device; HeartMate 3 system; Heart Surgery; Guideline Directed Medical Therapy

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases