How an Apple Watch Will Inform a $37 Million Clinical Trial with Rod Passman, MD

Erin Spain. MS [00:00:03] Welcome to Science in Translation, a podcast from NUCATS, Northwestern University, Clinical and Translational Sciences Institute. I'm your host, Erin Spain. There is an exciting new clinical trial about to launch here at Northwestern Medicine that uses an Apple Watch and an iPhone app. And it could revolutionize the standard of care for many with atrial fibrillation, the most common type of heart arrhythmia. With support from the NUCATS Institute and the CTSI Trial Innovation Network, Northwestern's Dr. Rod Passman is leading a team of Northwestern and Johns Hopkins University investigators that were awarded a $37 million NIH grant to conduct this work. Dr. Passman is the director of the Northwestern University Center for Arrhythmia Research. He is also a professor of medicine in the division of cardiology and a professor of preventive medicine, as well as a cardiac electrophysiologist at Northwestern Medicine. Welcome to the show. 

Rod Passman, MD [00:01:06] Oh, thank you very much for having me. 

Erin Spain. MS [00:01:07] You joined Northwestern in 1998 as an assistant professor, and since that time, you've become internationally recognized as a leader in cardiac monitoring and stroke prevention. And at some point during your career, you became focused on AFib as one of the heart arrhythmias that you study. Was there a particular moment you can take me back to in time or something happened that made you realize there was a way to improve the standard of care for AFib patients?  

Rod Passman, MD [00:01:35] You know, if I were to talk to my younger self, I would say, keep your eyes open, because there are things that we see every day taking of patients, whether it be in the hospital or in the clinic, things that don't make a lot of sense. So much of what we do in medicine is really based on what we think is best on expert consensus. And while there are many clinical trials in my field are showing us maybe what are the right things to do, there's still huge gaps in knowledge. So every day we're confronted with those gaps and we use our experience and our knowledge to make the best choice. But there's a lot of room for improvement, and my interest in this particular area grew out of an interaction with a specific patient who I met when I was younger in my career. I'll tell you briefly, he was a patient who had atrial fibrillation. And for those of you who don't know a lot about atrial fibrillation, let me just remind you that it is the most common arrhythmia. So if you're a cardiologist or cardiac electrophysiologist, there's no shortage of patients with this disease. And what's interesting is that some people are completely unaware that they have atrial fibrillation. They may not feel any of the palpitations. They may not feel any of the shortness of breath or lightheadedness that others feel. But whether you feel atrial fibrillation or not, it can have huge consequences. So people with atrial fibrillation are at higher risk of heart failure. They get more hospitalizations for heart disease, they're at higher risk of dementia and premature deaths. But perhaps the most feared consequence of atrial fibrillation is stroke. We know that people with atrial fibrillation have a 500% increased risk of stroke compared to patients without it. And these strokes tend to be severe. They tend to be large strokes that are often severely debilitating or life ending. So the good news is, is that since the 1940s, we've had blood thinners first Coumadin, which people have known about for a while, and then starting about a dozen years ago, these new medications called novel or direct oral anticoagulants, some call them no extra dose. And the good news is, is that these drugs reduce the risk of stroke by about two thirds. That's fantastic. The problem is their blood thinners and they can result in bleeding. And some of those bleeds can be major bleeds, bleeds inside the brain or bleeds in the stomach. And then there are these sort of nuisance bleeds that may not be life threatening but are problematic. So what winds up happening is that many patients who should be on a blood thinner are never started. And those that start maybe half or so stop within a year or two. So that's one issue, is that these medications have benefits and risks. The other interesting thing about atrial fibrillation is that it's sort of a one size fits all strategy when it comes to treatment. So we can assess someone's risk of stroke based on the scoring system that takes into account their age and their sex and other risk factors like hypertension and diabetes. And then we say, well, if you're at anything but low risk, you should be on a blood thinner forever. So what that means is that people who have seven or eight risk factors and are in atrial fibrillation 24 hours a day, seven days a week, are in the same lifetime of a blood thinner as that individual who has maybe one episode of atrial fibrillation a year or who have had a procedure like an ablation or on medications where the atrial fibrillation is completely eliminated. So imagine taking a drug that has risks for the rest of your life when you may have AFib very infrequently or maybe not at all as a result of a medication or an intervention. So that didn't make a lot of sense to me. But the reason we do that is because we don't have cures for atrial fibrillation, and atrial fibrillation can be silent. So how do we know that it's safe to stop a blood thinner in someone when they don't know sometimes when they're in atrial fibrillation? So there was a patient that initiated my interest. And really, I think if you take care of patients, you tend to remember your failures much more than you do your successes. So in this patient, we had him on a blood thinner. His atrial fibrillation was well controlled on medication. But our guidelines, which we sort of use as a rule book then and now, said. That he should be on continuous blood thinners because of his risk factors. And this patient came in with a bleed inside the brain, something called an intracranial hemorrhage. And it changed his life forever and never worked again. A day in his life was a phase like wheelchair bound, and it affected his life and the life of his extended family, maybe for generations. 

Erin Spain. MS [00:05:33] After this patient you started researching alternatives for AFib patients. Tell me how you started. You really wanted to see if there was some technology out there that could help patients. Take me through those early days of what you were investigating. 

Rod Passman, MD [00:05:48] If we were going to change this paradigm and say, listen, in many diseases you only take the medication when you're sick and then you stop it. So how do we change the treatment of atrial fibrillation in a similar manner? When you take the blood thinners only in response to an episode of atrial fibrillation? So two things needed to happen. Number one, we need a technology to let someone know when you're having atrial fibrillation, even when you don't know you're having atrial fibrillation. The other thing we needed is a blood thinner that would send the blood in a matter of hours, not days like Coumadin would take. And those both things happened. Company started to make devices called implantable cardiac monitors and then pacemakers and other devices that went inside. The heart came out that could record all episodes of atrial fibrillation. And then the concept of remote monitoring was introduced where patients didn't need to come to the doctor's office every few months to get the data downloaded from their device. It could be sent nightly through a transponder sitting by your bedside. And then about a dozen years ago, these new blood thinners came out that would send the blood in two or 3 hours as opposed to four or five days like Coumadin. So by leveraging these advances in both technology and pharmacology, we could conceive of researching a paradigm shift where we use a technology to alert the patient that they're in an episode of AFib. They take a blood thinner since about 2 to 3 hours and they only need to be on the blood thinner for a few weeks when we believe that the risk of stroke is at its highest. 

Erin Spain. MS [00:07:11] And you were really a pioneer in using these implantable cardiac monitors and you were on the cutting edge of this research. But at a certain point, new technology such as the Apple Watch came on the market. When did you start putting two and two together and thinking, hmm, maybe there's a better way because there are downfalls with using the implantable, right? 

Rod Passman, MD [00:07:32] Oh, yes. So I think that we sort of played the hand that was dealt to us. So when there were only implantable, we did a pilot study and we got funding from the company that made the device and we got a pilot grant from the National Institute of Health, and we did a pilot study in 60 patients where we showed that you could reduce the time on the blood thinner by about 95% and there were no strokes. So granted, it's a small pilot study. It was single arm, but there was a signal that really we could have great impact. And if we could reduce the time on the blood thinner, you could reduce bleeding risk and you could reduce cost and you could improve quality of life because people on blood thinners maybe don't want to go mountain biking or skiing or things of that nature. So there was certainly a signal there, but you hit the nail on the head is that this was really a proof of concept. But using an implantable device is not scalable for the tens of millions of people around the world who may benefit from this approach, because these devices are invasive, they're expensive, they have a limited battery life. But most importantly, these are really health care facing. The data from those devices today does not go to you as the patient. It goes to me as your doctor or our device team. So we would need to receive that information and then call you, which means we would need to be around seven days a week, weekends and holidays to respond in a timely manner. So as we were finishing up this pilot study, there started to be movement in the wearable field where you can have a consumer grade digital health wearable device that can assess your pulse, and that's actually been known for a very long time. Fitbits and whatnot that people wear for workout purposes are very accurate heart rate measurements. Well, what happened was that people started to write letters to these companies and say, Hey, your device saved my life because I was doing nothing. And it told me my heart rate was fast. And I went to the doctor and the doctor told me I had atrial fibrillation and a light went off at the CEOs of these companies and said, Well, if we could detect heart rate, we could detect heart rhythm, and if we could test heart rhythm, we could design accurate monitors for the detection of atrial fibrillation. 

Erin Spain. MS [00:09:34] So what year was this when all this started to change? Just take me back to sort of the genesis of what we have now, which is this clinical trial that is NIH funded. 

Rod Passman, MD [00:09:45] So we started to work with the implantable devices in, I would say about 2011 is when we started. We published those results in 2016 and it wasn't till I would say 2018 where we started to recognize that there was a wearable solution to this. 

Erin Spain. MS [00:10:01] It was around that time that you approached NUCATS for some help developing a study that uses an Apple Watch and an iPhone app. Tell me about NUCATS and the role that they played and bringing all of this together.  

Rod Passman, MD [00:10:16] You know, I think that we're very lucky to have NUCATS and to have really smart, invested people, because I am generally a clinician and I may have insights into where the gaps in knowledge are and may have some insights into how to begin to answer this question. But there's so many areas of expertise that are not and cannot be housed in one individual. So NUCATS was really essential. And first of all saying, hey, this is a good idea. And also helping me flesh out what a clinical trial would look like, what a budget would look like and what contracts would look like, helping me with some of the regulatory issues involved. And they also wisely pointed me in the direction of the Trial Innovation Network, which is a consortium of these academic centers, which were really key because number one in one sort of blast, we could send this concept out across the country to major players in clinical research and say, who's interested? And that's really important because I think that to get the NIH to fund a clinical trial, you do shows a lot of interest in it. So by getting dozens of centers to raise their hands and saying, we want this study and we have X number of thousands or in some cases tens of thousands of patients that would be eligible, that really established some degree of feasibility, which was critically important for us getting this grant. 

Erin Spain. MS [00:11:35] Well, let's talk about the specifics of the trial. How many people are involved? How long will it run and how is it designed? Give me the details.  

Rod Passman, MD [00:11:43] So this is a randomized trial. It will enroll 5350 patients from 80 to 100 U.S. centers. I would be remiss if I didn't mention that, first of all, the NIH for a trial like this requires the clinical coordinating center to be different from the data coding center. So we are incredibly fortunate to be teamed up with Johns Hopkins, who is a data coordinating center, and they bring just a whole new level of expertise to the DCC, and we're really instrumental in helping design so many aspects of this trial. And then we have another partner, Stanford University, who really are experts in digital health technologies. They ran the Apple Heart study, which was the first Apple Watch study that got the device cleared by the FDA, enrolled more than 450,000 individuals. So we have an incredible team. I think you can't really ask for a better team if you're running a digital health trial than the combination of Northwestern, Hopkins and Stanford. So the trial, as I said, would roll 5350 patients. We are specifically enrolling patients sort of on the lower end of the risk scale. These are patients who have maybe 1 to 4 risk factors for stroke out of the nine that are available. These are patients who have very little atrial fibrillation, either on their own or because they've had an ablation or because they're on medication, but they would otherwise be on a blood thinner for the rest of their lives. So half the patients will remain on the blood thinner, which is the current standard of care. And the other half will get this sort of customized studies, watch and do what we call pill and pocket anticoagulation. They will take their blood thinner for 30 days only in response to a multi-hour episode of atrial fibrillation. 

Erin Spain. MS [00:13:12] This really is personalized medicine, right? 

Rod Passman, MD [00:13:15] Absolutely. I think if you had talked about personalized medicine a decade or so ago, we would say, well, we need to understand your genetic makeup and we're going to decide what medication is best for you based on your genes. But here we're using technology to personalize care. We're not just shotgunning the one size fits all approach. We're saying you as an individual, we are going to treat you for a fixed period of time only in response to a period of time where you have the disease when you believe your risk of stroke is high. So this is using technology to offer a form of personalized medicine. 

Erin Spain. MS [00:13:44] And it wasn't a smooth road necessarily, this trial. Tell me about some of the roadblocks that you've faced.  

Rod Passman, MD [00:13:50] Well, nothing like this happens easily. Obviously, getting a large clinical trial funded is very challenging. And I think that there are challenges of a study like this that partners with a consumer electronics company. But I think that NUCATS really was critical in helping write the grant, helping organize all of the disparate pieces of information. I think that you have, I think, 12 pages to make your argument, but the grant may be 1300 pages. So the science behind it is a very small portion and a critical portion. They were very, very important. And I'll call out people like Keith Herzog and then good trial and Doctor Rich Dickwella who read every word of every page, making sure there were no errors. So I cannot overstate their value in getting this to the finish line. And across the finish line, which as I said, you know, whatever training I had or whatever insights are insufficient to go this process alone. 

Erin Spain. MS [00:14:42] Tell me about how you worked with Apple. How did they enter the conversation and what is the nature of their participation in this trial? 

Rod Passman, MD [00:14:50] We had gone to Apple early in the course of this study, actually, even before they released their atrial fibrillation sensing algorithms. There was another company called Cardea that had made a device that sort of piggybacked on to an earlier version of the Apple Watch and actually performed that same function of of searching the pulse for abnormal rhythms. So very early on through contacts with Apple. I was interested and had sort of agreed to help us with hardware and preexisting software. Then as we started to come to our first submission, Apple came out with their own product. So we sort of pivoted the discussion to say, Well, we need you, or we'd like you as a partner. I would say at this point, the American Heart Association and Nancy Brown, who's CEO and was a great advocate for this trial and helped us partner with Apple. And Apple continues to through the way provide hardware meeting watches for the study and also is allowing us to access the primary data that comes off the watch to alter the readings for the purposes of this study. Since the commercially available watches were not designed for the purposes that we're going to be using it for in this trial.  

Erin Spain. MS [00:16:00] Tell me about some of the motivations why people would want to be part of the trial.  

Rod Passman, MD [00:16:04] Well, you know, I think that for many people, being on a blood thinner, it really impacts their lifestyle. They're concerned about bleeding. Remember, too, that there's costs associated with these medications which are not trivial. And how many of us would want to take a medication that we may not be benefiting from, that may exposures to risk, particularly when we've had a procedure or on a medication. And every doctor's visit reminds us that we're in a normal rhythm and we question, why am I still taking a blood thinner when the disease that I am receiving it for is no longer seems to be apparent?  

Erin Spain. MS [00:16:33] Everyone is going to be given this specialized Apple Watch and there's also an app, and they're not really going to have to have a lot of interaction with the study team. Is that right? 

Rod Passman, MD [00:16:43] Because this is a randomized controlled trial. Half the patients will not get the watch because those patients are staying on their blood thinner. So half will get the watch. And I should also point out that we have a fourth partner, UC San Francisco Doctor Jeff Hogan and his team have really been invaluable players in the tech aspect. They have a research platform called Eureka, which has been used for 75 plus studies, which essentially allows participants to be in clinical trials remotely. So using their smartphones to enroll in clinical trials would be one of the great and novel parts of the study. Is that the only touch that you have with the patient is at the time of enrollment. All of the follow up is going to be virtual through the patient's smartphone. So we're going to be sending them surveys that they're aren't. Answer We will know if they've been hospitalized with geofencing and we could get those records. And I think this is really one of the most important features to do a large scale clinical trial virtually, which not only makes it more cost efficient, but from a patient's perspective, coming downtown and paying for parking at Northwestern just to partake in a clinical trial I think is a lot to ask. People have to take time off from work. They need to arrange for care of their family members. And I think that people who are involved in clinical trials are doing a great service and we should ask as little of them as possible. And that's what we're trying to do now. 

Erin Spain. MS [00:17:59] This is just one of the many innovative aspects of this trial. Are there other aspects that you can share that maybe NUCATS members would be interested in implementing in some of their own work? 

Rod Passman, MD [00:18:09] I would say that the partnership with Tech, I think, is something that people should keep an open mind about because it's estimated that maybe one in five Americans now own a wearable digital health device. We get incredible information from those devices, and I think that we need to think in a large scale very pragmatically, how we can use that data to run more efficient clinical trials. So I would say that what we're doing specifically for heart rhythm may be applicable to other disease states, and we just need to be really thoughtful and recognize their potential partnerships. 

Erin Spain. MS [00:18:40] Are there certain things that someone should keep in mind, an investigator, before approaching a tech company as big as Apple? 

Rod Passman, MD [00:18:47] Well, you know, I think that there are challenges and they're understandable. These are not device companies. These are not pharma companies that are used to running clinical trials. These are consumer electronics companies that happen to make amazing products that could impact the health of millions of people. So I think that places like Apple and Fitbit do have physicians working with them, and they are invested in trying to use this technology to help people. It does take some perseverance. I will tell the story that when we flew to California to pitch this idea, it was not lost on me that as we were going in, there was a group walking out and as we were walking out there, a group walking in, I imagine that a lot of people are pitching them ideas and I think if they see a potential opportunity where their devices can help people and the scenario is right and the investigators are right, I think they're open to those discussions. 

Erin Spain. MS [00:19:35] Here we are. It's the beginning of 2023. Enrollment is beginning in July. Is that right? 

Rod Passman, MD [00:19:41] Maybe a little earlier. But I would say sometime in the next six months or so. 

Erin Spain. MS [00:19:44] How often will you be getting updates on this trial? 

Rod Passman, MD [00:19:47] Because it's a randomized trial. I won't know what's going on until the end. We hope enrollment goes swiftly. We had the opportunity of assessing what the interest is in the A-fib community. And there are some wonderful Web sites, including one called Stop. Yes. Run by a dynamic woman called Melanie True Hills. And Melanie allowed us to submit a survey to the 1 million people who subscribed to her site in 24 hours. I think we got a few thousand responses, and about 85% of people said, I'm interested. So we expect enrollment to be brisk. We think that we are offering something that people want, and this will be, once we start enrollment, a five year study, we hope to enroll on the first two years and have the first patient enrolled, followed up to five years. We will not have results for another six and a half years. So I think that unless this trial is stopped prematurely, which you'll be hearing one way or the other, this is a long haul and that's what it takes in a clinical trial. It changes the practice of medicine. We need the highest levels of data. 

Erin Spain. MS [00:20:41] Well, thank you so much, Dr. Rod Passman, for coming on the show telling us about this exciting clinical trial and the help that NUCATS was able to lend and congratulations. 

Rod Passman, MD [00:20:51] Thank you very, very much. 

Erin Spain. MS [00:20:57] Subscribe to science and translation wherever you listen to your podcast. To find out more about NUCATS, check out our website nucats.northwestern.edu.