Ladies and gentlemen, thank you for standing by, and welcome to the iRhythm mSToPS Update Call. At this time, all participant lines are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Kevin King, CEO. Thank you. Please go ahead, sir.
Thank you, operator. Hi, everyone. Thanks for joining our call this afternoon. Before we get started, I want to remind everyone that we'll be making forward-looking statements during today's presentation. We encourage you to review the risk factors included in our most recent filings with the SEC. As you already know, iRhythm participates in a large and growing market for the diagnosis of cardiac arrhythmias for symptomatic patients. We're making great progress and substantial inroads into becoming the leading provider of services with our highly differentiated Zio platform. Today, I'm pleased that Dr. Steve Steinhubl is here with us today to discuss the three-year results of a real-world study, mSToPS, that is focused on a new opportunity, the detection of silent atrial fibrillation in at-risk asymptomatic individuals. We believe this opportunity is possibly several times larger in size than our core markets today.
Earlier today, Dr. Steinhubl presented the findings of this three-year study at the American Heart Association meeting. With that, I'll turn it over to Dr. Steinhubl. Dr. Steinhubl, thanks for joining us today.
Thanks, Kevin. I appreciate the opportunity to discuss the study and from the beginning, your support of this study. I'm going to start for everybody following the slides on slide number five as a background that I'll go through briefly, but I think it's important to understand the scope of the problem. Atrial fibrillation is the most common sustained arrhythmia in the world. When you look at adults over age 55, the lifetime risk of developing atrial fibrillation is about 40%. Even though a lot of the focus on screening for atrial fibrillation, asymptomatic atrial fibrillation, is appropriately based on stroke prevention, it's really important to recognize that atrial fibrillation is an independent risk factor for more than just stroke. In fact, it's a stronger independent risk factor for developing heart failure and almost a stronger risk factor for cardiovascular mortality.
If you look at the slides in the center or the diagrams in the center of this slide, the one on the left is a graph from a real-world evidence of 186,000 Medicare beneficiaries with a new diagnosis of atrial fibrillation with no clinical issues in the three months beforehand. With new onset of atrial fibrillation and looking at over five years follow-up, that the colors are hard to tell on the slide, but death is by far the highest risk clinical event that occurs. Next is heart failure, and third is stroke. It's really death, heart failure, and stroke, and then others. Death is a major component of that, and we know from another study shown in the pie chart that cardiac cause of death is by far the leading cause, about 46%.
Actually, less than 6% of death is related to stroke. Atrial fibrillation is frequently not diagnosed until the time of serious clinical event. In AFib-related stroke, it's about 20%-50%, depending on the study. About 21% of people who present with atrial fibrillation heart failure, atrial fibrillation presents at the same time as their heart failure does, and the 39% is before the heart failure, presumably actually contributing to the heart failure. Because those are the episodes we definitely wanna avoid, and that's really the main driver of screening asymptomatic individuals for atrial fibrillation so that we can prevent all serious complications of atrial fibrillation. Next, we'll go to slide six. The mSToPS trial was actually started maybe five years ago, six years ago.
Its primary focus was on looking at the value of the iRhythm Zio Patch in screening asymptomatic individuals for atrial fibrillation. That's been reported in a JAMA paper in 2018. Today, what I presented at the late breaking sessions in American Heart Association was a key secondary goal. That was to determine if screening for atrial fibrillation by wearing a Zio Patch can improve clinical outcomes at three years after that initiation of screening. On the next slide, on slide seven, is just a very brief overview of how mSToPS was carried out initially, where it was done within the Aetna's among Aetna member population or individuals who are eligible met inclusion criteria. I would say it's a moderate risk population, not necessarily a high-risk population that we were studying.
Almost all of the study was done digitally, outreach, consent, and after enrollment, individuals were sent a Zio Patch to their home at the beginning of their monitoring and then three months later. Each individual wore two Zio Patches or was asked to wear two Zio Patches, and it turned out on average, it was about 25 days of median time of monitoring on those two Patches. All the participants were sent their Zio Patch results. If they had anything actionable, I talked to them also. All participants were asked if they was okay for us to share with their providers. Anybody who had anything actionable agreed to that, we sent the results to the provider. Importantly, we didn't guide them as to what to do with the results.
We just sent them the results as they were. The next slide just shows in the green box what this analysis, and it is somewhat complicated how we got down there, but it built off of the per protocol population. The per protocol population are the individuals who actually wore the heart monitor. One of the mistakes I made in designing the trial is I didn't account for the gap after people had signed up. About 1/3 of people never wore the patch, but that's a failure of my trial design, not a failure of the monitoring. The key goal that we wanted to look at was looking at the outcomes of monitoring versus no monitoring. We looked at the per protocol population. That turned out to be about 1,718 actively monitored participants.
We compared that with an observational control cohort that was matched for age, sex, and CHA₂DS₂-VASc score. Because of the way the trial was designed, where there wasn't a face-to-face enrollment, which there's good and bad to that. One of the downsides were none of us felt it was ethical to actually send an outreach to somebody and say, "You may be at risk for atrial fibrillation and stroke. We want you to join the study." And then randomizing them to potentially receiving a placebo. Having the observational control, we thought was a key to keeping this trial as being participant centric. In the next slide nine, showing the primary outcomes, which was the time to first event of the combined endpoint of death, stroke, systemic embolism, or myocardial infarction. This was determined via claims data.
We had pre-specified that analysis to be carried out in two groups. First, in everybody who was diagnosed with the atrial fibrillation during that three-year period, and then secondly, in the entire per protocol population. The primary safety endpoint was the incidence rate of hospitalization for a primary bleeding diagnosis. The next slide shows the cumulative atrial fibrillation rate. This was over a median of 29 months of follow-up. In the control cohort, the AFib rate was 7.7%, 11.4% in the actively monitored, so actively monitoring associated a significantly higher rate. Difficult to tell on the slides, but after 18 months, the actively monitored rate had approximately absolute 1% lower rate of new AFib than the match control. We'd anticipate over the next several years that curves would catch up with each other.
It's important in the actively monitoring cohort that 32%, roughly 1/3 of everybody was diagnosed with new AFib, was diagnosed by the patch initially. Whereas 2/3 over the three-year period were diagnosed clinically. You can see by the curves that obviously the patch was very early in that. In individuals who were diagnosed with atrial fibrillation, only about 45% were started on anticoagulation, which unfortunately reflects real-world results and is reflective of care being up to the discretion of the individual's primary regular physician to make that decision or not. In the next slide, which is slide 11. These are just the baseline demographics. As I mentioned, we are matched for age, sex, and CHA₂DS₂-VASc score. In both groups, mean age was roughly 74, about 40% female, and a median CHA₂DS₂-VASc score of three.
You notice that for other comorbidities, there were imbalances in both groups, a higher rate of previous stroke in the actively monitored arm, but a higher rate of prior myocardial infarction in the observational cohort. These differences, we focus on the adjusted primary outcome, and we adjusted not only for all the measured baseline comorbidity differences, but also a Charlson Comorbidity Index, as well as baseline healthcare utilization. Differences in healthcare utilization among the different groups. The next slide shows the primary endpoint. On the left is in the entire cohort, about a one per 100 person year, lower, significantly lower rate of the combined endpoint in individuals in the actively monitored arm. That was statistically significant of adjusted hazard ratio of 0.79.
The majority of this difference was driven by the difference in individuals who were diagnosed with atrial fibrillation, which was a 5.4 per 100 person year difference, with the adjusted hazard ratio of 0.53. You look at the mode of diagnosis, which is in the next slide 13, and show this primarily just for mechanistic consideration. You'll note that, not surprisingly, that clinically diagnosed, both in the actively monitored arm, control arm, had very similar event rates. We'd expect because they essentially were at the same risk of presenting with atrial fibrillation at the same time as heart failure, at the same time as a stroke or a clinical event.
You'll notice that the population that really benefited were individuals who were diagnosed early and asymptomatically through the ECG patch. The next slide shows the safety endpoint that showed that active monitoring was actually associated with a significant decrease in hospitalizations for bleeding. Interestingly, even though it's been mentioned, this may seem counterintuitive. Actually, this is very consistent with a Scandinavian registry that found in a native population that when anticoagulations were started as inpatients relative to in the outpatient setting, that inpatient initiation anticoagulation was associated with a significantly higher rate of hospitalization for bleeding in the following year. We anticipate the mechanism for this is because of that initiation more likely as an outpatient than an inpatient.
Finally, in conclusion, our study, the mSToPS study, demonstrated that active screening for atrial fibrillation as part of a prospective, very pragmatic, direct participant nationwide study was associated with significant improvement in clinical outcomes as well as safety at three years relative to routine care. We'd also say, though, that independent replication of these findings is required in order to be confident that aggressive pursuit of diagnosing atrial fibrillation in people at high risk but without symptoms is warranted. I'll pass on. Speaker, I think, Dan, you're going to speak next.
Yeah. Thank you, Steve. Really appreciate it. First, would really like to thank you for all of your efforts involved in designing and running an important trial that aims to better the standard of care and improve patients' lives. A big thank you to all the mSToPS participants as well. Before opening up for questions, we wanted to spend just a couple of minutes to talk through what we see on the horizon from a market development standpoint, as well as touch on iRhythm's near and midterm strategy around silent AF. First, starting with the market opportunity on slide 17. As you know, and as Kevin mentioned, we operate primarily in the core symptomatic and ongoing management market today, which we estimate to be more than 5 million ambulatory cardiac monitoring tests annually.
We are less than 20% penetrated in this market and continue to focus on driving adoption of Zio and establishing Zio as the standard of care within this market. What we were talking about today is the silent AF market opportunity or the asymptomatic or undiagnosed AF market. We estimate that there are over 10 million individuals that have risk factors of AF that make them high risk of having undiagnosed AF. As Steve noted, there is nearly a 40% lifetime risk of AF for individuals over the age of 55. Very prevalent and unfortunately often not diagnosed until the time of a clinical event such as stroke. Today, proactive monitoring is not done for these individuals.
Our effort in this market is to detect AF earlier in a lower cost setting and to avoid devastating downstream clinical events such as stroke, heart failure, or death. Turning this slide here to slide 18. Looking at where we are from a market development standpoint. Developing this market, like any good market in healthcare, requires generating ample clinical evidence and specifically clinical evidence that supports the hypothesis that targeted detection of AF improves clinical outcomes, lowers healthcare resource utilization, and ultimately reduces cost. That clinical evidence is coming together and certainly advanced meaningfully with today's mSToPS three-year clinical outcomes. This is the first time that targeted detection has been linked to improved clinical outcomes. We've seen from earlier studies that targeted detection can have a positive impact on healthcare resource utilization as well. Making very good inroads.
Certainly more evidence is better and more evidence is likely needed to impact clinical guidelines and to continue to bolster the value proposition that we look to deliver to payers. The good news is that there are a number of trials ongoing, and we have listed a few of them here. I won't go through all of them, but these include STROKESTOP, which could be reading out soon as enrollment has now closed, and GUARD-AF, which we're participating in, which is a large randomized clinical trial that will also report on outcomes. We're also not done with mSToPS. We're looking forward to the publication of the results presented today and also expect to have the economic outcomes reported sometime next year.
As we look at the clinical evidence being generated by these trials, I think it's important to note that we believe it will also highlight the differentiated value of continuous ECG monitoring with Zio. Over time, we believe that the evidence generated from these trials, if positive, can influence clinical guidelines which are mixed in their current recommendations. As noted on the page here, the European Society of Cardiology recommends opportunistic screening for individuals over the age of 65, those who are hypertensive or have obstructive sleep apnea. They also recommend systematic ECG screening for those over the age of 75 or at high risk of stroke. The United States Preventive Services Task Force or the USPSTF, however, recommended in 2018 against routine screening, citing insufficient evidence. I would note, though, that the USPSTF recently opened a review and research plan to revisit the evidence.
Overall, we are very excited about the clinical evidence that has been generated to this point and the ongoing interest and engagement from the physician community to continue advancing the standard of care through clinical research. Turning quickly to our next slide here, covering iRhythm's strategy in silent AF. Our initial go-to-market strategy evolves around taking an mSToPS like model to payers and implementing targeted AF detection programs using Zio. We believe the evidence generated to date, notably a reduction in healthcare resource utilization and improved clinical outcomes, provides a compelling value proposition for payers. Payers motivated to reduce stroke in their population now have a model to consider to do just that. I would also note that due to COVID, there's more undiagnosed AF in payer populations than there was a year ago.
We know that these individuals, if not diagnosed and treated, have a five times increased risk of stroke. Thus, a virtual care pathway that delivers patient care independent of patient location can help address this unmet need. This will form the basis of our early commercialization efforts. As we roll out these programs, we expect to learn a lot, refine our business model, and ideally develop a turnkey solution for our customers. Longer term, we're also focused on continuing to strengthen our value proposition, which includes a number of different facets, but essentially boils down to delivering more benefit for every individual monitored. That could be done through better enriching patient populations through higher detection rates, potentially from longer duration monitoring, and better patient engagement that ensures the right follow-through to therapy and intervention.
We believe that our strengths and capabilities, including our patient database, our data analytics capabilities, and of course, our long-term continuous monitoring platform, position us well to continue to improve the value proposition over time. In closing, I'd like to summarize by highlighting a few points. First, we are really encouraged with the recent developments and are increasingly optimistic on the market opportunity following the mSToPS data today. Second, we have an early go-to-market strategy with a compelling value proposition that improves patient care and reduces healthcare utilization. During our initial commercialization efforts, we expect to learn a lot and expect to refine our go-to-market strategy and business model over the next several months. Not only do we see a clear path to the market developing, but we believe our strategy positions us well to be a market leader.
Most importantly, we're looking forward to continuing to establish a better standard of care and improve the lives of patients. With that, we would like to turn the call over to questions. Kevin, Judy, Doug, Dr. Steinhubl, and myself are all available to answer any questions. Operator?
Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of David Lewis from Morgan Stanley. Your line is now open.
Good afternoon. Thanks for taking the question. Maybe just one for the doctor and a couple others. Dr. Steinhubl, I just wonder, given the matching dynamics that you kind of walked through here in this trial and the two cohorts, what do you see as the strongest piece of clinical evidence that sort of emerged from this trial? I wonder, do you think it definitively answers the question about whether placing a Zio on a moderate risk patient is cost-effective?
I believe it'll prove to be cost-effective, but I think the formal cost analysis will have to look at that. We showed in our one-year healthcare utilization that we did increase cardiology outpatient visits, but at the same time decreased ER and hospital visits. It seems very likely. When you look at cost effectiveness, there are very few interventions that have been shown to decrease mortality, which we did show in that. To me, the strongest outcome of this is the primary outcome in showing we achieved that. I can't remember. You may have asked another part in there I didn't answer. Sorry.
Just in terms of the cost-effectiveness piece, but the strongest pieces of clinical evidence that you think that emerged in this trial or the things that surprised you the most?
I think the mortality benefit surprised me, but I think the strongest evidence, because it is the first time this evidence available, is that we showed a significant clinical benefit. This is in a population where historically, one of the benefits of the Zio is you're able to find lower burdens of atrial fibrillation. The discussion around burdens has always bothered me that because it's still a measure of a risk factor of something going on. Even despite the fact of the median burden of less than 1%, that we still had a significant impact on clinical outcomes.
Also, I'd point out that the way mSToPS was designed, it was really kind of exploratory in the sense that if implementing this clinically, you wouldn't say, "Okay, we're just going to give somebody one Zio or two Zios early and then do nothing," because you look at the AFib accumulators. What this tells us is that not only is it beneficial to do it earlier, but even you could do it in a serial way, and whether that's every six months or every year where somebody identified the right high-risk person gets identified, do that where you could really have a substantially even greater benefit.
Okay. Just maybe a quick one for Kevin and Dan, maybe a couple. The first would just be, obviously Aetna sponsored this trial. I'm kind of curious, Kevin, how you plan on engaging payers. Do you think that on one hand, I say guidelines changing may be necessary to move the payers, but then I've seen with Kaiser KP study and perhaps you've had impact on specific institutions with Zio data. To really move this market, is it going to be a subpopulation of analysis that are going to be required? Can you move payers with this data, or is it going to require guidelines moving or studies like GUARD-AF to really move the market into asymptomatic patients? Thanks so much.
Yeah, sure. David, it's Kevin. Look, I think with the 40% reduction that was demonstrated here, both payers and providers are going to prefer to manage patients in a preventative way than to wait for bad things to happen. Sort of in the absence of even more data, I think what we've got here is compelling proof or compelling evidence that early detection of AF, one, saves lives, which is what Steve just mentioned on the mortality side. Two, that major adverse events can also be improved upon. These things are going to be important. From my understanding of how healthcare professionals think, they would rather treat people preventatively than to wait for disaster to happen.
This is critically important for providers that may be capitated, whether it's a Kaiser or a large integrated delivery system that's capitated or a payer that doesn't want to bear not only the cost but prevent the downstream adverse events from happening. I think we've got sufficient evidence here to open up the market. At the same time, I don't think that markets that have 10 million potential patients open up like a light switch just on or off. This is going to be a gradual market development, but there is compelling evidence here. On the horizon of this will be further economic evidence or data that Dan highlighted, as well as other studies that are coming in. Judy or Dan can highlight some of those status of some of those studies as well. Dan or Judy, anything you want to add to those two comments?
Yeah. No, that's great, Kevin. The other point that I would like to just emphasize is that Aetna had reached out because they had had a problem with stroke rate in their Medicare Advantage population. The problem to be solved was how could we really stop the stroke rate in their population. That's why Aetna reached out to Steve and Topol at Scripps to really help solve for this problem. I think that was the genesis. I think as we're looking to health plans, that's the problem to be solved. On the status of the studies, as Dan shared, the AMALFI study, SCREEN-AF, mSToPS, and GUARD-AF all are Zio studies are using the continuous ECG, which we believe is very important in screening for AF as well.
Thank you, Judy.
Thank you, Kevin.
Thank you. Our next question comes from the line of Robbie Marcus from J.P. Morgan. Your line is now open.
Hi, this is actually Allen on for Robbie. I guess I wanted to start off with kind of a question about the timing of like a sales benefit, right? I think the tone you guys have taken on today's call has kind of been the closest to a kind of commercialization mindset, I guess I would say, than what we've heard from you previously. You've obviously highlighted that there is going to be the continuous need for more data and that mSToPS isn't like the final step, but it is a very important one. How do we think about your ability to kind of start generating revenues in this segment with today's Zio XT? Do, as you've highlighted, do we need to see a device with longer wear or with more kind of value add to patients to really start getting revenues in this segment?
I think what Dan was characterizing was that our market development efforts are now underway. They are underway with the current technology that we have, Zio. I think to Steve's point that he made on his prepared remarks, whether it's one Zio, two Zios or Zios applied sequentially over time or in a predetermined or pre-specified time frame, there's value to be created there. Now, we're not going to guide here to when we think we can generate revenue. Those market development activities are underway, as Dan had mentioned. As far as our relationship with Verily in building out our end-to-end system, this is meant to fortify that position that we have where we can continuously monitor patients for even longer periods of time, four to six months to seven-month period of time, and hopefully improve upon these rates of detection.
Steve, you want to add anything?
Kevin. Yeah, I would just add a couple points and maybe just a finer point. I would characterize our early commercialization efforts more as learning and business model development rather than revenue generating. I would characterize our efforts over the next 12 months around those vectors, less so from a revenue generating standpoint. We certainly hope, as we learn and develop the business model that translates to revenue generation. I would suggest it's too early to start building that in.
Got it.
No, go ahead. I'm sorry. Go ahead.
I'm sorry. Just like a quick one. On the reimbursement front, would usage in the asymptomatic patient population be something that's kind of already covered under your existing label, or is that another step that you'd also have to take? Is it technically covered, but maybe an expansion of the label would help with adoption? Anything on that front? Thank you very much.
Yeah. I think a big part of the market development activities here are first going to be done with payers or capitated health plans. The idea of submitting claims is less important. It's really about an economic model that provides a return to the health plan in exchange for providing a preventative service that we're providing here with Zio. Think of it more like a net risk or a capitated model. It's certainly contemplated in our CPT permanent codes that longer duration, repeat monitoring, things of that nature can be applied. This study here showing 25 days of monitoring certainly helps.
At the time of the CPT Editorial Panel meeting, we presented a study, a MESA study that was done on individuals that had 28 hours of monitoring, and we'll continue to build that evidence base that long-term continuous monitoring through a wearable sensor will be validated and valued by the appropriate entities over time. Initially, I would think of this more as a capitated at-risk or risk-sharing type business model to be developed along the lines of what Dan was saying. This is early market development work for us to figure out how best to not only capture the value, but capture the right revenue streams and so forth. Dan, anything to add there or no?
Nope. That was good.
Okay.
Thank you. Our next question comes from the line of Joanne Wuensch from Citi. Your line is now open.
Good evening, and thank you for hosting this call. A question for the doctor. Could you please talk about the different or individual components of the primary endpoint? I'm most interested in stroke.
In the overall cohort, there was about a 40% reduction in stroke, but that was not statistically significant. The P value was 0.06. In the AFib-only population, it was substantially lower. It was less than half the risk. I'm saying that because I don't remember exactly, but it was half the risk, and it was highly statistically significantly different. There was no difference in MIs. There was, again, a strong trend towards a decrease in systemic emboli and then a significant reduction in mortality.
Are any of those individual, the four components, particularly important to you, or do you look at the collective in evaluating the success of this trial?
Well, when we designed it, we powered it where we felt like we only had the power to be able to find a significant difference in the combined endpoints. I'm always thrilled to see a mortality benefit since, really, there's virtually no cardiovascular intervention or very few cardiovascular interventions, and especially something as easy and non-invasive as AFib screening that's been shown to have a mortality benefit. I could tell you if you'd asked me five years ago if we'd show a mortality benefit, I would've said probably no way. I'm excited that that is. Obviously stroke reduction is a major part of it, but stroke is a much less common endpoint than mortality. A study ends up being powered based on how many you're going to enroll, what you anticipate. Again, we powered it for the combined endpoint just for that reason.
For economic data, can you set the timeframe, either management or the doctor, on what we should expect and when we should expect it? Do you need that data in order to really move forward in a more constructive way towards commercialization? Thank you.
Yeah. Hi, Joanne, it's Dan. On the economic data, we said sometime next year. I think you can think about mid next year or later. In terms of whether or not that's needed to go to market, I believe it'll certainly help if it does show what we believe it will show. I think there is still a compelling argument to take to market today. In fact, now that we've shown statistically significant improvement in clinical outcomes, I think, almost lowers the bar for what we need to show from an economic evidence standpoint. Even if we're cost neutral but improving clinical outcomes, I think that there's clearly value in that as well.
Helpful. Thank you so much.
Thanks, Wuensch.
Thank you. Our next question comes from the line of Margaret Kaczor from William Blair. Your line is now open.
Hey, guys. Thanks for taking the questions. First one's for the doctor. We're talking a lot about stroke. You've mentioned a few times on the anticoagulants that they maybe weren't used as much as they should have to potentially drive that stroke benefit. Does that say anything on the development of the market? Are you going to not only need to find these patients but still figure out the best way to treat them?
There's always a little bit of that, and I think it's a great question, and I could spend a lot of time talking about that. There's always an issue of the implementation of evidence-based cares and creating that system of care that can do that. I think when you look at many of the other trials, so the SAFE-AF trial was recently presented and very similar, where they had a much higher, and Judy or can correct me, but I think it was close to a 90% anticoagulation use in the AFib diagnosed individuals in that. That is when the physicians are actually involved in looking for the atrial fibrillation. In that study, they were involved, whereas ours was a participant-centered, participant-focused and then the information passed on next. Unfortunately, then what happened is the low anticoagulation use was left up to the general practice.
I think, or I'd easily envision in a system where we actively involve screening and have engagement and buy-in by the payer, by provider, that the bar for starting anticoagulation would be much lower. I don't think it requires much of a nudge, but I think it would require somewhat of a nudge.
For the iRhythm team, on that same note, do you expect any pushback from payers on that lack of stroke benefits since that's probably more the cost aspect for them? Or do you think that lower hospitalization utilization can overcome that and the death and mortality benefit?
Margaret, it's Dan, and Judy and Kevin can chime in here. I do think the overall improvement for clinical outcomes, there was an improvement in stroke, not statistically significant for stroke alone, but overall with the other endpoints, there was a statistically significant difference. We believe there's value there. Add to that the reduction in healthcare resource utilization that was shown previously. I think that's another element of value. If we can add the economic evidence to that as well, you start putting that all together and there's very few things left to poke holes in. Like we said in our prepared remarks, we believe there's a compelling value proposition to take to payers today. With a model like STROKESTOP, we still have a lot to learn as we go into those efforts. We believe that we are starting with a compelling value proposition.
Kevin or Judy, anything you'd add to that?
I would add to or reiterate some of the comments made by Steve and by Judy. Judy made the comment that Aetna felt the pain and proactively sought us out for this study, right? They are feeling what Steve described. The 40% lifetime risk. The independent risk factors for heart failure, for cardiac mortality, things of that nature associated with AFib. Not having a diagnosis until these events occur is problematic for them. I think there's enough evidence there to have payers continue to initiate these types of studies. I'm very hopeful and very optimistic that the study here will produce action from payers or by health plans that are capitated. These capitated organizations have to proactively manage patients because the effects of this are disastrous when you think about heart failure or stroke and on the economic system.
Not to undermine the patient pain that happens there as well.
If I can squeeze one more in just on the USPSTF guidelines. Since you said they reopened that review, what drove them to review that guideline policy, I guess? When should we hear an update? I assume it'll be inclusive of this data set. Thanks, guys.
Yeah, Margaret, I'm not sure on timing on when to expect an update, but I think the reason for reopening the review was recognition that there's a number of clinical trials ongoing and additional evidence being generated. Judy or Dr. Steinhubl, I don't know if either of you have a view on timing of that.
Normally it's a slow process and slow meaning over years, a year or so.
Over a year.
With feedback. I would also say, to go back to your reason, when you look at, Dan showed on the slide, if you look, there's probably over 500,00 people worldwide involved in AFib screening trials right now. The amount of, and I think before the last guidelines, there were none, and none with really any data reported. It's such a remarkably fast-changing field. I think that's why.
Thank you all.
Margaret?
Thank you. Our next question comes from the line of Kaila Krum from Truist Securities. Your line is now open.
Thanks, guys, for taking the question. Just a question for the iRhythm team to start. You mentioned stroke rates are a problem for Aetna that they're trying to solve. You mentioned that mSToPS study was done in collaboration with Aetna. I guess I'd just love to hear how or if there have been any conversations directly with Aetna about these data, if they've given you any sense for what the process would be from here to get coverage or reimbursement for this population, just within their covered lives specifically.
Yeah. Hi, Kaila, it's Dan. Don't want to go too far here, but certainly as Aetna was a sponsor of this trial, and as Judy noted in her comment earlier, the problem to be solved for Aetna was a stroke problem. The data here demonstrated that we can make an improvement on stroke rates and overall mortality as well. They are absolutely on our target list. I don't want to go further than that, but certainly, they've obviously shown interest in models like this in the past, so they will certainly be on our target list.
Great. Just, Dr. Steinhubl, I realize the virtual conference format's a little awkward, but I would love to just hear any feedback that you've heard since your presentation this morning from other physicians. Just any pushback or items that have been sort of surprising to your peers. Anything would be super helpful. Thank you.
One of the nice things about it being a late-breaking session, it turns out that you share the results with some of the discussants and stuff beforehand. I've had not only some chance for a lot of people to digest it before and after. I think people were surprised by the strength of the data. I think part of it is finding the mortality benefit, finding the consistency and benefit in the overall per-protocol population, and particularly the safety benefit, which, as I briefly mentioned, was found to be counterintuitive. It led to what I think a lot of good studies do, a lot of discussions.
As you think about it, when I think back to when we designed the trial, there were so many things that we did not anticipate and did not know because there was no existing data at the time around that. I think the results, obviously the most interesting part of it, the overall efficacy results and the impact on clinical outcome, particularly mortality, but also the safety benefit and then the degree of both the safety benefit and then as I didn't really mention was on the slides, is the overall hospitalization, the degree of reductions in overall hospitalizations too.
Thank you.
Thank you. Our next question comes from the line of Bill Plovanic from Canaccord. Your line is now open.
Great. Thanks. My questions have been answered. Thank you.
Thank you. Our next question comes from the line of Gene Mannheimer from Colliers Securities. Your line is now open.
Thanks. Good afternoon. Appreciate the session. I wanted to ask Dr. Steinhubl, can you remind us what the CHA₂DS₂-VASc score was of the patients in the actively monitored cohort? For iRhythm as you develop out the business model, would the goal to be to have insurers like Aetna screen for populations with that score or three or higher, say, or possibly a broader and therefore larger population? Thanks.
Because we matched off CHA₂DS₂-VASc for both the observational and the active monitor, it was a median score of three, which is why I put it as a moderate risk group. If you look at STROKESTOP ages 75 or 76, SCREEN-AF ages 75 plus hypertension, a higher group. What's interesting, even though CHA₂DS₂-VASc is very important for driving anticoagulation, for when you look at just individuals where AFib is diagnosed at the time they present for stroke, those tend to be individuals who actually have lower CHA₂DS₂-VASc scores who have lower overall cardiovascular comorbidities, and that might be so they don't go in and see a healthcare provider as much. Anyway, I'm going beyond what you're asking. I think from a clinical standpoint, the CHA₂DS₂-VASc is a great measure for long-term stroke risk.
Maybe not the best measure for people who are at risk for the younger age. We need something more to look and then figuring out what to do with that too.
Thank you.
Gene, did that answer your question or did you have a follow-up for?
Yeah. It sounds like, based on the doctor's comments, that the insurers, when you've developed this out, could screen for larger populations of lower CHA₂DS₂-VASc scores if they're still at risk. I think that answered it for me.
Let me. There are some really, we think a lot about anticoagulation and stroke prevention, but try to emphasize heart failure is a more common problem after AFib diagnosis than even stroke, and obviously has its severe impacts on outcome. There are so many other things that physicians can and we should be doing besides anticoagulation. Looking for young people who have sleep apnea and diagnosing and treating that, pushing weight loss and alcohol abstinence are two lifestyle management problems or management programs that we can include that substantially decrease the risk of AFib burden and the progression of atrial fibrillation. When we look for atrial fibrillation, I think it'll be important as we think way beyond just anticoagulation and stroke reduction.
That's interesting. Thank you. Appreciate it.
Steve.
Thanks, Gene.
This is more of a means to an end than just the end, is the way I interpret what you just said.
Absolutely.
Yeah.
Thank you. Our next question comes from the line of Marie Thibault from BTIG. Your line is now open.
Hi. Thank you for taking the questions and hosting this event. Just a very quick one. I know there is some emphasis on the importance of randomized clinical trials going forward. You're part of GUARD AF. Could you remind us on the timing for that and when we may start to see some early data? I know that's a long-running trial. Thank you.
Yeah, sure. Judy, why don't you go ahead?
Okay. Hi. Yes. GUARD-AF is actually enrolling. They hope to close enrollment, basically it's 52,000 participants, 26,000 which will be wearing Zio, the anticipated close is August next year, 2021.
The follow-up for that, Judy, I think it's at least a minimum of 2.5 years.
That's correct.
Great. Thank you.
Thanks, Marie.
Thanks.
Our next question comes from the line of Suraj Kalia from Oppenheimer. Your line is now open.
Good afternoon, everyone. Dr. Steinhubl, a couple of questions for you, if I may. The sleep apnea incidence at baseline for the actively monitored arm was statistically higher than controls. There is a body of evidence suggesting greater AFib incidence due to OSA. I guess my question is, could there be any selection bias introduced which is probably explaining the time to AF diagnosis? By the same token, prior MI was higher in the control arm-
Right
explanation of the mortality difference?
Well, it's hard for me to say no to those. As you note, there was imbalances going both ways. There was a higher stroke, prior to stroke risk in the actively monitored arm. As you note, the higher sleep apnea, but more COPD and more myocardial infarctions in the observational control arm. The ones we know about, we can adjust for. We can adjust for those risks. I can with confidence say, I don't think that explains the difference we see in mortality benefit. If we had just done the straight numbers, then that might be more of an issue. The concern in anything that's not the direct randomized trial is that you worry about the unmeasured confounders that we don't see. That is always a concern, but I think for your specific questions, I feel good about that that doesn't explain the difference.
Steven, one final thing, and I'll hop back in queue. Steven, all of us are dancing around this whole issue about strokes, right? Aetna specifically reached out on the stroke issue. When you objectively look at the control arm, you all had expected a stroke rate 12%, 5% in the actively monitored arm. What should we read? The technical part of success, we get it, because of the mortality difference. Clinically, isn't stroke by and large the key metric in AFib? At least based on the data, it is not statistically significant. What are we missing in this picture? Thank you for taking my questions.
Yeah. Well, I would say historically we have thought of just stroke, and I think that's really driven commercially because we have a lot of really great novel anticoagulant agents that are pushing the stroke message and pushing the stroke message in AFib. I think that's great because it's a horrible problem. They're big strokes. When you look at contemporary data, AFib is an independent risk factor for stroke. It doubles it 2.5x . It's 5x the independent risk factor for the development of heart failure, and it's 2x the development of cardiovascular mortality. All of that is, yes, we think about stroke, that's because there's more of a message around stroke. There's a lot of marketing around stroke prevention. To your question about not having a statistically significant difference is we didn't have the power.
We didn't have enough patients to anticipate finding a difference in the entire cohorts to be able to show that. I still think we had, again, a non-significant, so inferior to that, but a 20% reduction in the entire cohort, though, of what we've been seeing. If you look at it was a 50% reduction in just the AFib cohorts with the limitations in that. Just in the AFib cohort, that was significant, but there's a lot of caveats to that. I'll stick with the non-significant but still impressive 20% reduction. Because it wasn't statistically significant, I don't think we can make anything of that because the study wasn't powered to show that.
Thank you. Dan, do you want to take us home here and wrap up?
Yeah. Thank you all again for joining us today and for your interest in the mSToPS study. Again, a big thank you to Dr. Steve Steinhubl for his efforts in the study and for joining us today. Also a thank you to Judy Lenane, who's our Chief Clinical Officer and been involved in this from the very beginning. Wishing you all a good day. Stay safe, and look forward to speaking again soon. Take care.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.