Non-ischaemic Heart Preservation Versus Standard Cold Storage in Human Heart Transplantation

The overall aim of this study is to compare a new state-of-the-art ex-vivo organ preservation method with standard ischemic cold static storage of donor hearts in adult cardiac transplantation.

Standard heart preservation before transplantation consists of cold ischemic storage of the heart. Clinical studies have shown that the morbidity and mortality risk increases with the extension of the allograft ischemic time over four hours. For each additional hour the mortality risk increase with 25% the first year. This time constraint is costly and results in severe logistical problems, leading to loss of transplantable organs. The preliminary results from our safety study, where six patients transplanted with the new state-of-the-art ex-vivo organ preservation method, have shown promising results.

The study is a multicenter, prospective, open, blinded endpoint, randomized, controlled clinical trial. The primary end-point is survival free of acute cellular rejection (ACR) and retransplantation within 1-year post-transplant. ACR will be assessed blinded. The secondary end-points are ischemia/reperfusion injury, early graft dysfunction, and QoL.

SURVEY OF THE FIELD Ischemia and reperfusion (I/R) - elicited tissue injury contributes to morbidity and mortality. In organ transplantation, it is a major challenge. The imbalance in metabolic supply and demand within the ischemic organ results in tissue hypoxia and microvascular dysfunction. The following reperfusion enhances the activation of innate and adaptive immune responses resulting in a cell death program.

A damaged endothelium increases the risk of allograft rejection within 1-year after transplantation and a drug treated rejection increases the risk of chronicle rejection and five-year mortality. An improved preservation of the endothelium of the coronary arteries is therefore instrumental to achieve an improved short- and long-term outcome for the transplanted patients.

Standard heart preservation before transplantation consists of cold ischemic storage of the heart. Clinical studies have shown that the mortality risk increases sharply with extension of the allograft ischemic time over four hours. For each additional hour, the mortality risk increases with 25% the first year. Different myocardial cardioplegic preservation solutions and ex-vivo perfusion machines have been developed. Despite some promising experimental results, no consistent differences in outcome have been found. Our first-in-man pilot study, including 6 NIHP cases, show the device's feasibility and provide the first pieces of evidence that machines improves outcome of heart transplantation. However, as these results are based on a non-randomized study design with a few patients, a randomized study is needed to ensure the effect.

PURPOSE AND AIMS The purpose of this study is to compare a new state-of-the-art non ischemic heart preservation (NIHP) method, on heart allograft function, rejection episodes, and quality of life, with the standard ischemic cold static storage (SCS) method of donor hearts in adult heart transplantation.

STUDY DESIGN The study is a multicentre, prospective, randomized, open, blinded endpoint, controlled clinical trial. The study will randomly assign eligible patients to be transplanted with a donor heart preserved with either a new ex-vivo perfusion method (NIHP) or the standard cold static storage (SCS). The study will be performed at Skane University Hospital, Karolinska University Hospital, Linköping University Hospital, and Uppsala University Hospital, which cover two-thirds of the population in Sweden. Patients listed at these centres will be transplanted at Skane University Hospital and then returned to their centre for post-transplant care. The data collection, statistical analysis, and presentation of results will be done according to the CONSORT criteria. The main outcomes will be reported on intention to treat basis.

PICO Population: Adult patients with end-stage heart failure eligible for heart transplantation.

Intervention: Recipient transplanted with a donor heart preserved using NIHP. Control: Recipient transplanted with a donor heart preserved using SCS. Outcome: Survival, rejection, graft function, and quality-of-life.

STATISTICAL ANALYS PLAN Populations for analysis The full analysis set will consist of all randomized patients. Following the intent-to-treat principle, patients will be analyzed according to the preservation methods (NIHP and SCS, respectively) to which they were assigned at randomization. Efficacy variables will be analyzed based on all randomized patients as the primary population.

Patient demographics/other baseline characteristics Baseline value is defined as the last non-missing assessment prior to the transplantation. Summary statistics will be provided by treatment group for demographics and baseline characteristics, including age, sex, weight, height, body mass index (BMI), diagnosis, prior hospitalization, need for inotropic support pre-transplant and/or ECMO, CK-MB, TnI, proBNP, and vital signs. Continuous variables will be summarized using n, mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized using frequency and percentage. The difference between treatment groups will be compared using the Chi-square test for categorical variables or using Mann-Whitney U-test for continuous variables. The p-values will be provided for descriptive purposes and will not be considered to define any formal basis for determining factors to be included in statistical models.

Analysis of the primary efficacy variable and outcomes The primary objective of this study is to evaluate the survival free of allograft rejection and re-transplantation after heart transplantation comparing two preservation methods (NIHP versus SCS).

Time-to-event variables (primary efficacy variable) will be analyzed using the Cox proportional hazard model. The estimated hazards ratio and the corresponding two-sided 95% confidence interval will be provided. A supplemental log-rank test will be performed. Survival function for each treatment group will be estimated by Kaplan-Meier method and the Kaplan-Meier curves will be presented. The frequency and percentage of patients who reach the primary composite endpoint will be provided by treatment group for the population.

Analysis of secondary efficacy, exploratory, and safety variables and outcomes The secondary objects of this study are to test if the new preservation technique (NIHP) is superior to standard preservation technique (SCS) in I/R injury (cTnI and CK-MB), immediate graft function, QoL and severe adverse events. Furthermore we will analyse the postoperative renal function (minimum creatinine clearance, need for CRRT), postoperative liver function (ASAT, ALAT), postoperative pulmonary function (hours in ventilator), SAE, time to no improvement in physical activity, resource utilizations (length of stay, and number of visits to professional healthcare).

Continues variables (cTnI, CK-MB, inotrope score, minimum creatinine clearance, hours of ventilator, physical activity (calorie use), length of stay, and number of visits to professional healthcare, EQ-5D index and EQ VAS) will be analysed using Mann-Witney U-test. Additionally, the baseline value of the corresponding variable may be included as a covariate if appropriate. The estimated treatment effect and the corresponding two-sided 95% confidence interval will be provided.

Binary variables (primary graft dysfunction, LVEF\<40%, RVEF\<40%, severe adverse events) will be analysed using logistic regression. Additionally, the baseline value of the corresponding variable may be included as a covariate if appropriate. The estimated treatment effect and the corresponding two-sided 95% confidence interval will be provided. EQ-5D descriptive system will be analysed by using χ2-test and Fisher's exact test.

SAFETY The assessment of safety will be based primarily on the frequency of adverse events and laboratory abnormalities. Other safety data will be summarized as appropriate. Laboratory data will be summarized by presenting shift tables using extended normal ranges (baseline to most extreme post-baseline value), by presenting summary statistics of raw data and change from baseline values (mean, medians, standard deviations, ranges). An interim assessment of the initial 10 patients in the intervention group will be performed when all of them has passed 30-days post-transplant or expired.

Eligibility Criteria:
Inclusion Criteria recipient:

* Age ≥18 years
* Signed informed consent form
* Listed for heart transplantation

Exclusion Criteria recipient:

* Previous solid organ transplantation
* Grown-up congenital heart disease (GUCH)
* Kidney failure eGFR\<40, calculated by CDK-EPI Creatinine, or ultrafiltration or dialysis or rapidly deteriorating kidney function due to a diagnosed renal disease
* Coagulopathy due to known hepatic disease or heparin induced thrombocytopenia
* Ongoing septicemia defined as positive blood culture (including with a durable VAD)
* Incompatible blood group
* Not able to understand the information provided during the informed consent procedure
* Patients under pre-transplant desensitization protocol
* Short term mechanical support pre-transplant (ECMO)
* Patient diagnosed with Systemic Lupus Erythematous, sarcoidosis or amyloidosis
* Combined organ transplantation candidates
* Patient already consented for another transplant related intervention study

Inclusion criteria donor:

* Age ≤70 years
* Accepted as heart donor by the transplant team (research consent from the donor if required in country)

Exclusion criteria donor:

* Previous sternotomy
* DCD hearts