Lisa Mielniczuk, MD - phaware® interview 501

Dr. Lisa Mielniczuk, a cardiologist at the Mayo Clinic in Rochester, shares her personal journey of becoming interested in pulmonary hypertension and the challenges faced by patients in accessing care. Dr. Mielniczuk emphasizes the importance of building connections with patients and involving them in decision-making. She discusses the CRAVE study, which aims to test novel and repurposed therapies for right heart failure using a platform trial design. She highlights the importance of patient involvement in the trial design and its upcoming feasibility study.

My name is Lisa Mielniczuk. I am a cardiologist and Sr. Associate Consultant at the Mayo Clinic in Rochester, formerly from the University of Ottawa Heart Institute in Ottawa, Canada for many years. I am a specialist in what's called advanced heart disease. So, my area of interest and specialty is looking after patients with very serious and complex heart disease. That includes things like heart failure. I look after patients who have or have had or need a heart transplant, as well as patients who require mechanical circulatory support or heart pumps to help to keep them well. I would say quite honestly that one of my biggest interests and passions in my career thus far has been being involved in the pulmonary hypertension community and looking after patients with pulmonary hypertension.

I'm really excited to talk to you a little bit more about some of the research that is launching here in Canada to help to improve the outcomes of our patients with pulmonary hypertension and right heart failure. 

Before I do that, though, maybe I'll tell you a little bit about myself in terms of why I got interested in the field of pulmonary hypertension. That was many, many years ago when I first started my clinical practice, I was on staff probably about a year or less, and I was working in the intensive care unit. We had admitted a patient with heart failure and she was a very young girl. She was only 19 years old, very nervous, appropriately so.  It was quite obvious to all of us that she was very sick.

Now, initial echocardiogram or ultrasound of her heart showed that she had significant right heart failure and she had severe pulmonary hypertension. She was very unwell and a very high-risk patient. Immediately, all of us as a team rallied and wanted to do everything we could to help her in this journey of diagnosis and management. In fact, actually very quickly, it became apparent that this wasn't the first step in her diagnosis. In fact, she had had symptoms for many, many months before she came into the intensive care unit. Like many patients with pulmonary hypertension, her symptoms were attributed to other things, other things that might be more common in a woman with shortness of breath. That, like for many of our patients, led to a delay in her diagnosis. So, by the time she had her diagnosis, unfortunately, she was very ill. That was an important realization for us that we needed to do better.

Then, there was a second realization that happened in the care of this patient. That was that, at that time, many years ago, in the infrastructure in Ottawa, we did not have a Pulmonary Hypertension Clinic. In fact, we didn't have a PH program at all. So, all of our patients that were diagnosed or needed treatment for pulmonary hypertension had to either go to Montreal, which is about two hours away, or to Toronto, which is about four and a half hours away. We ended up transferring the patient to the excellent care of the Toronto program, and she did very well. But can you imagine being told that you have a very serious disease and then being told that you now have to be transferred away from your family, away from your home, to an external institution to receive care and treatment? It was right then that I knew that, in Ottawa we needed to do better. We needed to do better for our patients and our community. 

So, along with some incredible collaboration with a colleague of mine from the pulmonology side and some excellent collaboration with nursing support from the Heart Institute and even support from industry partners, within a year, we were able to start a PH Clinic here in Ottawa. Our little program grew. I'm really happy to say that now we are certainly one of the larger programs in the country and really actively involved in research, support, and education. We've really been fortunate to make a huge difference to the care and the quality of our patients with pulmonary hypertension. That's a little aside, but it tells you a little bit about our story, and why I'm here, and why I think being here is so important. 

One of the things that I think is just as important as the medical therapy of pulmonary hypertension is the connection that we build with our patients. Myself and my colleagues have been really lucky to work very closely with incredible patient partners and organizations to unite our community. I've been working with Pulmonary Hypertension Association of Canada for many years now, previously as vice chair. I can tell you quite honestly that it is probably the most fun part of my work. In everything we do, we realize how important it is that we have our patients and our caregivers first and foremost with all the decisions we make. 

With that as kind of an introduction, I'd like to tell you a little bit about some of the research that we do. Now, my area of research interest for many years now has been in the field of right heart failure. Now, if you haven't heard of that before, and I tell my patients all the time, "Heart failure sounds like a terrible thing, right. My heart is failing," and we need to come up with a better term for that. But essentially, what that means is almost you can think of it as a supply-demand mismatch between what your heart is able to give in terms of cardiac output and blood flow through your body and what your body needs to feel well to do the things that we love to do, whether it's exercise or even walking, talking sometimes just eating and feeling comfortable at rest. Whenever there's an imbalance there where the heart is unable to provide the needs of our body with what we need to feel well, we develop the symptoms of heart failure. Those symptoms can include things like shortness of breath, fatigue, chest discomfort, fluid retention, exercise intolerance. Unfortunately, many of our patients that live with pulmonary hypertension are at risk of developing right heart failure.

Now, why is right heart failure so important? It's very important for a number of reasons, but I'm going to share with you probably two that have really inspired me to do the research that I'm doing. The first is that right heart failure is one of the most important predictors of what we call prognosis. How we determine how we need to worry about a patient in the short or long term? We know that if patients develop symptoms of right heart failure, that they're going to struggle a lot more. So, it's a very, very important thing to identify. 

The other thing that's known about right heart failure is it's not so much the severity of the pulmonary hypertension or how high the blood pressure is in your lungs that determines whether or not you get right heart failure. It's a much more complicated algorithm. In fact, we don't even know all the pieces of what makes somebody predisposed to right heart failure and what makes somebody relatively spared from right heart failure. But those are some of the things that in my research I've been trying to answer over the last few years. 

The second thing that I want to share about right heart failure is that unlike left heart failure, which is a very common type of heart failure that I also look after in other clinics, in other areas of my job, the treatments for right heart failure are very, very limited. In fact, we have great medications that work really, really well on failure of the left heart to improve quality of life, improve survival, and actually sometimes even improve pumping function of the heart. Yet, those same medications, when applied to the right side of the heart, are either shown to be not effective or, in some cases, dangerous. So, there's a lot of uncertainty about how we identify right heart failure, how we predict right heart failure, and importantly, how we treat right heart failure.

This is where we are focusing on our energy. My colleague, Dr. Jason Weatherald, and I have been talking about this for quite a few years now, because we want to develop a research line of focus that can help us to move forward faster and more efficiently, potential treatments for right heart failure. One of the things that we think is very, very important when we're talking about clinical research is when we used to do clinical research many, many years ago, it was really thought about from the level of the healthcare professional. The study was designed by the healthcare professional. We enrolled patients who participated in the clinical study, and then we analyzed the results and came up with conclusions. We hoped that the patients would agree with our conclusions, but they historically weren't given a lot of information or attention into how those results may impact them.

I can say very gladly that the landscape for this has changed quite dramatically. We now understand that for medication to be successful, for patients to take medications and feel good about medications and be engaged in the whole interaction of their clinic encounter with their healthcare team, they have to be at the table. Not only do they have to be at the table, but they are the most important part of the conversation. So, one of the things that we're trying to do with our CRAVE study is engage our community partners, our patient partners, our people with lived experience, and their caregivers at every step of a clinical trial design. What that means is we want to know what matters to our patients. What clinical endpoints in a clinical trial are relevant to them? What type of clinical study would they feel comfortable participating in? What type of clinical study would they feel very uncomfortable with? What sort of result would be meaningful to them, so meaningful that they might actually feel very good about taking a particular therapy, or what sort of result would be not consistent what they think is in their best interest? So, with CRAVE intertwined into the design of our project is going to be partnership, and we've been so grateful to have excellent partnership through PHA Canada to really engage our patients at every step of the trial design. 

The last thing I'd like to say is just to tell you a little bit about the trial design. As you might imagine, from everything I've been saying, CRAVE is designed to look at novel or potentially repurpose therapies for right heart failure. By repurposed, I mean treatments that have been shown to be effective in one clinical condition to see whether or not they're effective in patients with chronic right heart failure. One of the things that we've also struggled with in the land of pulmonary hypertension and right heart failure research is it's very hard to do large clinical trials, because we know that there are not hundreds and hundreds and hundreds of thousands of patients with pulmonary arterial hypertension. 

Oftentimes, clinical trials are smaller as a result, and their endpoints or their results may be limited because you may not have enough power in the study to find a meaningful result. One way around that is a novel statistical design called a Platform Trial. That's what we are trying to build with CRAVE, whereby not only are we testing one treatment at a time, but we may, in fact, be testing multiple treatments at a time in different scenarios and over different arms. By following things very closely, we might be able to identify, early on, a clear winner of these early studies, a drug that shows a lot of promise, and we can shift the design and the nature of the study to preferentially enroll patients in a treatment that might be showing good promise.

Alternatively, in a treatment that may not be showing very good promise, we can stop studying that treatment earlier on and shift our focus without having to end a study and start over again and, therefore, lose time. We had meetings in Edmonton, Alberta, recently of a number of engaged stakeholders and community partners to sit down for a day and a half and really just talk about what would this CRAVE trial look like. What sorts of things are important to us, what therapies might be good candidates to trial, and how might we launch this as we go forward? I'm really excited about the next steps. We are in the process of launching what we call a Feasibility Study, which is sort of a mini-scale version of what we anticipate the larger trial may be, and we're very, very excited about launching this in Canada in 2024.

But we're also really hopeful that we'll be able to partner with some excellent colleagues and friends in the United States and potentially consider this a North American initiative, because we do feel that it is so important. We are really excited about this new day of clinical trial research, where research is not just on the patients, but the patients and the caregivers, and everyone are working collaboratively together, all at the same table all at the same time. 

My name is Lisa Mielniczuk, and I am aware that my patients are rare.

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