DEFINE-HT Clinical Trial Shows Prospera™ Heart Accurately Predicts Outcomes and Outperforms Biopsy in Heart Transplant Surveillance
Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA (cfDNA) and genetic testing, has announced the results of its landmark DEFINE-HT clinical trial, offering compelling evidence that its Prospera™ Heart test with DNA Quality Score (DQS) provides a more accurate and less invasive method for predicting adverse outcomes in heart transplant recipients. The findings were presented in an oral session today at the International Society for Heart and Lung Transplantation (ISHLT) 45th Annual Meeting, held in Boston, Massachusetts.
The DEFINE-HT (Donor-derived cfDNA Evaluation to INform Outcomes after Heart Transplantation) study represents the first large-scale, prospective, multicenter investigation aimed at determining whether elevated levels of donor-derived cell-free DNA (dd-cfDNA)—as measured by Prospera Heart with DQS—are predictive of clinical events following heart transplantation. By comparing these molecular biomarkers with the traditional method of endomyocardial biopsies (EMB), the study offers a transformative view on how clinicians may manage post-transplant surveillance in the near future.
A Paradigm Shift in Heart Transplant Monitoring
Heart transplantation remains a life-saving procedure for patients with end-stage heart failure, but the risk of graft rejection and dysfunction persists even after successful surgery. Traditionally, surveillance for transplant rejection has relied heavily on EMB—a procedure that involves inserting a catheter through a vein into the heart to extract small samples of tissue from the endocardium for histological analysis. While EMB has long been the standard of care, it is invasive, resource-intensive, and prone to sampling errors and inter-observer variability.
The emergence of non-invasive biomarkers like dd-cfDNA presents an opportunity to revolutionize this monitoring paradigm. Donor-derived cfDNA, which refers to small fragments of DNA released from the transplanted organ into the recipient’s bloodstream, offers a sensitive and real-time measure of allograft injury. By leveraging Natera’s advanced Prospera technology, the DEFINE-HT study was able to evaluate the clinical validity and utility of this biomarker in a diverse population of heart transplant recipients.
Study Design and Patient Cohort
DEFINE-HT enrolled participants from multiple transplant centers across the United States, ensuring a robust and diverse sample reflective of real-world clinical practice. The study followed patients for up to one year after heart transplantation, performing regular Prospera dd-cfDNA assessments alongside standard EMB-based rejection monitoring. More than 1,100 dd-cfDNA samples were collected during this period, providing a comprehensive dataset for analysis.
The study’s primary endpoint was a composite measure of clinical events, including treated acute rejection, graft dysfunction, re-transplantation, and death within the first year post-transplant. By correlating dd-cfDNA levels with these outcomes, researchers aimed to assess the predictive value of the Prospera Heart test and determine whether it could serve as a reliable alternative or complement to EMB.
Key Findings Highlight Predictive Power of dd-cfDNA
The results of DEFINE-HT were compelling and statistically significant. Patients who experienced at least one elevated dd-cfDNA reading during the first year were found to be at substantially higher risk for adverse outcomes compared to those with consistently low dd-cfDNA levels.
- Elevated dd-cfDNA measurements were associated with a 2.56-fold increase in the risk of experiencing a major adverse event (Hazard Ratio: 2.56; p=0.0299). This means that a single elevated reading could act as an early warning signal for clinicians, potentially enabling timely intervention.
- Prospera outperformed biopsy in predicting graft dysfunction, showing a threefold improvement in predictive accuracy. This finding has far-reaching implications, as graft dysfunction is one of the most critical threats to transplant success, often leading to re-hospitalization, reduced quality of life, or the need for re-transplantation.
- Prospera with DQS provided a stronger correlation to clinical outcomes than donor fraction alone, suggesting that the integrated DNA Quality Score enhances the accuracy and reliability of the test.
These insights suggest that not only can Prospera serve as a predictive tool, but it may also reduce the reliance on EMB, offering a safer and more patient-friendly alternative for transplant monitoring.
Expert Perspectives on Clinical Utility
Dr. Palak Shah, M.D., M.S., the national principal investigator for the DEFINE-HT study, emphasized the clinical importance of these findings during her presentation at ISHLT. Dr. Shah is the director of the Inova Cardiovascular Genomics Center and medical director of mechanical circulatory support at Inova Fairfax Medical Campus.
“The results of DEFINE-HT show that dd-cfDNA can predict clinical outcomes after heart transplantation, which can allow for improved and personalized patient management based on individual risk,” Dr. Shah stated. “Through vigorous research, we continue to drive innovative advancements in heart transplantation, finding less invasive approaches that lead to better patient outcomes.”
Echoing her sentiments, Dr. Michael Olympios, M.D., medical director of heart transplant at Natera, noted the broader implications of this research for clinical practice and patient care.
“In combination with a better understanding of the association of dd-cfDNA and clinical outcomes, DEFINE-HT underscores the utility of Prospera as a tool to help identify patients who may be at risk for adverse outcomes,” said Dr. Olympios. “Importantly, the insights gained from this study suggest that Prospera has the potential to obviate invasive surveillance EMB.”
Future Directions: From Discovery to Implementation
The promise shown by Prospera in the DEFINE-HT trial has set the stage for further research. Natera is now initiating a multi-center, randomized, comparative effectiveness study—ACES-EMB—that will directly compare outcomes from dd-cfDNA surveillance to those from traditional EMB. The goal is to definitively determine whether EMB can be safely replaced or supplemented by molecular diagnostics in routine post-transplant care.
If successful, such a shift could alleviate the burden on both patients and healthcare systems by reducing the frequency of biopsies, lowering complication risks, and improving quality of life for transplant recipients. Additionally, earlier detection of rejection or dysfunction using dd-cfDNA may lead to more proactive clinical decisions, potentially extending the longevity of transplanted hearts.
Prospera™ Heart is part of Natera’s Prospera transplant assessment product line, which includes tests tailored for kidney, lung, and heart transplant recipients. The test uses Natera’s proprietary single-nucleotide polymorphism (SNP)-based cfDNA assay to precisely measure the fraction of donor-derived DNA in the recipient’s blood. With the addition of the DNA Quality Score (DQS), Prospera Heart further improves specificity and interpretability.
Natera is a pioneer in cfDNA technology, with a broad portfolio spanning oncology, women’s health, and organ health. The company’s mission is to transform the management of disease through early detection and personalized monitoring, with products that have been clinically validated across multiple large-scale trials.
The DEFINE-HT study represents a milestone in the field of heart transplantation, providing robust evidence that donor-derived cfDNA—measured non-invasively using Natera’s Prospera Heart test—is predictive of serious clinical outcomes. By outperforming EMB in identifying patients at risk for graft dysfunction and other complications, Prospera is poised to redefine how post-transplant surveillance is conducted. As the medical community continues to embrace precision medicine, tools like Prospera may soon become the new standard in ensuring long-term transplant success.
