Duration of Bridge-to-Transplant Extracorporeal Membrane Oxygenation and Heart Transplant Survival

Background . Te 2018 Organ Procurement and Transplantation Network (OPTN) heart allocation policy change prioritizes patients bridged to transplant with mechanical circulatory support (MCS) devices, including extracorporeal membrane oxygenation (ECMO). As a result


Introduction
In October of 2018, the Organ Procurement and Transplantation Network (OPTN) implemented an updated heart allocation policy with the goal of increasing waitlist stratifcation and improving access to transplant for the most medically urgent candidates.Prior to this policy change, Status 1A received top priority and included stable patients with durable mechanical circulatory support devices for a period of time, encompassing groups with signifcantly heterogeneous waitlist mortality risk [1,2].After the policy change, patients previously assigned to Status 1A were redistributed into Statuses 1-3 within the new, six-tier allocation system.As a result, patients with extracorporeal membrane oxygenation (ECMO) are prioritized by assignment to Status 1 during the frst week following implantation and to Status 3 after seven days of ECMO only if durable mechanical circulatory support is no longer contraindicated and if specifc hemodynamic qualifcations are no longer met [1,2].Early evidence has suggested that the policy change has accomplished several of its intended goals, including improved waitlist patient stratifcation and increased rates of transplantation for medically urgent groups while causing minimal impact to waitlist mortality and posttransplant outcomes [3].Despite some evidence that waitlist duration, waitlist mortality, and rates of transplantation have been improved by the policy change, there remains a lack of consensus as to whether posttransplant mortality is unchanged or increased in the postpolicy change era [3][4][5][6][7][8][9].
In response to the policy change, several groups raised concerns that the prioritization of patients bridged to transplant with ECMO would increase the incidence of this high-acuity intervention, leading to increased transplantation of critically ill patients at the expense of recipient survival [10,11].Several reports have confrmed that the use of mechanical circulatory support, including ECMO, has increased following the policy change [5,7,9,12,13].Tis is concerning for two reasons: ECMO may not only result in adverse vascular events, infection, renal complications, and neurologic impairment during use but also increase the incidence of adverse outcomes following transplant, including prolonged length of stay, sepsis, bleeding, reoperation, and acute renal, hepatic, or respiratory failure [14][15][16][17].A recent review of the OPTN database found that recipients bridged with ECMO survived an average of 16.6 fewer months than non-ECMO bridged counterparts [18].We also raise the concern that increased use of ECMO as a bridge to transplant may eventually result in longer durations of ECMO use in this critically ill subset of patients, further worsening post-transplant outcomes.Te relationship between pre-transplant ECMO duration and post-transplant outcomes has not yet been characterized.We therefore sought to determine whether longer duration of pretransplant ECMO use was associated with increased posttransplant mortality at short-term (one year) and long-term (fve years) follow-up prior to the 2018 policy change.Among patients with longer durations of ECMO, we also compared those who underwent transplant to those who died on the waitlist.Should the duration of pre-transplant ECMO use rise in the postpolicy change era, these fndings will provide insight into the mortality and morbidity risks faced by ECMO-bridged patients on the waitlist and after transplant.If no change to ECMO duration occurs, these data may still inform clinical decision making regarding the use of prolonged ECMO prior to transplant.

Study Population.
Te Organ Procurement and Transplantation Network (OPTN) database was queried for adult (≥18 years) patients undergoing heart transplant after bridge with ECMO between January 1 st 2000 and the OPTN heart allocation policy change on October 18 th 2018.Patients with multiple temporary mechanical circulatory support (tMCS) devices, no tMCS devices, prior transplants, or ECMO duration longer than 180 days were excluded.
Patients were sorted into two groups of approximately equal size to compare the upper 50 th percentile of pretransplant ECMO duration to the lower 50 th percentile, resulting in two groups: <7 days (short duration) and ≥7 days (long duration).Pearson's chi-squared test and Fisher's exact test were used to measure diferences in categorical demographic and clinical characteristics between these two groups.Analysis of variance (ANOVA) was used to assess diferences in variables with normal distributions between the groups, while the Kruskal-Wallis H test was used to assess diferences in continuous variables with nonnormal distributions.

Survival Analysis.
Kaplan-Meier survival functions of short-duration and long-duration ECMO patients were compared at one year, fve years, and ten years using logrank tests.Te risk of mortality associated with shortduration ECMO at each post-transplant time point was calculated using univariate Cox proportional hazards regression.In this and subsequent survival analyses, patients were censored at time of retransplant or loss to follow-up after transplant.Survival time was calculated as the time between transplant and death or censorship event.
Log-rank tests and univariate Cox proportional hazards regression were subsequently used to determine the association between other clinically relevant continuous and categorical variables, respectively, with post-transplant survival at fve years.Variables with p ≤ 0.20 were included in a multivariable Cox proportional hazards regression model.Tree clinically relevant variables with p > 0.20, including organ ischemic time, donor age, and recipient gender, were also included in this model.Ten variables were included in the multivariable model, and the association between pretransplant ECMO duration and post-transplant survival at one year, fve years, and ten years was calculated with adjustment for other variables.Te proportionality of hazards assumption was satisfed in our multivariable Cox model.
Logistic regression was used to assess the incidence of secondary outcomes in each group, including graft failure, acute rejection, treatment for rejection in the frst year after transplant, hospitalization for rejection at any time, posttransplant stroke, or new post-transplant dialysis requirement.Other OPTN adverse outcomes, such as posttransplant coronary artery disease, new pacemaker requirement, or hospitalization for infection, could not be analyzed due to missing data or low incidence.
Finally, the incidence of waitlist outcomes (death or transplantation) was compared between short-duration and long-duration ECMO groups.Among patients with longduration ECMO, we further compared the demographics and clinical characteristics of patients who received transplant vs. those who died on the waitlist.ANOVA and the Kruskal-Wallis H test were used to assess diferences in continuous variables based on normality of distribution, as above.
All statistical analyses were performed using Stata 15/SE 22 with a p value of <0.05 considered statistically signifcant.Institutional review board approval was obtained for analysis of the OPTN database in a prognostic study of survival following heart transplant, with no requirement to obtain informed consent.Our study was compliant with the ISHLT Ethics statement.

Demographics.
A total of 801 adult patients were on ECMO while on the waitlist for heart transplantation between January 1 st 2000 and October 18 th 2018 (Figure 1).Of this number, 362 (45.2%) received a transplant and were eligible for inclusion in this study.Of these 362 patients, 163 (45%) were bridged with <7 days (short-duration group) of ECMO and 199 (55%) were bridged with ≥7 days (longduration group).

Conclusion
In our analysis of patients bridged to heart transplant with ECMO, roughly half of the study population utilized ECMO for <7 days (short duration) and half for ≥7 days (long duration).Long-duration ECMO patients were younger, spent more time on the waitlist and on ECMO, and were more likely to experience periods of waitlist inactivity.Long-duration patients were also more likely to have used dialysis in the past but were otherwise similar with regard to hemodynamic and clinical characteristics.After adjustment for relevant clinical variables in a multivariable model, long-duration ECMO patients had comparable survival to short-duration patients at one year, fve years, and ten years.ECMO duration was similarly not associated with incidence of post-transplant complications such as graft failure, rejection, and stroke.Prolonged duration of ECMO has been associated with increasing risks of morbidity and mortality in nontransplant patient populations, and ECMO duration ≥7 days may now result in a lower priority waitlist status for transplant patients who are eligible for durable mechanical circulatory support and do not meet specifc hemodynamic qualifcations [1,2,[18][19][20].However, it remains unclear whether longer durations of ECMO as a bridge to transplant are also associated with adverse post-transplant outcomes.In our analyses of the OPTN database, we found that patients with ≥7 days of pre-transplant ECMO did not experience increased risk of post-transplant mortality or morbidity compared to their counterparts with <7 days.Despite a nearly 4-fold increase in median waitlist time and ECMO duration, patients in the long-duration ECMO group experienced a trend towards improved survival resulting in >10% improved Kaplan-Meier survival estimate at fve years, but this did not reach statistical signifcance.At frst glance, this similarity might be attributed to more rigorous patient selection: patients with ≥7 days of ECMO were less likely to receive a transplant, but those who did were largely similar to their <7 day counterparts in most demographic, clinical, and hemodynamic respects.However, patients transplanted after ≥7 days of ECMO were more likely to have experienced waitlist inactivity, which may contribute to longer waitlist periods and ECMO duration despite similar clinical characteristics.With adjustment for other clinically suggesting that bridge-to-transplant with ECMO ofers comparable long-term survival and a viable approach for sickest patients requiring heart transplant [18].Within the long-duration ECMO group, we also compared patients who underwent transplant to those who died or were removed from the waitlist.Here, clinical diferences were more substantial: patients who did not undergo transplant had even longer ECMO duration and more frequent waitlist inactivity as well as greater BMI, lower cardiac output, higher pulmonary capillary wedge pressure, and greater frequency of inotrope use at listing.Tese differences likely represent both a diference in clinical condition at listing and progressive decompensation with prolonged ECMO use.Tese observations likely suggest that while duration of ECMO support lends itself to increasing morbidity, those who are spared from complications on ECMO may experience similar or short-and long-term outcomes after transplant.Further study is needed to validate this concept.
Our study was subject to several limitations, including those associated with any retrospective analysis of a large, national database.One such limitation was the inability to confrm whether very long durations of ECMO (e.g., >180 days) were the result of outlier clinical courses or inaccurate device implant/explant dates.As a result, we excluded four ECMO-bridged transplant patients with the rationale that, even if the reported device duration was accurate, outcomes for these patients would not accurately represent those of a group whose median ECMO use was 14 days.It is further limited by missing data, in particular for the variables of cardiac output and pulmonary capillary wedge pressure, where data were missing for 30-34% of the cohort.A related limitation is that the OPTN does not always specify how data are collected.For example, it is not specifed how cardiac output, specifcally, is measured for each patient.Next, our study focused on post-transplant outcomes up to fve years and so did not include patients transplanted after the 2018 policy change.However, ECMObridged patients following the policy change are similar to or clinically healthier than their prepolicy change counterparts, suggesting that survival among the patients bridged to transplant with ≥7 days of ECMO may be similarly independent of ECMO duration [21,22].In addition, although ECMO duration ≥7 days was not associated with posttransplant mortality among patients who were transplanted, this analysis only included patients who were not removed from the waitlist due to illness or death and thus does not represent potential outcomes of any patient with longer duration of ECMO use.Finally, it should be noted that fveyear mortality described in this study was worse than expected based on OPTN reports for 2019 [23].We expect that this diference is due, in part, to improving outcomes over the course of our 2001-2018 study period and worse outcomes for ECMO-bridged patients in general related to critical illness requiring this high-acuity intervention.
Increased utilization of ECMO in the post-policy change era raises two major concerns.First, that ECMO will be inappropriately used as mechanical circulatory support to increase the likelihood of organ allocation.Although some studies show improving clinical characteristics among patients bridged to transplant after the policy change, suggesting possible use of this high-acuity intervention in a new population, waitlist mortality and survival to transplant have both improved for these patients, reducing concerns that it might be used unnecessarily [21,22].Te second concern is more complex: patients bridged with ECMO have experienced improved waitlist and post-transplant outcomes since the 2018 policy change.It has been suggested that this is the result of shorter waiting times and fewer ECMO-related complications [4,21,22].Increased use of ECMO and an expanding population of Status 1 patients may undermine this novel waitlist mobility, producing a higher number of patients at risk for ECMO-related complications without relief by rapid organ allocation and transplant.Our study provides reassurance that patients bridged to transplant with ECMO, although at increasing risk for adverse outcomes while receiving mechanical circulatory support, do not experience increased mortality or morbidity in the short-or long-term periods following transplant.Prolonged ECMO use among waitlisted patients without clinical deterioration should not raise concerns for worsening post-transplant outcomes in the post-policy change era.

Figure 2 :
Figure 2: Kaplan-Meier survival curves of patient survival following heart transplant bridged with <7 days (solid line) or ≥7 days (dashed line) of ECMO.Morbidity outcomes are comparable at fve years (p � 0.27) and at ten years (p � 0.30, not shown).ECMO, extracorporeal membrane oxygenation.

Table 1 :
Demographic, clinical, hemodynamic, and organ donor characteristics for patients bridged to heart transplant with ECMO, by duration of recipient pre-transplant use.

Table 3 :
Multivariable Cox proportional hazards model for fve-year mortality following transplant.

Table 2 :
Kaplan-Meier survival estimates at one year, fve years, and ten years for patients receiving <7 or ≥7 days of pre-transplant ECMO.

Table 4 :
Comparison of patients with ≥7 days of ECMO who either underwent transplant or did not, either due to death or removal from the waitlist.