Trial Affirms Safety of Circulatory-Death Heart Transplants

Transplants from circulatory-death donor hearts assessed with a perfusion machine did just as well as those procured after brain death and cold storage, a randomized trial showed.

Recipients of a circulatory-death heart had noninferior risk-adjusted 6-month survival compared with brain-death heart recipients (94% vs 90%) in the as-treated population, with a 3-percentage point advantage by the least-squares mean difference calculation in the primary endpoint (P<0.001 for noninferiority).

There were also no "substantial" differences in serious adverse events at 30 days post-transplantation, Jacob N. Schroder, MD, of the Duke University Medical Center Heart Transplantation Program in Durham, North Carolina, and colleagues reported in the New England Journal of Medicine.

"Until recently, brain-dead donors were the only donors for heart transplantation because brain death permitted in situ assessment of the viability and function of the heart," they noted. With extracorporeal machine perfusion to reanimate the heart, that's possible for circulatory-death donors as well.

Some 80% of people who sign up to be organ donors die with severe brain injury but do not meet the criteria for brain death and thus are unable to donate hearts, noted Nancy K. Sweitzer, MD, PhD, of Washington University in St. Louis, writing in an accompanying editorial.

"Safely increasing the number of heart donors is critical to meeting demand," she wrote.

The study results were an "exciting" proof of safety and feasibility for this approach to expanding the donor pool, Sweitzer said. "The percentage of donor hearts used was an important secondary endpoint -- nearly 90% of hearts from circulatory-death donors were ultimately transplanted, a finding that suggests that programs supporting donation after circulatory death will increase transplantation procedures meaningfully."

Along with more research, she noted that the infrastructure around circulatory death organ donation will require work: "The systems and support that are needed for programs at transplantation centers to initiate donation after circulatory death are substantial, since organ donation after controlled circulatory death (modified Maastricht category III) involves the controlled withdrawal of life support with the expectation of cardiac arrest in the patient. The process has attendant infrastructural, multidisciplinary, and ethical implications that necessitate institutional support."

However, there was one key aspect of the trial that might have oversold the results, Sweitzer suggested.

The trial randomized adult candidates for heart transplantation in a 3:1 ratio to the circulatory-death group or the brain-death group. The latter got only hearts preserved with the conventional cold storage process after brain death of the donor. The circulatory-death group could either receive a heart after the circulatory death of the donor or from a brain-death donor if one matched to the patient first in order to protect the chance to receive a heart transplant without unnecessary delay.

But because the trial was unblinded, there were differences in priority status assigned by the United Network for Organ Sharing (UNOS) between groups.

Circulatory-death organs rarely went to the sickest patients on the waiting list and instead went largely to those with scores of 3 to 6 on the 6-point scale. Patients transplanted while listed at status 2 were 2.5 times more likely to get a brain-death than circulatory-death donor heart. Of the status 1 patients transplanted, only one got a circulatory-death donor heart versus five getting brain-death donors hearts.

"The clear imbalance in this trial suggests an unwillingness of transplantation teams to accept, in an unblinded manner, hearts from circulatory-death donors for the extraordinarily ill patients at status 1 or 2 who were waiting for heart transplants," Sweitzer noted. "This imbalance undoubtedly contributed to the success of the trial in meeting its noninferiority endpoint."

Safety of the approach in the sickest heart failure patients is not clear and will take careful assessment of use patterns and impact as it expands in use, she added.

Selection criteria for circulatory-death donors included Maastricht category III (donation after controlled withdrawal of life support and subsequent cardiac arrest and cardiocirculatory death), ages 18 to 49 years, and no more than 30 minutes of warm ischemia from the time mean systolic arterial blood pressure dropped below 50 mm Hg or peripheral oxygen saturation to less than 70% to aortic cross-clamp and start of cold cardioplegia.

After being flushed with cold crystalloid solution and reanimated with the perfusion machine, donor hearts had to have stable or downward-trending circulating lactate levels, stable perfusion levels, and clinical acceptance for transplantation by the transplanting surgeon or cardiologist. Overall, 89% of hearts were accepted and used.

The brain-death donors didn't have an upper age limit. Both groups had similar criteria for health heart of the donor.

Circulatory-death donors were about 4 years younger, 6 percentage points more likely to be male, and half as likely to be Black compared with brain-death donors; their recipients were also 4 years younger and 9 percentage points more likely to be Black.

Unadjusted 6-month survival was 95% with circulatory-death transplants and 89% with brain-death donor hearts. Kaplan-Meier estimates of 1-year survival were 93% (95% CI 86-97) and 85% (95% CI 76-91), respectively.

"Predictable issues occurred," noted Sweitzer, pointing out that severe graft dysfunction within the first 30 days occurred in 15% of circulatory-death donor heart recipients compared with 5% in the other group. The researchers said that was expected, "given the period of warm ischemia that occurred from the beginning of the agonal phase to the infusion of cold cardioplegia solution."

But Sweitzer added that "such graft dysfunction appeared to be manageable; graft failure and retransplantation occurred in only two recipients, both of whom were in the control group (eligible to receive a heart only after the donor's brain death)."

In addition, protocol deviations in six cases where hearts spent more than 30 minutes in functional warm ischemia or had continuously rising lactate levels did not show any impact on primary graft dysfunction.

"Although caution and continuous evaluation of data are warranted, the increased use of hearts from circulatory-death donors appears to be safe in the hands of experienced transplantation teams and will launch an exciting phase of learning and improvement," Sweitzer concluded.

Schroder and team acknowledged that 5-year follow-up of hearts obtained after circulatory death would clarify the long-term ramifications of the approach.

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