End-stage Heart Failure
Conditions
Keywords
Heart Failure, End-stage, Not inotrope-dependent, Left Ventricular Assist Device, HeartMate 3 system, Heart Surgery, Guideline Directed Medical Therapy
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.
Interventions
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.
DEVICEHeartMate 3 TM Left Ventricular Assist System
The HeartMate 3 TM Left Ventricular Assist System will be implanted within 21 days of randomization.
Sponsors
Hospices Civils de Lyon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of urgent heart transplantation | 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. |
| Number of LVAD implantation | 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. |
| All-cause mortality rate | 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. |
| Number of urgent ECMO implantation | 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. |
| Distance in meters at 6-min walking test | 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. |
| Number of unplanned hospitalization for heart failure | 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. |
| Quality of life assessed by KCCQ score | 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
| Measure | Time frame | Description |
|---|---|---|
| number of ECMO implantation | at 1 month | — |
| number of urgent heart transplantation | at 1 month | — |
| VAD implantation rate | at 1 month | — |
| Unplanned hospitalization for heart failure rate | at 1 month | — |
| Recurrent hospitalizations rate | at 1 month | Defined as total number of hospitalizations |
| Number of patients with a persistence of the eligibility to LVAD implantation | at 12 and 24 months | In the GDMT group only |
| Number of days alive out of hospital | at 24 months | — |
| New York Heart Association (NYHA) status | at inclusion | — |
| Distance in meters at 6-min walking test | at inclusion | — |
| Quality of life assessed by European Quality of Life-5 Dimensions (EQ-5D) questionnaire score | at inclusion | — |
| Quality of life assessed by KCCQ score | at inclusion | — |
| Right ventricular function assessed by echocardiographic parameters | at inclusion | — |
| Heart failure assessed by N Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) rate | at inclusion | — |
| Cardio-renal syndrome assessed by rates of Soluble urokinase-type Plasminogen Activator Receptor (SuPAR) | at inclusion | — |
| Cardio-renal syndrome assessed by rates of Interleukin-6 (IL-6) | at inclusion | — |
| Cardio-renal syndrome assessed by rates of Kidney Injury Molecule-1 (KIM1) | at inclusion | — |
| Number of adverse events (AEs) | at 1 month | — |
| All-cause mortality rate | at 1 month | — |
Countries
France
Contacts
CONTACTGuillaume BAUDRY, Dr
CONTACTGéraldine SAMSON
PRINCIPAL_INVESTIGATORGuillaume BAUDRY, Dr
CHRU Nancy
Outcome results
None listed