Early Versus Emergency Left Ventricular Assist Device Implantation in Patients Awaiting Cardiac Transplantation

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to assess whether, in patients who are listed for cardiac transplantation in transplantable (T) status, early implantation of a left ventricular assist device is superior to the current therapeutic strategy of medical heart failure therapy and assist device implantation only after serious deterioration of the patient's condition.

Detailed Description
-----------------
Heart transplantation is considered the gold-standard therapy for end-stage systolic heart failure but the shortage of donor hearts in Germany and other countries has led to widespread use of left ventricular assist devices (LVAD). Even on the transplant list, patients' condition often deteriorate due to worsening heart failure so that they need an LVAD as a bridge until transplantation. The high mortality (one in five patients on the waiting list dies within 1 year) reflects the severity of the disease. In comparison, technical progress has reduced the complication rate seen with assist devices and, according to recent data, mortality during LVAD support is low. Patient status prior to LVAD implantation is a strong indicator for postoperative outcome, i.e. patients in worse condition are more likely to develop complications. Thus, the comparison between the standard indication and early LVAD implantation (T-status) appears timely and clinically necessary. The paucity of donor hearts necessitates the prospective evaluation of alternative treatment regimens. The aim of the study is to assess whether, in patients with end-stage heart failure awaiting cardiac transplantation, a strategy involving early LVAD implantation is superior to a strategy of conservative medical heart failure therapy and assist device implantation only after severe deterioration of heart failure. The investigators expect to gain insights that will be trail-blazing for the future treatment of patients with heart failure on the transplantation waiting list, including aspects of their medical care. If the study hypotheses are confirmed, the treatment of these seriously ill patients could be, on the one hand, further optimized. On the other hand, positive economic effects are highly probable. The results will form the basis of future guidelines for the treatment of this group of patients. Thus the study will also make a contribution to solving the problem of the ever increasing number of patients on the waiting list as opposed to the decreasing willingness to donate organs for transplantation. As a mean of quality control of the conducted study and to retrieve more data in this population all patients who fulfill the eligibility criteria of the study but do not consent to randomization are included in a standard treatment registry.

Official Title
-----------------
Early Versus Emergency Left Ventricular Assist Device Implantation in Patients Awaiting Cardiac Transplantation

Conditions
-----------------
End Stage Heart Disease

Intervention / Treatment
-----------------
* Device: Early VAD implantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Patient (male or female) eligible for heart transplantation and accepted in T Status (transplantable) on the waiting list Age 18 to 65 years Signed informed consent >30% 1-year mortality with the Seattle Heart Failure Model (SHFM) or at least three of the following criteria (a) to (f): cardiac index (CI) <2.5 l/min/m² pulmonary capillary wedge pressure >15 mmHg maximal oxygen uptake (VO2max) ≤10.0 ml/kg/min or ≤12.0 ml/kg/min in patients intolerant of a ß-blocker ratio of minute ventilation (VE) to carbon dioxide (VCO2) production (VE/VCO2) slope of >35 at least two hospitalizations for heart failure within the previous 12 months documented increase of brain natriuretic peptide (BNP) or NTproBNP levels despite optimal medical therapy Exclusion Criteria Listing for transplantation of other organs in addition to heart Previous cardiac surgeries (other than pacemaker or ICD surgeries) Contraindications to assist device implantation (e.g. mechanical aortic valve, aortic insufficiency) Contraindications to anticoagulation Expected need for a right ventricular assist device/biventricular support expected (e.g. due to tricuspid valve insufficiency grade 3+, right ventricular ratio short/long axis ≥0.6, ratio of right to left ventricular end-diastolic diameter (RVEDD/LVEDD) >0.72, restrictive cardiomyopathy) Presence of catecholamine support or intra-aortic balloon counterpulsation (IABP) Overt infections Fixed pulmonary hypertension (i.e. pulmonary arterial pressure (PAP) >60 mmHg and mean transpulmonary gradient (TPG) >15 mmHg or pulmonary vascular resistance (PVR) >6 Wood units despite optimal medical treatment) Renal insufficiency (glomerular filtration rate (GFR) <30ml/min or need for hemodialysis or hemofiltration) Significant coagulopathies Systemic lupus erythematosus, sarcoid, or amyloidosis that has multisystem involvement and is still active Drug abuse and/or alcohol abuse Incompliance Elevated panel reactivity levels of >50 % Pregnancy or breast feeding in women Participation in other investigational trials

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early VAD implantation<br>The experimental intervention is early implantation of a left ventricular assist device (early VAD). Patients randomized to early VAD implantation will obtain a VAD within 28 days after randomization. | Device: Early VAD implantation<br>* Implantation of a left ventricular assist device<br>|
| No Intervention: Emergency VAD implantation<br>The control intervention is conservative heart failure treatment, with LVAD implantation in the case of worsening heart failure (emergency VAD). All patients randomized to the control intervention will be treated according to standard medical practice. In brief, these patients are closely monitored (scheduled regular visits to outpatient department depending on the patient's condition and at least every 6 months). If the condition worsens the patient may qualify for high urgency (HU) listing and/or for VAD implantation. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | The time to the composite end-point of all-cause death, high urgent cardiac transplantation, disabling stroke , HF hospitalizations (including emergency room HF visits >6 hrs). | Randomisation untill month 60 (60 months at the most, 48 months on average) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke | Freedom from disabling and non-disabling strokes | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Listing for high-urgency (HU) cardiac transplantation |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients with de novo right heart failure measured by decreasing right heart ejection fraction, increasing central venous pressure and/or secondary organ failure needing catecholamines and/or right ventricular circulatory support |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients with hospitalizations due to device failure |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients with adverse events due to device failure |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of device infections requiring antibiotics and/surgical intervention |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients with major bleedings (needing >4 Units of blood) following VAD implantation and major bleedings due to anticoagulation therapy | Bleeding needing hospitalisation, blood transfusion and/or surgical interventions | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Cardiovascular Death |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients suffering from secondary organ failure | Time to event of renal and/or hepatic failure | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Maximum oxygen uptake (VO2 max) |  | Measured every 6 months from randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Heart failure survival score |  | Measured every 6 months from randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Seattle heart failure score |  | Measured every 6 months from randomisation untill month 60 (60 months at the most, 48 months on average) | 
| New York Heart Association class (NYHA) |  | Measured every 6 months from randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients requiring urgent VAD implantation |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Rate of recurrent hospitalizations |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Number of patients receiving a donor heart |  | Randomisation untill transplantation (60 months at the most, 48 months on average) | 
| VAD explantation due to myocardial recovery | Time to event | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Short Form-36 (SF-36) | Quality of life questionnaire (QoL) | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Minnesota Living with heart failure questionnaire (MLHFQ) | Quality of life questionnaire (QoL) | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Mini-mental state examination (MMSE) | Quality of life questionnaire (QoL) | Randomisation untill month 60 (60 months at the most, 48 months on average) | 
| Quality-adjusted life year (QALY) |  | Randomisation untill month 60 (60 months at the most, 48 months on average) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
End stage heart disease, Ventricular assist device