Temporary mechanical circulatory support (tMCS) enables clinicians to stabilize cardiogenic shock patients until HTx (1, 2). Since the 2018 heart allocation update, tMCS utilization has tripled (3). Intra-aortic balloon pump (IABP) or Impella (5.0 and, more recently, 5.5 versions) is used in approximately half of heart transplantation patients. These devices significantly differ in hemodynamic effects, vascular access, and complication risk profile. The majority of IABP and Impella evidence comes from the population of acute coronary syndrome or peri-cardiac intervention use. Identifying the suitable device for the right patient at the right time to achieve optimal pre and post-HTx outcomes remains a formidable task and a knowledge gap (4).

In the current healthcare landscape, precision medicine is gaining momentum, and machine learning (ML) is proving to be a valuable resource for clinicians to understand intricate relationships between hemodynamics demographics, tMCS, and medical history and the dynamics of HTx listing practices. Previous studies have investigated the application of ML on United Network for Organ Sharing (UNOS) data for predicting post-heart transplant mortality (5–7) and survival on waiting lists (8). However, the reported model performances ranged from an AUC of 0.5–0.7, indicating the challenges associated with the complex nature of the data and patient characteristics highlighted by the heterogeneous clinical phenotypes, high acuity, and rapidly developing tMCS.

It is worth noting that many of the ML models were developed using data from before the 2018 heart allocation update was implemented and at a time when mechanical circulatory support was rarely used and linked to unfavorable outcomes. This study aims to employ explainable ML methods to rank and weigh the clinical factors determining the failure of status two listings. Developing and optimizing such models is vital for the upcoming continuous distribution heart transplant system to be adaptable to demographic and practice changes, unlike its predecessors (9).

In our study, we analyzed data from 4,178 patients listed as Status 2. Among them, 12% experienced primary outcomes indicating Status 2 failure. Impella 5.0 or 5.5 was used in 15.6% (650 patients) of the cohort, while the remainder were supported with IABP. Table 1 compares demographic, clinical, and biochemical characteristics between the failure group (N = 504) and the non-failure group (N = 3,674). Several variables such as age, BMI, height, race, blood group (A, B, AB, or O), device type used (IABP vs. Impella), sodium, vasoactive medications, and UNOS region (11 regions) show statistically significant differences between the two groups. Notably, the failure group was slightly younger and had higher BMI, had lower creatinine, albumin, sodium, and INR, and had a different distribution of blood groups and vasoactive medications used.

The ML model's performance in predicting the primary outcome (status 2 failure) across various UNOS regions is outlined in Table 2. The area under the curve (AUC) of the comprehensive model was 0.71 (±0.03) for all regions, with a range between 0.44 (±0.08) and 0.74 (±0.01). The models' specificity (survival on Status 2) ranged between (0.75–0.96). The accuracy varies by region, with the highest accuracy of 0.90 being achieved in Region 5 and the lowest accuracy of 0.69 being observed in Region 4. The table also shows the balanced accuracy, a more nuanced measure when classes are imbalanced. The balanced accuracy scores were generally lower across all regions, with an overall value of 0.65. The AUC suggests moderate predictive power at 0.71 overall, but this metric also shows regional variations. The sensitivity scores were notably low across all regions. On the other hand, specificity scores were consistently high, indicating good performance in identifying true negatives (success on Status 2).

The SHAP ranking, illustrated in Figure 1, shows the top 15 most essential features in predicting Status 2 failure. We found that the lead outcome determinants were sodium (region 1), the number of inotropes (region 2, overall), PAPi (region 3), BMI (region 4, 5, 10), international normalized ratio (INR) (region 7, 8), on antiarrhythmics (region 9), height (region 11). The number of inotropes, creatinine, sodium, BMI, and blood group were the top five most important predictors in the overall model. The number of inotropes has the highest impact on predicting status 2 failure; higher numbers increase the likelihood of status 2 failure. Similarly, elevated creatinine levels increase the risk of status 2 failure. Sodium, BMI, Blood Group, INR, Region, Height, and Albumin seem to have a neutral impact on predicting the outcome. The concentration of heart resting points suggests that higher values could be associated with increased risk in some patients. PAPi, race, PCWP, and age are centered around zero SHAP value, indicating a lower influence on predicting the outcome. The device ranked 15th among all included variables (out of 19), indicating lower importance. Figure 2 shows the heatmap summarizing the rank of features across models trained for different UNOS regions. Finally, Supplementary Table S2 shows the device utilization ratio (# IABP: # Impella) and the ratio between the number of patients successfully bridging to transplant and those who failed across regions.

In this study, we aimed to use explainable ML methods to develop and validate a data-driven model that predicts the failure of status 2 listing and ranks the clinical features that have the most impact on the primary outcome. The latter function is vital as it provides patients and care teams with actionable targets to address so they can improve the outcomes of tMCS or specific reasons to consider an alternative BTT strategy. Our results show that the specificity of the ML models was consistently high, indicating good performance in identifying true negatives (success on Status 2). There is, however, significant regional variability in feature ranking, which indicates that such ML methods need to be tuned to accommodate not only the patient and the machine but also the HTx practice context. While the models seem adept at identifying BTT failure (high specificity), it has limited ability to confidently assure that those predicted to do well until transplantation will indeed remain stable (low sensitivity). Despite this shortcoming, the current ML model proves clinically helpful in highlighting patients at risk so that intensified monitoring, optimization, and care escalation can be selectively lamented.

The most predictive features vary across regions, and notable patterns emerge. The number of inotropes consistently appeared important in predicting status 2 failure in most regions. A higher number indicates greater disease severity and contributes positively to the risk of status 2 failure. Elevated serum creatinine and International Normalized Ratio (INR) indicate that poor kidney and liver function reserves are also major outcome determinants. BMI also appeared in many regions, suggesting the role of both obesity and malnutrition as influencing factors. Further investigation is needed to understand whether weight affects BTT outcomes due to intrinsic patient factors or by affecting waitlist time. The role of race is highlighted in many areas, which suggests the potential for racial disparities in healthcare utilization. Finally, the significance of age and blood group were not uniform between regions, indicating that these factors can be mitigated by optimizing practice patterns.

Contrary to expectations, the type of tMCS device (IABP vs. Impella) was less significant than patient-related factors in predicting Status 2 failure. However, it shows that using Impella can increase the risk of failure to bridge to transplantation, which is consistent with the current stream of evidence that IABP-supported patients fare better than most other status 2 listed patients (14, 15). Impella provides robust circulatory support for the left ventricle, with maximal blood flow over 5 L/min. However, this benefit is often reduced by some degree of aortic regurgitation and decreased LV preload (16). On the other hand, the IABP requires smaller vascular access (8 Fr vs. 23 Fr) and has a variable hemodynamic response that depends on vascular stiffness, body size, and the ability of the left ventricle to augment function in response to afterload reduction [8]. In reality, most status 2 patients require partial left ventricular unloading, and the transplant community continues to lack any pragmatic prospective study in comparing IABP vs. Impella, specifically as BTT. The available data from post-acute coronary syndrome state is not translatable to a population with a high prevalence of acute on chronic systolic failure that are likely to utilize the device for weeks rather than hours or days.

A few studies have explored the potential of ML for predicting post-heart transplant mortality (5–7) and survival on waiting lists (8) using UNOS data. These models, with AUC values ranging from 0.5 to 0.7, highlight the complexities associated with the data and the diversity of patient demographics. Notably, a significant portion of these models was based on data that predates the 2018 heart allocation update. Additionally, during that time, mechanical circulatory support was still in its early stages and often resulted in suboptimal outcomes. Our study addressed this knowledge gap by using explainable ML methods and focusing on contemporary data, especially after the 2018 heart allocation update, to create a more refined predictive model. Our work aimed to overcome the limitations of previous models and provided a better understanding of the factors that influence transplant outcomes in today's medical landscape. A direction to include explainable ML models in a continuously learning national transplant system will allow continued data feed for model training and lead to optimized performance that matches the current state of the HTx practice environment.

This innovative approach naturally comes with several limitations that any adopter of these results must understand. First, the model is trained on a dataset with high missing rate that has inherent variability in reporting. Second, the model does not reflect variation between different health systems within each region. Third, the performance parameters were derived using 5-fold cross validation from the same dataset, which is less ideal than external validation. However, external validation was not possible and is not necessarily relevant because the model is fitted explicitly to a region and practice era. Ideally, resting this model will require prospective testing of a locally optimized version of the ML model to guide decisions and prove its effect on outcomes.

ML XGboost model can identify UNOS status 2 patients at high risk of deterioration while on tMCS with high specificity and limited sensitivity. This is an innovative approach to selecting the right tMCS for the right patient, identifying targets for intensified patient monitoring and optimization guided by the model's feature selection and developing an adaptive and continuously learning heart transplant system.