Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. And today, we're discussing the Phase 3 ENHANCE Trial of Novel Contrast Agent for Cardiac Bubble Studies. Joining me is Dr. Akhil Narang. He's an Associate Professor of Cardiology at Northwestern Medicine Bluhm Cardiovascular Institute, and the Director of the Echocardiography Laboratory at Northwestern University.

Dr. Narang, thank you so much for joining us today as we get into this really interesting study. Tell us a little bit about bubble studies themselves and the current indications for use. Where are we seeing these done?

Dr. Akhil Narang: Sure. Absolutely. Thank you for having me. So, bubble studies are a fundamental component of an echocardiography exam in certain situations. And they are performed usually when there's a suspected right to left shunt, for instance, a PFO or an atrial septal defect. But we also use it for evaluation of unexplained hypoxemia, and also stroke or systemic embolism of unclear etiology. So, there are multiple indications in which a provider might order an agitated bubble study or solution study.

Melanie Cole, MS: Well, thank you for that. So before we dive into ENHANCE, briefly walk us through the current standard of care for these cardiac bubble studies using agents like agitated saline, as you were just mentioning. What works well? What are some of the pain points? Why are we doing the study?

Dr. Akhil Narang: Absolutely. So in the current practice, agitated saline or bubble studies are performed by taking an 8 cc syringe or 9 cc syringe filled with saline. One cc is air, and the two syringes are agitated together to be able to produce microbubbles, which are then injected in the vein. And ultrasound is then used to detect opacification of the right side of the heart, and then to determine if there are any bubbles that pass into the left side of the heart.

So, the current process right now utilizes usually two people, a three-way stopcock and a manual agitation process. And as you can imagine, there's a lot of variability in that process. So, how quickly the bubbles are agitated, it requires multiple people. It creates non-uniform bubble sizes. And so, the current process right now relies on separate techniques such as coughing in order to enhance the opacification of the right side of the heart and improve detection of the bubbles into the left side. The problem with what I mentioned is the non-uniformity that we have in the current practice.

And so, the ENHANCE study aims to investigate a new device that will standardize saline contrast for echocardiography. So, this is a prospective trial that uses an attachment to the saline syringe, and it uses a compound called polysorbate 80, which acts like a small surfactant that coats the bubbles and allows for more clear opacification of the right side of the heart, And also uniformity in terms of the bubbles. And it also can be done with a single user as opposed to needing to have two users at the bedside.

Melanie Cole, MS: That's fascinating. That's just so interesting. So, expand a little bit. Give us an overview of ENHANCE itself, and the objectives, and your role as the primary investigator.

Dr. Akhil Narang: So as I mentioned, it's a prospective clinical study evaluating a novel standardized saline contrast tool for echocardiography. And the objective is to improve consistency, reliability, and diagnostic accuracy of saline contrast imaging, particularly for shunt detection and right-sided to left-sided shunts.

So, as the principal investigator for this multicenter trial that expands over five sites in the United States and Canada, my role is to oversee the design, implementation, and clinical integration of the trial while ensuring that the results are meaningful, not just academically, but for real-world echo practice. So, I oversee the extent of the trial across all of the five different sites in addition to oversight of the trial itself.

Melanie Cole, MS: So, how does it aim to improve that diagnostic efficiency? You mentioned, you know, the many people involved and reproducibility, and how can clinicians expect the use of this new contrast agent to streamline those workflows that you were just discussing in the echo lab?

Dr. Akhil Narang: Absolutely. So, saline contrast is widely used right now, but it's highly variable depending on how it's agitated, injected, timed. And so, this variability can lead to suboptimal opacification, inconsistent bubble size and often non-diagnostic studies, which lead to repeat imaging. So, the ENHANCE study attempts to address this with this ready-to-use standardized contrast tool that produces more uniform microbubbles, resulting in a clearer, more reproducible imaging.

So, the goal is to reduce operator dependence on more than one person being at the bedside, improve diagnostic confidence across patient's, also sonographers and repeat the need for repeat injections or testing. So, this potentially could lead to shortened exam time, minimize equivocal results. For clinicians and sonographers, this means less troubleshooting, fewer repeat studies, and potentially faster diagnostic decisions, which can translate to improved lab efficiency and better patient throughput and care.

Melanie Cole, MS: Dr. Narang, who's eligible to enroll? What patients can benefit from ENHANCE? And as the first patient-enrolled moments come with a lot of operational choreography, tell us a little bit about what went into getting the echo lab, cardiology team, and all of the people involved.

Dr. Akhil Narang: So, patients undergoing a clinical echo exam where saline contrast study is clinically indicated, such as for evaluation of intracardiac shunts, or detection of ASDs or PFOs in the setting of unexplained strokes. These are patient's that are involved or could be recruited for the study. This could be in inpatients or outpatients. We're limiting this to adult-only patients, who are also of non-pregnant status as well. And so, these are the patient's that are already coming into the echo lab for a saline contrast study. And from that patient population, we can recruit them into the clinical trial.

Melanie Cole, MS: So, cardiac bubble studies are generally low risk, as you and I discussed a little bit. But any new injectable still has to clear that safety bar. What do we know so far about the safety profile from early phase data?

Dr. Akhil Narang: The product is actually used in Canada at present, and there have been no known contraindications for the use of the device. And so, it's a very safe device to be able to use. As I mentioned, there's polysorbate 80, which is basically a non-ionic surfactant that's commonly used in pharmaceutical preparations. That's part of the tool that we're using for the agitated saline study. It's a larger group of polysorbates, which are well-characterized and have a common structure similar to other things that are already used medically. And so, the safety profile has been very safe at this point in time. The U.S. FDA has really high thresholds after which polysorbate become potentially unsafe. And so, the agent is well under those maximum daily exposure thresholds for the agent.

Melanie Cole, MS: And what are the implications for care at Bluhm Cardiovascular Institute? How does this demonstrate how the team is leading the way in cardiovascular advancements? It's very exciting.

Dr. Akhil Narang: Definitely. So, this trial reflects Bluhm's commitment to innovation that directly improves everyday clinical care. And so, rather than only focusing on novel therapeutics, ENHANCE addresses a fundamental diagnostic tool used in daily echocardiography. And this is part of many clinical trials at Bluhm Cardiovascular Institute that span all disciplines within the cardiovascular space, including many in the echocardiography laboratory.

And I think, furthermore, it demonstrates that our team continuously evaluates advances in imaging and echocardiography to improve quality, efficiency, and also patient experiences while helping shape best practices that could be adapted nationally and beyond.

Melanie Cole, MS: Dr. Narang, as we wrap up, anything else you'd like other physicians to know about this trial? And for clinicians listening today, what's the one thing you want them to understand about why this specific trial matters?

Dr. Akhil Narang: I would say this ENHANCE trial is really rooted in real-world clinical practice and addresses a problem that we encounter all the time in echocardiography with the current state of practice with bubble studies. So if ENHANCE is successful, it could meaningfully change how saline contrast is performed across echo labs around the world, really improving standardization and diagnostic reliability. And I think this exemplifies how thoughtful or pragmatic research led by Bluhm Cardiovascular Institute and many of the teams here can have really an outsized impact on patient care and clinical workflows.

Melanie Cole, MS: Thank you so much, Dr. Narang, for joining us today and sharing your expertise on this trial. And to refer a patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/cardiovascular to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.