Rationale and design of the randomized ‘early ventricular assist device’—Trial (VAD‐DZHK3)

Abstract

Aims

Bridge to transplantation (BTT) with durable, continuous‐flow left ventricular assist devices (LVAD) of patients is a well‐established treatment concept in patients awaiting heart transplantation (HTx). However, the role of elective LVAD implantation in patients with less advanced HF, but increased risk of decompensation remains uncertain.

Methods and results

The VAD‐DZHK3 trial is an investigator‐initiated, randomized controlled trial designed to assess whether an early strategy of elective LVAD implantation improves outcomes compared with a conventional approach involving optimal medical therapy and delayed device implantation only after clinical deterioration. Eligible patients are those with end‐stage HF listed for cardiac transplantation. This is an event‐driven study, that is, the study is completed once 120 events of the primary composite endpoint have been observed and all patients have at least 1 year of follow‐up unless they died earlier. Patients meeting inclusion criteria who decline randomization are enrolled in a parallel observational registry reflecting standard care. The primary efficacy endpoint is survival free from high urgent cardiac transplantation, disabling stroke and HF hospitalizations (including emergency room HF visits >6 h).

Conclusions

The VAD‐DZHK3 trial will provide guidance on the optimal timing and patient selection for LVAD implantation in heart transplant candidates, potentially redefining current standards of care.

The VAD‐DZHK3 trial is a randomised controlled study evaluating whether elective LVAD implantation improves outcomes in end‐stage heart failure (HF) patients listed for heart transplantation compared with delayed implantation after clinical deterioration. The primary endpoint is survival free from urgent transplantation, disabling stroke or HF hospitalisation. This event‐driven trial aims to define optimal timing for LVAD therapy in high‐risk transplant candidates.

Background

Heart failure (HF) is the leading single cause for hospitalization in in the USA and Europe ¹ , ² and number of cases is steadily increasing. ³ Despite improvements in medical management, a relevant number of patients develop advanced heart failure. ⁴ Advanced heart failure is defined as persistent symptoms despite guideline directed optimal medical and device therapy. Heart transplantation (HTx) remains the gold standard in the absence of contraindications to improve quality of life, functional status and survival in these patients. ⁵ However, shortage of donor organs has led to an increase in waiting time resulting in an increased use of left ventricular assist devices (LVAD) to bridge end stage HF patients until an organ is available. Morbidity and mortality of patients on LVAD support have progressively improved in recent years, mainly by the use of newer generation centrifugal‐flow pumps for whom 5‐year survival rates of up to 77.4% have been reported. ⁶

According to the Eurotransplant annual report 2022 the average waiting time for a HTx in Germany is between 8 to 18 months and there is a significant risk of death while waiting. ⁷ In 2022, 14% of patients on the waiting list for heart transplantation died before they could receive a donor organ. ⁸ It is important to note that the highest mortality is not in the group of ‘highly urgent’ (HU) listed patients who are hospitalized (INTERMACS level 2–3), but in the group of listed patients who are waiting at home (INTERMACS level 4). Given the improved survival rate with LVAD therapy and the mortality risk on the heart transplantation waiting list, we challenged the common approach of using LVADs only in patients who are unstable despite optimal medical and device treatment. An earlier implantation of a LVAD, i. e. at the time of listing for HTx, could reduce the risk of deterioration or even reverse heart failure associated end‐organ function and improve survival. Patient status prior to LVAD implantation can be classified by INTERMACS level which is a strong predictor for postoperative outcome. ⁹ However, an earlier implant may be associated with more device related complications. Hence the decision has to be balanced between the potential benefits and the adverse events that are associated with LVAD therapy (e.g., ischaemic strokes, infectious and bleeding complications). Therefore, the comparison between the current practice (LVAD as an emergency indication) and early LVAD implantation (at the time of listing for heart transplantation) seems timely and is highly clinically relevant.

To answer this question, we initiated a randomized controlled trial of ‘early’ versus ‘emergency’ LVAD implantation in patients with advanced heart failure who meet the criteria for heart transplantation and who are at an increased risk of death while awaiting heart transplantation.

We hypothesized that an earlier implantation of a LVAD reduces the composite end‐point of all‐cause death, high urgent cardiac transplantation, disabling stroke and heart failure hospitalizations (including emergency room HF visits >6 h) in comparison to the current standard (i.e., conservative heart failure therapy and LVAD implantation in the case of worsening heart failure). This investigator‐initiated trial is funded by the German Center for Cardiovascular Research (Deutsches Zentrum für Herz‐Kreislauf‐Forschung; DZHK).

Study design

Rationale and study design

The VAD‐DZHK3 (Early Versus Emergency Left Ventricular Assist Device Implantation in Patients Awaiting Cardiac Transplantation VAD Study; ClinicalTrials.gov: NCT02387112) is an investigator initiated randomized controlled trial designed to assess whether, in patients with end‐stage heart failure awaiting cardiac transplantation, elective LVAD implantation is superior to optimal medical heart failure therapy and assist device implantation only after severe deterioration of heart failure. The lead ethics committee of the Charité Berlin (reference number: EA4/089/13) and all local ethics committees approved the study protocol prior to inclusion of patients. The study is conducted in accordance with the Study Protocol, the Declaration of Helsinki, Good Clinical Practice (GCP/ICH guidelines in the current version), the Medical Devices Act and ISO EN 14155 1 and 2 guidelines.

The study flow is shown in Figure 1 , and the participating centres are listed in Appendix S1 . As a mean of quality control all patients who meet the eligibility criteria of the study but do not consent to randomization are invited to be enrolled in a standard treatment registry (Figure  2 ).

Figure 1.

Study flowchart of the VAD‐DZHK3 Trial. Enrolled severe HF patients in T‐status on heart transplantation list and increased mortality risk (definition please see Table 1 ) are randomized in a 1:1 ratio to early LVAD Implantation or guideline‐directed optimal medical therapy, with potential emergency LVAD Implantation.

Figure 2.

Registry flowchart of patients that meet the eligibility criteria of the study but do not consent to randomization.

An independent data and safety and monitoring board is responsible for monitoring patient safety and evaluating the efficacy and conduct of the study (Appendix S1 ).

Eligibility criteria

The complete eligibility criteria are shown in Table 1 . In brief, patients between 18 and 65 years of age eligible for heart transplantation and accepted in T‐status which corresponds to stadium 4 in the INTERMACS classification qualified for inclusion. ¹⁰ Additionally, they had to have a 1‐year mortality risk in excess of >30% according to the estimates based on the Seattle Heart Failure Model (SHFM) or at least three of the following criteria (a) to (f):

1. cardiac index <2.5 L/min/m²;

2. pulmonary capillary wedge pressure >15 mmHg;

3. peak oxygen consumption, VO₂ ≤ 10.0 mL/kg/min or ≤12.0 mL/kg/min in patients;

4. intolerant of a beta‐blocker;

5. ratio of minute ventilation to CO2 production, VE/VCO2 slope of >35;

6. at least two hospitalizations for heart failure within the previous 12 months;

7. documented increase of BNP or NT‐proBNP levels despite optimal medical therapy.

Table 1.

Eligibility criteria

Inclusion criteria: 1. Patient (male or female) eligible for heart transplantation and accepted in T status 2. Patient aged 18 to 65 years 3. Patient provided signed informed consent to participate on the study 4. >30% 1‐year mortality with the Seattle Heart Failure Model (SHFM) or at least three of the following criteria (a) to (f) a : (a) cardiac index <2.5 L/min/m2; (b) pulmonary capillary wedge pressure >15 mmHg; (c) peak oxygen consumption VO2 ≤ 10.0 mL/kg/min or ≤12.0 mL/kg/min in patients; (d) intolerant of a beta‐blocker; (e) ratio of minute ventilation to CO2 production, VE/VCO2 slope of >35; (f) at least two hospitalizations for heart failure within the previous 12 months; (g) documented increase of BNP or NT‐proBNP levels despite optimal medical therapy. b Exclusion criteria: 1. Patients listed for transplantation of other organs in addition to heart 2. Prior cardiac surgeries (other than pacemaker or ICD surgeries) 3. Contraindications to assist device implantation, that is, mechanical aortic valve or aortic insufficiency 4. Contraindications to anticoagulation 5. Expected need for a right ventricular assist device/biventricular support expected, for example, 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 6. Presence of catecholamine support or intra‐aortic balloon counterpulsation (IABP) 7. Overt infections 8. Fixed pulmonary hypertension that precludes heart transplantation 9. Renal insufficiency (glomerular filtration rate, GFR < 30 mL/min) or need for haemodialysis or haemofiltration 10. Significant coagulopathies 11. Systemic lupus erythematosus, sarcoid, or amyloidosis that has multisystem involvement and is still active 12. Drug abuse and/or alcohol abuse 13. Incompliance 14. Elevated panel reactivity levels of >50% 15. Pregnancy or breast feeding in women 16. Participation in other interventional trials

^a Detailed definition: three applying criteria will only replace the 1‐year‐mortality criterion, not the first three inclusion criteria though.

^b Detailed definition: this increase can be detected at the time of inclusion to the VAD study or previously. Crucial is a documented increase between two or more sequential BNP or NTproBNP values despite optimal medical therapy. Whether increasing BNP values decline again, for example, following absolute bed rest, is not relevant.

A predefined set of exclusion criteria was selected to allow for feasible and save study enrollment. These comprised contraindications to heart transplantation or durable mechanical circulatory support, restrictive cardiomyopathy prior open‐heart surgery and expected concomitant heart surgery (e. g. aortic valve replacement) at the time of LVAD implantation. As this study aimed to study the effects of early isolated LVAD support, patients with expected need for right ventricular assist device or biventricular support were also excluded. Expected need for right ventricular support was defined by echocardiographic criteria: (i.e., 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). ¹¹

Randomization and treatment

After screening and informed consent was obtained, T‐ listed patients were randomized in a 1:1 ratio to early LVAD, or to emergency LVAD implantation. Patients randomized to early LVAD implantation will obtain a LVAD within 28 days after randomization. The randomization is carried out using a central computerized system as block randomization, stratified by centre, with allocation ratio 1:1. There will be no study‐specific intervention other than LVAD implantation in T status (‘early VAD’) and no interference with the organ allocation system related to this study.

Selection of LVAD systems

There are no restrictions on the type of LVAD system. Centres may use all types of commercially available durable LVAD for full left ventricular support that are CE‐marked for left ventricular support at the start of the study or is expected to be CE‐marked during the study.

Control intervention

The control intervention is guideline‐directed optimal medical 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 will be closely monitored (scheduled regular outpatient visits depending on the patient's condition and at least: 1 month, 3 months, 6 months after randomization and as of then every 6 months, thereafter). If the condition worsens, the patient may qualify for HU listing and/or for LVAD implantation.

Registry

All patients who meet the eligibility criteria of the study but do not consent to randomization will be invited to be enrolled in a standard treatment registry, where the follow‐up data will be collected at comparable visits to the study.

Follow‐up

Study and registry patients will be followed up for at least 1 year, unless they die earlier.

The expected median follow‐up time is 3 years.

Study endpoints

The primary efficacy endpoint is the event‐free survival, that is, 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 h) (Table  2 ).

Table 2.

Primary and major secondary endpoints

Primary efficacy end‐point The primary efficacy endpoint is event‐free survival, that is, 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 h). Key secondary efficacy end‐points Minnesota Living with Heart Failure Questionnaire (MLHFQ) score 6‐min walking test distance Rate of recurrent heart failure hospitalizations Secondary efficacy end‐points Time from randomization to each of the components of the primary composite endpoints: All‐cause death High urgent cardiac transplantation Disabling stroke HF hospitalizations (including emergency room HF visits >6 h) Time from randomization to each of the following events: Heart transplantation Urgent VAD implantation VAD explantation due to myocardial recovery Changes over time in the following scales and outcomes: Peak VO2max Heart failure survival score (change in risk group) Seattle heart failure score New York Heart Association (NYHA) class Health related quality of life • Short Form (36) Health Survey (SF‐36) score • EQ‐5D • Cognitive function (Mini‐Mental State Examination, MMSE) Quality‐adjusted life years (QALY) Additional secondary endpoints to be analysed: Rate of recurrent hospitalizations (all‐cause) Safety end‐points All SAEs and AEs including Disabling stroke Minor stroke Listing for high‐urgency cardiac transplantation De novo right heart failure Hospitalization due to device failure Device failure Device infection Major bleeding (transfusion requirement of more than 4 units of packed red blood cells in 24 h) Cardiovascular death End‐organ failure: renal failure (glomerular filtration rate <30 mL/min, electrolytes), hepatic failure (Child–Pugh score >5)

Secondary efficacy end‐points of the study are the components of the primary composite end‐points and the time to a clinically relevant outcomes and change in the scales listed in Table 2 .

As the study is designed to improve survival and quality of life not only disease‐related end‐points will be included but also quality of life (Short Form Health Survey [SF‐36], Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and cognitive deficits (Mini‐Mental Status Examination [MMSE]) scores to assess the impact of the disease and its treatment on the patient's daily life. Thus, the end‐points are not only clinically but also psychosocially relevant.

In addition, it is planned to test for statistically significant differences in quality‐adjusted life years (QALY) to cover health economic issues.

To assess the safety of the study intervention, defined safety endpoints listed in Table 2 will be studied. In brief, these endpoints comprise coagulation related complications, listing for high‐urgency cardiac transplantation, De novo right heart failure, hospitalization due to device failure, device failure, device infection, cardiovascular death and end‐organ failure: renal failure (glomerular filtration rate <30 mL/min), hepatic failure (Child–Pugh score >5).

Statistical considerations

Assuming a hazard ratio of 0.6 a total of 120 events is required to achieve a power of 80% at a one‐sided significance level of 2.5% in this event‐driven trial. The assumed hazard ratio (HR) of 0.6 is, for example, supported by the findings of the Momentum Trial and the ROADMAP study. ¹² A group‐sequential design (O'Brien‐Fleming stopping boundaries) is used; an interim analysis takes place once 60 events have been observed, that is, at 50% of the maximum information of 120 events.

Following the intention‐to‐treat (IIT) principle, primary and secondary analyses are performed using the full analysis set (FAS) consisting of all randomized patients, whether or not they completed all protocol requirements, including all patients with at least one post‐baseline measurement. Per protocol analyses are conducted as sensitivity analyses. All details of the statistical analysis are prespecified in a statistical analysis plan (SAP).

Following the stagewise hierarchical approach ¹³ key secondary endpoints will be tested using a group sequential design with Pocock boundaries. ¹⁴ Control of the familywise error rate (FWER) in the strong sense at each data look (interim and final) across the primary and key secondary endpoints will be achieved as follows: First, the primary endpoint is tested at the significance level provided by the O'Brien‐Fleming alpha spending function. If the primary endpoint is statistically significant, then the key secondary endpoints are tested using adjusted P‐values obtained from the Bonferroni–Holm procedure, and significance level provided by the Pocock alpha spending function.

The primary composite endpoint is analysed by means of a Cox proportional hazards regression with intervention and centre as factors. The intervention effect is reported as HR with 95% confidence interval and P‐value testing the null hypothesis of no intervention effect (i.e., HR = 1). In a supporting analysis, the primary endpoint is analysed using the win‐ratio approach. ¹⁵ For this purpose, the events of the primary composite endpoint are ranked in the following order (most severe first): (1) death (all‐cause); (2) urgent heart transplant; (3) disabling stroke; and (4) (recurrent) HF hospitalizations (including emergency room visits >6 h).

Time to event outcomes, for example, each component of the primary endpoint, follow the same lines as the analysis of the primary endpoint, if sufficient numbers of events have been observed.

Longitudinal outcomes among the secondary endpoints are analysed using a mixed model with random intercept and random slope for individual patients. The model will include treatment and the stratification variable of the randomization (centre) as factors.

Safety analyses follow standard procedures for the reporting of (serious) adverse events; these are reported as frequencies (percentages) by treatment arm.

VAD registry

The registry data are analysed following the lines of the analyses for the randomized controlled trial. However, as the comparisons between early vs. emergency VAD are not based on randomized groups, special care has to be taken to deal with confounding. Therefore, these analyses will be adjusted for propensity scores. If the data from the registry appear to be consistent with the data of the RCT, it would be desirable to integrate the observational data into the RCT to gain efficiency. This can be achieved by Bayesian hierarchical modelling, discounting the observational data in the comparison to the RCT data, so‐called dynamic borrowing ¹⁶ .

Update on study progression

The first patient was randomized on 23 June 2015. The study was stopped early, as planned and recommended by the DSMB, after recruitment of 101 patents in the trial and 78 in the registry. Recruitment and follow‐up have been completed and data are currently being prepared for analysis and potential substudies.

Discussion

Due to donor organ shortage and technical advances in mechanical circulatory support, bridge to transplantation (BTT) with durable, continuous‐flow left ventricular assist devices has become a mainstay in the management of heart failure patients awaiting heart transplantation, and is becoming increasingly important in Europe. ¹⁷

Although heart transplant centres now have active LVAD programs across the board, the mortality rate on the waiting list is still significant. ⁸ Of particular concern is the fact that out‐patients have a significantly higher mortality risk than hospitalized patients, who are under constant medical supervision. In 2016, the 1‐year mortality rate on the Eurotransplant waiting list for U‐list outpatients was 37.9%, compared with 11.2% for HU‐list inpatients. In France, waitlist death or urgent heart transplantation at 12 months after listing was 25.6% in high‐risk patients. ¹⁸ Currently, effective strategies to decrease this unacceptable mortality are lacking. International guidelines do not advise for appropriate means to take the individual mortality risk of this cohort of patients into account, ⁵ , ¹⁹ Consequently, the level of knowledge regarding VAD therapy varies substantially among cardiologists, ²⁰ and international utilization rates differ markedly. ²¹

The VAD‐DZHK3 study was therefore designed to fill an important knowledge gap in the treatment of end‐stage heart failure. With the exception of the REMATCH trial ²² published in 2001, there have been no controlled, randomized trials comparing LVAD therapy with optimal medical therapy. Since 65% of the patients in the LVAD group in this study were already catecholamine‐dependent and ineligible for transplantation, the 1‐year survival rate was only 52%. This highlights the need for further research into the use of LVAD therapy in more stable patients with a more favourable prognosis. The relevance of the VAD‐DZHK3 study is underscored by the initiation of three additional trials—either already recruiting or soon to begin—that address the question of early ventricular assist device (VAD) implantation in the outpatient setting: the SweVAD‐ (NCT02592499), the AmbuVAD‐ (NCT04768322), and the TEAM‐HF trial (NCT06526195).

One of the major challenges for designing the present study was to define strong clinical predictors of an increased risk of death on the HTx waiting list. Although the International Society of Heart and Lung Transplantation (ISHLT) criteria ²³ are useful for identifying patients at risk of HF, a more stringent risk selection is required to demonstrate the benefit of a highly invasive strategy such as LVAD implantation, which itself carries a substantial risk. To identify high‐risk patients, we use a Seattle Heart Failure Model predicted 1‐year mortality of greater than 30% as the main inclusion criterion. ²⁴ Alternatively, three out of six selected criteria of the HFSS ²⁵ and the current European HF Guidelines ⁵ were chosen as inclusion criteria reflecting disease severity and an expected 1‐year mortality >30%.

One key element of the standard listing criteria is maximum achieved oxygen consumption (peak VO₂) on cardiopulmonary exercise testing (CPET), where a cutoff for peak VO₂ of ≤12 mL/kg/min in the presence of ß‐blocker therapy and of ≤14 mL/kg/min without a ß‐blocker is recommended to guide listing. ²³ The 1‐year survival rate for patients with peak VO₂ ≤ 14 mL/kg/min was 70% in the original publication, ²³ thus unsuitable for identification of a high‐risk situation with sufficient survival benefit for the study intervention. Accordingly, the thresholds for the present study were fixed at a lower level (peak VO₂ ≤ 10.0 mL/kg/min or ≤12.0 mL/kg/min in patients intolerant of a ß‐blocker). ²³ As a further CPET criterion, a ratio of minute ventilation to CO₂ production (VE/VCO₂ slope) of >35—associated with an increased cardiac‐related mortality ²³ was determined. In addition, an increase of N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) ²³ and at least two hospitalizations for HF within the previous 12 months instead of constant efforts for therapy optimization should particularly indicate a failure of conventional therapy and worsening HF. ⁵

As a main exclusion criterion, the anticipated need for a right ventricular (RV) assist device/biventricular mechanical support was determined because of the exceptional low survival rates in those patients. ²⁶ Inclusion of those would have counteracted the survival benefit achieved by LVAD treatment. Numerous scores have been developed for prediction of RV failure after left ventricular assist device implantation, but none of them has been generally established. ²⁷ For the present study, well established echocardiographic parameters of advanced RV failure have been chosen as well as presence of restrictive cardiomyopathy and severe pulmonary hypertension. ¹¹ , ²⁸ , ²⁹ , ³⁰ Other exclusion criteria include established contraindications to Htx and established LVAD contraindications such as presence of a mechanical aortic valve.

Ethical considerations

Through technical improvements, primary implantation of LVADs in selected end‐stage HF patients listed for heart transplantation may be superior to emergency implantation in decompensated HF. However, VAD therapy still carries risks and complications. Current LVAD patients are particularly affected by infection, haemorrhage and thromboembolism. The ethical justification for this trial arises from the fact that end‐stage HF patients without VAD support awaiting heart transplantation are also at risk of serious adverse events such as stroke or death. These patients are critically ill, despite optimal medical management and affected by a significant risk of death while waiting for a transplant, whereas the actuarial survival rate for BTT patients supported by an axial flow pump has reached 88.8% and 76.8% at 1 and 2 years, respectively. ³¹ In addition to this survival benefit there are potential advantages such as improved functional capacity, better end‐organ function and improved quality of life. ³² At present, the risk/benefit ratio of elective LVAD implantation versus medical management with LVAD implantation in an emergency setting in this patient cohort is not well understood. There are no data from clinical trials or registries to inform physicians or patients about the relative risks and benefits with the regard to different therapeutic strategies in non‐inotrope‐dependent HF patients awaiting heart transplantation. However, the current major ethical concern is not to expose these patients to undue risk of thromboembolic and infectious events by implanting a VAD that outweigh the projected benefits.

In absence of prospective randomized data, this trial in patients with a high risk of dying on the waiting list seems ethically justified and of high clinical relevance.

All participating institutions will adhere to applicable international guidelines such as the Declaration of Helsinki and guidelines on Good Clinical Practice. Approval by the local ethics committees was sought and, additionally, the independent Data Safety Monitoring Board (DSMB) was installed to monitor safety and trial integrity.

In summary, the VAD‐DZHK3 Trial will provide important and urgently required evidence about LVAD therapy in sufficiently stable patients with advanced HF. We sought to identify those patients with an exceptional high mortality risk on the waiting list for heart transplantation by tailored inclusion criteria. Exclusion criteria served to minimize risk factors diminishing survival benefit of the investigational therapy. We hypothesize that early LVAD implantation in patients listed for heart transplantation with an expected 1‐year mortality risk >30%, however before the onset of irreversible end organ failure, will lead to a marked improvement of event‐free survival and quality of life.

Limitations

This trial is limited mainly to Germany with a primary white population, so no conclusion regarding differing ethnicities can be drawn. The development of right HF is difficult to predict and the exclusion of patients with an increased risk to develop right HF will withhold early VAD implantation from a patient population that may have potential benefit.

Conclusions

The VAD‐DZHK3 Trial is an investigator–intended, industry independent, multicentre, randomized study. It assesses whether a strategy involving elective LVAD implantation is superior to a strategy of optimal medical HF therapy and assist device implantation only after severe deterioration in patients with end‐stage HF awaiting cardiac transplantation. The trial builds on the current scientific and medical evidence. Its results will help to further define the optimal treatment strategies for patients with end‐stage HF awaiting heart transplantation.

Conflict of interest

Volkmar Falk: educational grants, research and study funds, fees for lectures, speeches or professional consultation from Medtronic GmbH, Biotronik SE & Co., Abbott GmbH, Abiomed Inc., Boston Scientific, Edwards Lifesciences, LivaNova, Berlin Heart, Novartis Pharma GmbH, JOTEC GmbH, Zurich Heart. Andreas J. Rieth: speaker fees from AstraZeneca, Bayer, Corvia and travel support from Johnson&Johnson. Gerd Hasenfuß: honoraria for lectures: AstraZeneca, Novartis, Medupdate; advisory board activities: AstraZeneca, Boehringer Ingelheim, Corvia Medical, Novartis. The rest of the authors declare no conflict of interest.

Funding

The VAD‐DZHK3 (Early Versus Emergency Left Ventricular Assist Device Implantation in Patients Awaiting Cardiac Transplantation VAD Study) is an investigator‐initiated trial. Funding is provided by the DZHK (German Center for Cardiovascular Research, funding code: 81X1100301) assuring the independence of the trial. ³³

Legal Position

The study is covered by paragraph 23b of the Medical Devices Act (Medizinproduktegesetz, MPG) entitled Exceptions for Clinical Testing (‘Ausnahme von der klinischen Studie’). All VADs to be used in the study are CE‐certified and will be applied only in accordance with the purposes for which they are certified.

Supporting information

Appendix S1. Supporting Information.

Knosalla, C. , Färber, G. , Rieth, A. J. , Wachter, R. , Placzek, M. , Albert, W. , Hasenfuß, G. , Falk, V. , Friede, T. , and for the VAD‐DZHK3 Investigators (2025) Rationale and design of the randomized ‘early ventricular assist device’—Trial (VAD‐DZHK3). ESC Heart Failure, 12: 3731–3740. 10.1002/ehf2.15376.