Clinical trial NCT04393181: IMPact of Donor Heart Function on Recipient Outcomes - a prospectiVE Study to Increase the Utilization of Donor HEARTs
Official title: IMPact of Donor Heart Function on Recipient Outcomes - a prospectiVE Study to Increase the Utilization of Donor HEARTs
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Heart Transplantation
Lead sponsor: Vastra Gotaland Region
Sponsor class: OTHER_GOV
First posted: 2020-05-19
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects with severe heart failure accepted for heart transplantation at Transplantationscentrum, Sahlgrenska University Hospital, Gothenburg, Sweden

Brief summary: Severe heart failure is a diagnosis with a very poor prognosis. Heart transplantation is the best treatment for terminal heart failure but this type of treatment is limited by the number of available organs. About 20-25% of possible donor hearts are not considered for transplantation because they have some form of functional impairment. The functional impairment affecting organ donors is, however, usually reversible. A number of retrospective studies show that cardiac function recovers and recipients of hearts with dysfunction do not have worse outcomes compared to recipients of hearts with perfect cardiac function. However, there are no prospective studies on whether the functional impairment of the donor heart is of significance for the recipient. With a systematic and simple investigation of the heart, it should be possible to identify the hearts that are safe to transplant. This will thus increase the number of available donors.

Detailed description: Severe heart failure is a diagnosis with a very poor prognosis where the 2-year mortality rate for serious heart failure is over 50%, which exceeds many cancer diagnoses. Despite advances in pharmacological treatment and mechanical pumps, heart transplantation is considered to be the best treatment for terminal heart failure. However, heart transplantation as a treatment for terminal heart failure is limited by the number of available organs. If the investigators could take care of more organs, more patients could be transplanted. It is therefore of the utmost importance that every heart that can be transplanted successfully is considered.

According to current recommendations, a heart should be in near perfect condition to be considered for transplantation. For a donor heart to be transplanted, it should not exhibit:

* More than mild-to-moderate cardiac impairment (EF \< 40%)
* Regional discrete wall motion abnormalities
* Need for excessive inotropic support (dobutamine \>20µg/kg/minute)
* Intractable ventricular arrhythmias.

Cardiac dysfunction in organ donors, however, is usually secondary to the disease that led to brain death and is reversible; there is nothing wrong with the heart itself but it has ended up in an unfavorable environment that temporarily affects its function. A common cause of cardiac dysfunction in organ donors is stress-induced cardiomyopathy/Takotsubo cardiomyopathy. Stress-induced cardiomyopathy is a relatively newly described acute cardiac syndrome in which the heart develops regional wall motion abnormalities caused by severe catecholamine stimulation of the myocardium. In the organ donor, a strong catecholamine storm is observed in combination with compression and the development of brain death, which can trigger stress-induced cardiomyopathy. This type of change is seen in 20-25% of potential organ donors. One of the most important characteristics of stress-induced cardiomyopathy is its rapid recovery, however, and cardiac function is usually normalized within a few hours or Days 8-10. This is not only seen as a functional recovery, but also a structural and biochemical recovery of the heart. In addition to organ donors with intracranial events, stress-induced cardiomyopathy is also seen in patients with hypoxic/anoxic brain injuries as a result of hypoxic cardiac arrest, and even in these cases, cardiac events are temporary.

There are potentially differential diagnoses for stress-induced cardiomyopathy in potential donors. The most important is ischemic heart disease which can quickly and relatively easily be diagnosed with coronary angiography. Coronary angiography is performed today on approximately one-third of potential donors and then primarily on donors with a risk profile for coronary artery disease. Another different diagnosis is myocarditis, which does not have the same reversibility as stress-induced cardiomyopathy and usually gives a different echocardiographic image.

The recommendation not to utilize hearts with regional wall motion abnormalities has inadequate scientific support. The recommendation is based on a retrospective study that is over 30 years old and did not have cardiac dysfunction as the primary outcome measure. Upon review of this article, the data does not support the idea that regional wall motion abnormalities would be associated with worse outcomes. Despite this, this recommendation has been the basis for deciding whether to transplant the heart or not. There is a wariness, especially with American thoracic surgeons, to take into account such hearts. There is a number of retrospective studies that show that the outcome is not worse for patients who have been transplanted with hears that have/have had dysfunction. The main studies are presented below:

* A study based on material from the USA (UNOS database) in which patients who received a heart with ejection fraction \<50% (n=740) were identified and compared with recipients of hearts with normal function (n=30253). No difference in mortality at one year after transplantation was observed between the groups.
* A study based on the same material showed that long-term survival was not inferior for recipients of hearts with ejection fraction\<50%. Cardiac function was also the same for recipients of hearts with normal function and impaired function one year after transplantation.
* In a study based on the same database (UNOS database) 472 recipients who received a heart with improved function, defined as EF≤40% at one examination and EF≥50% at a follow-up examination, were identified. The control group were recipients of hearts with normal function EF≥55%. There was no difference in mortality, primary graft failure, allograft vasculopathy between the groups, even when propensity score matching was applied.
* A study based on other material from the USA (California Transplant Donor Network) reported figures where low ejection fraction (EF\<50%, number of patients not reported) or regional hypokinesia (n=197) did not affect outcome.
* An older study based on material from the USA showed that regional hypokinesia has no bearing on recipients' mortality. The number of patients with regional hypokinesia was not reported but 1719 patients were included in the study.
* A study from Transplantation Centre, Sahlgrenska, analyzed donors and recipients during a 10-year period. In total, 641 donors were included in the analyses and 155 (24%) of the donors had cardiac dysfunction. Recipients of hearts with dysfunction (n=42) did not have worse outcomes (death, retransplantation) compared to recipients of hearts with normal function. Short-term outcomes (intensive care unit (ICU) care time, advanced hemodynamic support, postoperative dialysis, rejection) also did not differ between the groups. Cardiac function was rapidly recovered in the recipients and both groups had the same ejection fraction already a few days after transplantation.

These retrospective studies form a relatively good foundation and cover almost 1400 patients. However, prospective studies on transplantation of hearts with functional impairment are missing.

At Transplantation Centre, Sahlgrenska, there are many years of experience of handling hearts with impaired function. This clinical experience suggests that it is not associated with complications. The studies referenced above confirm this experience.

Overall, there is room to increase the number of heart donors, and thus the number of heart transplantations, if the heart donors with reversible dysfunction are utilized. This study aims to prospectively investigate the cardiac function of donors and evaluate if it is of significance to the outcome of the recipient. The study sets guidelines for investigative procedures as well as which hearts should be transplanted, based on previous retrospective studies. The investigators expect that the recipients' outcome will not be affected by the cardiac function of the donor, provided the study's recommendations are followed. Our data shows that approximately every fourth potential heart donor suffers from functional impairment. This is in line with other studies that observed that about 20% of hearts are refused due to affected function. The investigators estimate that a systematic consideration of these hearts can increase the number of transplantations by 20-30%.

Eligibility criteria: Inclusion Criteria:

* Patient who has been accepted for heart transplantation at the participating transplantation center

  * The research subject has given written consent to participate in the study
  * Aged 18 years or older

Exclusion Criteria:

* • Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation

  * Another study, where the patient is included, which is not considered compatible with the current study.

Primary outcomes:
measure: Dead
timeFrame: One year after heart transplantation.
Secondary outcomes:
measure: Frequency
timeFrame: 24 hour after transplantation
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hostpial
state: Västra Götaland
Study officials:
affiliation: Vastragotalandsregionen, Sahlgrenska University Hospital,Gothenburg, Sweden
name: Göran Dellgren, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: