“When we do something novel, we have to subject the patient to risk related to our inexperience”

Emilia Chiscop-Head, PhD, Scientific Integrity Associate, ASIST


Read an interview with Dr. Carmelo Milano, Duke heart transplant surgeon who successfully implanted first artificial heart ever in the US

Carmelo Alessio Milano, MD is a heart surgeon and heart transplant surgeon at Duke University where he is also Chief of the Section of Adult Cardiac Surgery, Surgical Director for LVAD Program and Professor of Surgery. As a researcher, Dr. Milano is leading the Cardiothoracic Surgery Translational Research Laboratory. His internationally recognized heart research and clinical practice at Duke reached recent an outstanding accomplishment which makes history: Dr. Milano successfully implanted an artificial heart, the first in the United States, as part of a clinical trial where he is also the principal investigator.


ECH: Dr. Milano, we were honored to have you in our recent integrity roundtable “Reproducibility of research”, shortly after your most recent accomplishment – the successful first artificial heart implant in the United States, as part of a clinical trial conducted for approving this product by Food and Drug Administration (FDA). What are the main ethical issues that you have encountered or may encounter during this revolutionary human subject research?

Carmelo Milano: We were asked by the sponsor to be involved in the clinical trial because Duke is a leading Center internationally in terms of advanced heart failure treatments, innovation with regards to heart transplantation and mechanical circulatory support. Given our involvement in those areas, the sponsor approached us to participate in this trial, and we were able to go through the training and get to be the first site to plant the device. One important ethical challenge is maintaining the balance between gaining patient's confidence, remaining optimistic with the patient and with their family on one side, while still being honest that you're doing something to them that is very invasive and that has not been done before on the other side. Total artificial technology will be important and will save lives, but on the other hand, it's very invasive. And, as we are at the beginning and don't have any kind of previous experience there is high risk which is hard to quantify and understand. We want to emphasize the positives and we want to maintain the trust of the patient and their family, but we also want to be honest. The patient has to understand that this is something new, something that we don't have a great deal of experience with and that, unfortunately, can go along with adverse outcomes. This is a key ethical issue and a practical issue as well.

“There needs to be 10 cases to be completed before the product will be reviewed with the FDA”

ECH: Yes, especially given that you are in this trial as clinician, while you are also a researcher...

CM: First of all there is an institutional involvement, as there are many different parties involved. But we must say that we were not involved in the development of the device. We also provide oversight at other sites, in order to determine whether other potential candidates could be enrolled.

ECH: How many patients are needed for approval?

CM: There needs to be 10 cases to be completed before the product will be reviewed with the FDA. So, it's really a very early feasibility trial, results of which will be discussed with the FDA for the expansion of the trial. In Europe and Eastern Asia the device was implanted in ten patients.

ECH: And how many patients are surviving?

CM: The endpoint is really six months of survival or survival until a biological heart was transplanted. And the majority of these cases have reach this expected outcome.

“I was fortunate enough to match to a residency in Surgery at Duke”

ECH: How did you get were you are today in your career and what were the top factors of your success?

CM: I was fortunate enough to match to a residency in Surgery at Duke. This was probably the most important factor regarding my career success because I encountered a number of very bright people that were really devoted to clinical investigation. During my training I had the opportunity of being exposed and work with great investigators. It was a great chance to work with Nobel Laureate Robert Lefkowitz. Whatever success I have is a result of those experiences.

ECH: So it is all about research mentoring…

CM: Very much so.

ECH: When do you think that the artificial heart will be available in the United States?

CM: Well, this is truly research and when we do research we don't know the outcome. Technically it's very difficult to predict that. Something functioning as somebody's heart has to be durable and reliable. Compatibility with blood is critical, because if clots form on the device this can result in serious injury to the patient. So, the compatibility, durability and reliability of the device will be determined by the clinical trial. The FDA approval will be dependent on demonstrating safety in these areas. If we do 10 cases and the patients don't have any kind of issues with those factors, then I think it's possible that we could get an early approval.

“There may be another 4000 patients who could benefit from a total artificial heart technology”

ECH: How many patients could benefit from this product and how accessible this would be to those in need?

CM: Currently we have pumps that replace just the left portion of the heart. There are about 4000 patients treated each year with these types of pumps. Many other patients are turned down because they also have limitations.  Some patients who received the pump still have heart failure related to the right portion of their heart or have abnormal heart rhythms, such as ventricular tachycardia, which makes the success of left sided only support much less successful. There may be another 4000 patients who could benefit from a total artificial heart technology provided it had a very good safety and efficacy profile.

ECH: What is the life expectancy from the moment of the heart transplant?

CM: Conventionally, these different types of pumps, including the total artificial heart have been used as a bridge until patients can receive a biological heart transplant. But the hope is that, as the reliability and durability of these products improve, the device could be used as a primary treatment. For the current trial of the CARMAT device we're only looking at patients who are transplant eligible. But the hope is that, because transplant is so limited, these devices could be used not only as a bridge, but as a permanent destination therapy.

“I think the only way to make the product cost effective is to really enhance the durability”

ECH: How the conflict between need and cost can be balanced?

CM: If FDA approved the artificial heart, it would be funded by third party partners, like federal government insurance or private insurance. The cost of the device alone would be over $100,000. This expense really offsets the cost of developing the product, all the preclinical testing, the clinical testing, and the regulatory process. I think the only way to make the product cost effective is to really enhance the durability. If a patient could live for 5 or 10 years after the implant, I think it would be cost effective.

ECH: You wrote many scientific articles on left ventricular assist devices (LVAD),   coronary artery bypass graft (CABG) and Heart Mate II (which is a high speed, electric blood pump) in prestigious journals. What has been the most impactful research that you conducted so far?

CM: When I started in this this field 20 years ago the left ventricular assist devices were purely limited short term bridge support strategies. But because of improvements in the technology we now have advanced heart failure patients who have lived more than 10 or 12 years with such devices. And they've lived reasonable quality of life years. The average survival now is five or six years, so I think my participation in the evolution of the LVAD technology is probably the most impactful thing I've done. And, of course that represents an engineering advancement, a design advancement, but also an advancement in terms of clinical trials.

ECH: What do you think was your most difficult ethical challenge that you faced during these 20 years?

CM: I may go back to the initial remark I made. We constantly want to evolve in terms of our surgical treatments. But, in doing so, we have to do things we haven't done before. We have to use novel devices and perform novel surgeries with which we do not have experience because we have never done them before. For some operations a surgeon will have done them 1000 times before, and there's a great deal of comfort and safety with that experience. But when we're truly trying to do something novel, we have to subject the patient to risk related to our inexperience. An important challenge is conveying that to a patient while trying to advance the field, while still being safe and honest with our patients and their families. This is the biggest ethical challenge that I have been facing.

ECH: I read patients reviews and I know that your patients value your compassion and your honest communication. Communication is key in medicine and science. Do you have any advice for young scientists and medical doctors on how to build these important skills?

CM: My advice would be to put themselves in the position or in the mindset of the patient as much as possible and as frequently as possible.  To think about what it must be like to be the patient. As we grow older and have health problems ourselves, we unfortunately get to experience that firsthand, but when you're young, you may not have the personal experience with severe illness. I think as doctors, we have to constantly think about the situation from the perspective of the patient. To understand the incredible anxiety and fear that one must experience, having to undergo these enormous operations or deal with these incredible health problems. When we start thinking from that perspective, then we are more effective.

“As teachers we have to be supportive, even during hard times, when our students are failing”

ECH: What is your mentoring style and philosophy in the lab and clinic?

CM: I try to find a balance between trying to keep the patient safe, but provide an opportunity for young trainees to have autonomy and enough guidance to gain experience and confidence. If I take you by the hand and lead you, you will never gain as much as if you're forced to find your way on your own.

ECH: These are key skills and key components of mentoring for sure. Have you had a situation in your career, where a mentoring relationship didn't work out? I would be curious to know how you solved it?

CM: I have dealt with students or trainees, who have made profound mistakes, who have really done some things that were difficult to excuse or difficult to be supportive of.  But I've also seen very, very successful researchers and clinicians after they learned from those mistakes. This motivates me to be supportive and even more understanding, because people can change, people can develop. Even when they start very slowly in terms of their progression in their learning, they still may be destined to very great final outcomes. As teachers we have to be supportive, even during hard times, when our students are failing.

ECH: Like parents do so. How far do you think heart surgery clinical research would get in 30 years from now?

CM: There are two big areas where we'll see advances. One is being able to perform procedures or rectify certain conditions through less invasive approaches. Today most heart surgery is done through a very large central incision. This is a big operation to recover from. But there are more and more procedures that can be done through lesser incisions or through catheter endovascular approaches. And those are wonderful advances. I think we will continue to see a progression towards less invasive procedures but accomplishing the same important things. The second area in which I think we'll see important advances in is this area of organ replacement. There will be a great deal of advancement with regards to mechanical replacements for the heart, lung or other organs.

ECH: Heart was seen for centuries and perhaps still is seen in some cultures, as the house of the soul. Do you think that these tremendous scientific advances could change the way we perceive human life and the essence of humanity?

CM: Well, I think we're proving that the soul is not in the heart. We transplant the heart and don't transplant the soul. However, the heart and our central circulation is something that people view with a great deal of gravity. Patients who go through these procedures experience incredible emotional stress. Sometimes surgery will rectify the circulation, while the hardest thing is to help our patients overcome depression and other mental or emotional issues. This needs to remind us to be mindful and sensitive of the psychological and emotional implications of these big and sometimes revolutionary surgeries that we perform.