Donor Hearts Fare Better With Novel Method After Circulatory Death

Using transplanted hearts preserved by thoracoabdominal normothermic regional perfusion (taNRP) after circulatory death results in better clinical outcomes than using those retrieved via direct procurement and perfusion (DPP), according to an observational analysis.

One year after transplantation, patients with hearts retrieved using the taNRP approach had less severe primary graft dysfunction and biopsy-proven acute-cellular rejection (ACR) than those with hearts taken with DPP, but there was no difference in mortality between the two techniques, investigators reported in a study published this week in JACC: Heart Failure.

“Severe primary graft dysfunction, where the patient requires a machine to help their circulation posttransplant, which is usually ECMO and sometimes a right ventricular assist device, is about two-and-a-half times lower in the taNRP group,” lead investigator John Louca, MB BChir (University of Cambridge, England), told TCTMD. “That difference is pretty significant. It’s really quite exciting because it means these patients are probably doing better post-op and not requiring as much support.”

The data warrant confirmation in a larger randomized trial, but conducting such a study, or even being able to broaden the use of taNRP, could prove to be a challenge given some of the logistical and ethical challenges. There’s a moratorium on taNRP in several countries, such as Belgium and the UK, and outright prohibitions in Australia, Canada, and many parts of the US. In Spain, normothermic regional perfusion in organ procurement has been implemented since 2008.

The taNRP technique has been increasingly used as a way to decrease the ischemic insult that occurs between the stoppage of life-sustaining treatment and the confirmation of circulatory death. It involves restoring partial circulation in the donor’s body after circulatory death is declared, which has raised concerns about whether it violates the “dead donor rule” that states the donor must meet the criteria for brain or circulatory death at the time of organ procurement.

Radha Gopalan, MD (Banner – University Medical Center Phoenix, AZ), director of advanced heart failure, transplantation, and mechanical assist devices at his center, called the observational study “informative but not definitive.” While there might be difficulties with getting a randomized comparison between taNRP and DPP launched, the observational data help in this regard, he noted.

“This study suggests there is no difference in mortality,” Gopalan told TCTMD. “One-year and 3-year survival is comparable between the two, which is a good thing right now. It means that we can go to any patient and say, ‘We are going to randomize you to getting the organs one way or another—are you okay with it? There is no difference in survival.’ That allows us to have that conversation with the patients, because it’s a very tough thing to do in a heart transplant [setting].”

To TCTMD, Louca noted that while there was no statistically significant difference in mortality between taNRP and DPP, the event curves show a separation favoring normothermic reperfusion. “I will say there may be a difference in survival, but we haven’t shown anything significant,” he said.

Comparing taNRP vs DPP

Expansion to organs donated after circulatory death has increased the donor pool by as much as 30%, according to some estimates.

One limitation of using these organs, however, is the resulting ischemia that can lead to irreversible organ damage. With taNRP, the heart is perfused in situ before it is recovered and then preserved either with ex situ perfusion or static cold storage after explantation. DPP, on the other hand, involves retrieving the heart immediately after circulatory death and preserving it with machine perfusion during transportation from the donor to recipient hospitals.

With DPP following circulatory death, transplant teams are removing to-be-donated organs that have suffered an extended period of ischemia already, Ashish Correa, MBBS (The Mount Sinai Hospital, New York, NY), an advanced heart failure and transplant physician, told TCTMD. As the organ is taken from the donor to an extracorporeal perfusion machine, there is further ischemia, among other issues.

“It is technically challenging and complex to put [the organ] on these external perfusion devices,” said Correa. “It is also expensive.”

There is currently a paucity of data comparing taNRP and DPP heart outcomes, which led investigators to collect data from 20 transplant centers in Belgium, Spain, the United Kingdom, and the United States.

What matters most to our patients is, are they going to be alive? Ashish Correa

Between 2023 and 2024, there were 504 transplantations using hearts after confirmation of circulatory death: 223 were retrieved and preserved with taNRP and 281 with DPP. There was no difference in donor height, weight, age, sex, or sex-mismatched transplants between the groups. Additionally, there were similar numbers of livers and lungs retrieved per donor in the taNRP and DPP groups, although more kidneys were retrieved with DPP. 

The DPP group had a significantly shorter functional warm ischemic time, defined as the time from donor systolic blood pressure < 50 mm Hg to cold paraplegia, than the taNRP group (median 13 vs 15 minutes; P = 0.005). However, functional total ischemic time, defined as the time from donor systolic blood pressure < 50 mm Hg to reperfusion, was significantly shorter with taNRP (median 15 vs 39 minutes; P < 0.001). There was also a significantly shorter ex situ perfusion time with taNRP donor hearts.

There was no difference in recipient survival after transplantation at 30 days, 1 year, 3 years, or across the entire study period (median times from transplant to censor date were 1,069 and 744 days in the DPP and taNRP arms, respectively). Similarly, in mixed-effects Cox modeling, neither procurement method was associated with better survival over the other.

Primary graft dysfunction was smore common in patients with hearts procured via DPP (19.2% vs 7.6%; P < 0.001). In a logistic regression model, procurement via taNRP was associated with a lower use of mechanical circulatory support after transplantation (OR 0.32; 95% CI 0.18-0.59). Overall, 25.3% of patients in the DPP group had an episode of ACR requiring treatment in the first year after transplantation compared with 13.0% in the taNRP group (P < 0.001). The risk of rejection-free survival censored for death was better with taNRP (HR 0.45; 95% CI 0.30-0.69).

Less primary graft dysfunction with taNRP makes “intuitive sense,” because the DPP method is associated with longer ischemic times, said Correa. Like Gopalan, he sees the absence of a survival advantage with either approach as good news.

“What matters most to our patients is, are they going to be alive?” Correa told TCTMD. “By either technique, it seems there is no difference.”

Advantages With taNRP

At this stage, Louca said research groups aren’t yet close to launching a randomized comparison between the procurement approaches, but he isn’t sure one is warranted. In addition to their work, others have shown there are advantages with taNRP, including lower cost and greater number of organs taken per donor.

“We’ve done a lot of work with donors over the years,” he said. “That’s that person’s legacy in many ways, and we have a responsibility to make the most of that, to honor their legacy. Anything that can help, and similarly for the recipients, but anything that gets the organs quicker and [gets them] off the waiting list is a good thing. Then there’s our paper, which is starting to suggest that there may be actual tangible benefits to using taNRP in a recipient.”

In addition to shortening the ischemic time with taNRP, Correa said there are other advantages of procuring the heart this way.

“With DPP, once you’ve resuscitated the organs, you have to make an assessment about whether they are viable just by looking at them beat on the machine,” he said. “That’s a more challenging way to make an assessment, whereas with thoracoabdominal normothermic regional perfusion you can assess how the organs are doing in a much more natural state. The heart is loaded appropriately, and you can see how it would potentially be in the recipient.”

There also are blood and imaging tests that can be performed with taNRP that can’t be done once the heart is placed on the organ care system. If the donor is located close enough to the recipient hospital, the taNRP approach allows hospitals to transport the retrieved hearts using static cold preservation.

Gopalan said his hospital procures the heart with taNRP following circulatory death, but he doesn’t believe the retrospective analysis will change cardiac transplantation procurement procedures in those that use donor hearts after circulatory death. Among the 20 centers included in the study, all have different ways of performing cardiac transplantation and caring for the heart in follow-up. Protocols and policies around immunosuppression or biopsy, for example, all differ, he said. This could lead to potentially confounded results.

“When you combine multiple centers, you have to take [the results] with a grain of salt,” said Gopalan. “Nevertheless, it highlights important points. Am I impressed with the paper? Yes. Will it change practice? Not yet.”

Correa pointed out that more recipient patients in the DPP group required inotropic support, which may have contributed to the higher risk of primary graft dysfunction. The DPP group also had long preservation times, he noted. For this reason, a randomized trial would be warranted, although it would require large numbers, a challenge in the transplant world, as well as nationwide consensus on the ethics of taNRP, he said.