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The study intends to compare standard ischemic cold static storage (ICSS) of retrieved hearts intended to be transplanted, to non-ischemic heart preservation (NIHP) in a randomized clinical multicentre trial. The primary hypothesis is that the non-ischemic hypothermic cardioplegic preservation (NIHP) is safe and superior to ischemic cold static storage (ICSS) of donor hearts. The study will investigate the safety and superiority of the new methodology in terms of improved immediate and prolonged organ function in adult heart transplanted patients.
This study will investigate if non-ischemic heart preservation (NIHP) with the XVIVO heart preservation devices could improve clinical outcome of patients receiving hearts after use of the technology compared to after use of standard cold ischemic preservation. This will be investigated in a European multicentre randomized controlled clinical trial. For technical reasons, blinding to the involved clinical personnel is not possible, however, biopsies will be blinded to study pathologists. The trial will include 202 recipients that have been randomized through their heart donor. The primary outcome of the study is a clinically relevant composite including graft survival, primary graft dysfunction, rejection and use of circulatory mechanical support, within 30 days and also including Cardiac Allograft Vasculopathy within 12 months. As secondary outcomes, molecular markers related to cardiac injury CKMB, ProBNP and TNI will be investigated as well as markers of the inflammatory response. Safety aspects such as effect on other organs and machine defects will also be monitored. The study population is adults, listed for heart transplantation and donors accepted as heart donors according to standard hospital procedures. Specific recipient exclusion criteria related to pre-transplant ECMO support, patients undergoing pre-transplant desensitization protocol, patients with Grown-Up Congenital Heart Disease, patients with severe kidney or liver dysfunction, patients with septicaemia, and patients diagnosed with Systemic Lupus Erythematous, sarcoidosis or amyloidosis are excluded. Cardiac death donors and donors with previous sternotomy are excluded. The study hypothesis is that NIHP better preserves the endothelium and myocyte function of the heart resulting in improved short- and medium-term recipient outcome, without inducing any new significant risks to the retrieved heart or the recipient. This is believed to be accomplished through continuous oxygenation of the heart via perfusion of the coronary arteries using an optimized preservation solution, mimicking the normal environment for the endothelium.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Non-ischemic heart preservation (NIHP) | Experimental | Continous cold cardioplegic perfusion of hearts |
|
| Ischemic cold static storage (ICSS) | Active Comparator | Standard preservation technique |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| XVIVO heart preservation devices | Device | The intervention is to preserve hearts during transportation cold, cardioplegic and non-ischemic, with a high oncotic and hormone supplemented perfusate. |
| Measure | Description | Time Frame |
|---|---|---|
| 30 days mortality and 30 days graft dysfunction | The Primary End-Point is defined as time-to-first-event of cardiac related death, moderate or severe primary graft dysfunction of the left ventricle or primary graft dysfunction of the right ventricle (according to Kobashigawa et al., 2014), acute cellular rejection ≥2R (according to Stewart et al., 2005) or graft failure (use of mechanical circulatory support or retransplantation) within 30 days. | 30 days |
| Measure | Description | Time Frame |
|---|---|---|
| 1 year mortality and 1 year graft dysfunction | The key secondary endpoint is defined as time-to-first-event of either any cause of death, moderate or severe PGD-LV or PGD-RV (according to Kobashigawa et al., 2014), acute cellular rejection ≥2R (according to Stewart et al., 2005) or graft failure (use of mechanical circulatory support or retransplantation) or CAV ≥ 1 (according to Mehra, 2010) within 12 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Serious adverse device effects | Incidence of any serious adverse device effects. | 1 year |
| Adverse device effects | Incidence of any adverse device effects |
Inclusion Criteria recipient:
Inclusion criteria donor:
Exclusion Criteria recipient:
Exclusion criteria donor:
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| Name | Affiliation | Role |
|---|---|---|
| Filip Rega, MD, PhD | UZ Leuven | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Allgemeines Krankenhaus der Stadt Wien | Vienna | Austria | ||||
| UZ Leuven |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39153817 | Derived | Rega F, Lebreton G, Para M, Michel S, Schramm R, Begot E, Vandendriessche K, Kamla C, Gerosa G, Berman M, Boeken U, Clark S, Ranasinghe A, Ius F, Forteza A, Pivodic A, Hennig F, Guenther S, Zuckermann A, Knosalla C, Dellgren G, Wallinder A; NIHP2019 investigators. Hypothermic oxygenated perfusion of the donor heart in heart transplantation: the short-term outcome from a randomised, controlled, open-label, multicentre clinical trial. Lancet. 2024 Aug 17;404(10453):670-682. doi: 10.1016/S0140-6736(24)01078-X. | |
| 38154894 |
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| Standard ICSS | Device | Cold static preservation using standard preservation solution |
|
| 1 year |
| 30 days and 1 year mortality and graft dysfunction | The individual variables included in the composite primary endpoint at 30 days and 1 year analyzed as time-to-first-event. | 30 days and 1 year |
| CKMB | Creatine kinase MB (CKMB) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal | 3 days |
| TnI | Tropinin I (TnI) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal | 3 days |
| ProBNP | Pro Brain Natriuretic Protein (ProBNP) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal | 3 days |
| Stay in ICU | Length of Stay at Intensive Care Unit, reported as number of days | 1 year |
| Cardiac Transplant Events | Incidence of Major Adverse Cardiac Transplant Events | 1 year |
| Postoperative use of mechanical circulatory support | Incidence of use of postoperative mechanical circulatory support, reported as number of days | 1 year |
| Postoperative duration of mechanical circulatory support | Duration of use of postoperative mechanical circulatory support, reported as number of days | 1 year |
| Overall success/failure 30 days | Success is defined as a recipient that are transplanted and alive at 30 days without any of the complication in the primary endpoint before 30 days. | 30 days |
| Overall success/failure 1 year | Success is defined as a recipient that are transplanted and alive at 1 year without any of the complication given in key secondary endpoint before 1 year. | 1 year |
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage within 24 hours after transplantation | 24 hours |
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage 1 week after transplantation | 1 week |
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage 6 months after transplantation | 6 months |
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage 1 year after transplantation | 1 year |
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage within 24 hours after transplantation | 24 hours |
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage 1 week after transplantation | 1 week |
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage 6 months after transplantation | 6 months |
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage 1 year after transplantation | 1 year |
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm within 24 hours after transplantation | 24 hours |
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 1 week after transplantation | 1 week |
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 6 months after transplantation | 6 months |
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 1 year after transplantation | 1 year |
| 1 year |
| Device dysfunction resulting in loss of transplantable heart | Number of transplantable hearts lost due to device dysfunction | 12 hours |
| Intra operative details; duration of ECC | Duration of ECC in minutes | 12 hours |
| Intra operative details; duration of cross clamp | Duration of cross clamp in minutes | 12 hours |
| Intra operative details; duration of surgery | Duration of surgery in minutes | 12 hours |
| Intra operative details; attempts to wean off ECC | Number of attempts to wean off ECC | 12 hours |
| Intra operative details; need for inotropic support | Need for inotropic support (inotropic score) | 12 hours |
| Intra operative details; need for pulmonary vasodilator | Need for pulmonary vasodilator | 12 hours |
| Intra operative details; defibrillations | Number of defibrillations | 12 hours |
| Intra operative details; arryhythmias | Occurence of arryhythmias | 12 hours |
| Intra operative details; conduction abnormalities | Number of conduction abnormalities | 12 hours |
| Intra operative details; Left ventricular ejection fraction (LVEF) | LVEF in percentage | 12 hours |
| Intra operative details; Right ventricular ejection fraction (RVEF) | RVEF in percentage | 12 hours |
| Intra operative details; Mitral valve regurgitations | Grade of mitral valve regurgitations | 12 hours |
| Intra operative details; Tricuspid valve regurgitations | Occurence of tricuspid vavle regurgitations | 12 hours |
| Arterial blood gas lactate | Arterial blood gas lactate at 6 hours | 6 hours |
| Arterial blood gas lactate | Arterial blood gas lactate at 24 hours | 24 hours |
| Pro-BNP during follow up | Pro-BNP at predefined time points during follow-up. | 1 year |
| Leuven |
| Flemish Brabant |
| 3000 |
| Belgium |
| Institut de cardiologie, Chirurgie thoracique et cardiovasculaire La Pitié Salpetrière | Paris | Paris Cedex | 75651 | France |
| Hôpital Bichat Claude-Bernard | Paris | France |
| Klinikum der Universität München | München | Bavaria | 81377 | Germany |
| Deutschen Herzzentrum Berlin | Berlin | Brandenburg | 13353 | Germany |
| Universitätsklinik der Ruhr-Universität Bochum | Bad Oeynhausen | Germany |
| Universitätsklinikum Düsseldorf | Düsseldorf | Germany |
| Hannover Medical School | Hanover | Germany |
| Azienda osedalaria di Padova | Padova | Padova PD | 35121 | Italy |
| Hospital Puerto de Hierro | Madrid | Majadahonda Madrid | 28222 | Spain |
| Sahlgrenska University Hospital | Gothenburg | Västra Götalands Regionen | 412 34 | Sweden |
| Freeman Hospital | Newcastle | Newcastle Upon Tyne | NE77DN | United Kingdom |
| Queen Elisabeth Hospital | Birmingham | B152TH | United Kingdom |
| Royal Papworth Hospital | Cambridge | United Kingdom |
| Derived |
| Brouckaert J, Dellgren G, Wallinder A, Rega F. Non-ischaemic preservation of the donor heart in heart transplantation: protocol design and rationale for a randomised, controlled, multicentre clinical trial across eight European countries. BMJ Open. 2023 Dec 28;13(12):e073729. doi: 10.1136/bmjopen-2023-073729. |