Robert Underwood, MD (Host): Welcome to Advancing Worsening Heart Failure Treatment, Exploring Cutting Edge Therapies and Addressing Disparities. I'm Dr. Bob Underwood. I'm joined today by my colleague, Dr. Erin Michos, Director of Women Cardiovascular Health Research and Associate Director of Preventive Cardiology at the Johns Hopkins University School of Medicine, Co-Director of the IMPACT Center at Johns Hopkins University, and Co-Editor-in-Chief of the American Journal of Preventive Cardiology. For full, relevant financial disclosure information, please see iridiumce.com/hf.

This educational activity is supported by an independent educational grant from Merck, Sharp and Dohm, and we would like to thank them for their support for this initiative. The learning objective for this program is to describe innovative medical and device-based strategies for prevention or treatment of worsening heart failure. Dr. Michos, welcome back.

Erin D. Michos, MD: Thank you for having me back on your program.

Host: Yeah, absolutely. So as we get started, can you start us off with some information on edema in worsening heart failure?

Erin D. Michos, MD: Yeah. So, edema is one of the primary manifestations of worsening heart failure. So, what's happening as heart failure is progressing, there's this overstimulation of the renin-angiotensin-aldosterone system, or RAS, as well as the sympathetic nervous system, and this leads to promotion of sodium and water retention. When there is atrial and verticular stretch, natriuretic peptides are released to compensate for the overstimulation of the RAS system. But as disease progresses, the natriuretic peptides lose their effectiveness. And then, there's this downward spiral where there is more sodium retention, more volume and pressure overload, more vasoconstriction. And this leads to adverse structural remodeling of the heart, the vasculature and the kidney, including fibrosis and left ventricular hypertrophy.

Host: So, you kind of already, I think, alluded to it a little bit, water retention. So, why are diuretics commonly used in worsening heart failure?

Erin D. Michos, MD: Sure. So, diuretics are the mainstay to manage edema. So, again, they don't have a class 1 indication for heart failure per se, but they play an important role for decongestion for management of edema. If initiated in the outpatient setting, initiating early, that might help prevent further progression and worsening of heart failure to help keep people out of the hospital. Sometimes we even have the emergence of bridge clinics where sometimes, for heart failure patients, we can even give them a course of IV Lasix in the clinic to help keep them out of the hospital. Usually, loop diuretics are what we're using for heart failure for decongestion. These work by blocking the reabsorption of sodium and chloride in the loop of Henle in the kidneys and that causes more water to be excreted. Potassium is excreted as well, so there can be hypokalemia, you know, or other electrolyte imbalances. So, you do have to monitor labs. And the common loop diuretics that we use are furosemide, torsemide. And then, there's other diuretics that we use, including hydrochlorothiazide, indapamide and chlorthalidone.

Host: Absolutely. So, we're going to move on a little bit. So, recently, soluble guanylate cyclase or SGC has been recognized as a target for the treatment of worsening heart failure. So, can you describe how heart failure affects the production of cyclic guanosine monophosphate or cGMP in reference to the nitric oxide-sGC-cGMP pathway?

Erin D. Michos, MD: Yeah. So, that's a big question, and I want to get into that in a minute. But first, before we talk about soluble guanylyl cyclase, I just want to emphasize to our audience, and we're going to get into this in our segment three episode, about the four pillars of HFrEF therapy, which all have class 1 indications. So, that includes an ACE and ARB or an ARNI, evidence-based beta-blockers, Mineralocorticoid receptor antagonists and SGLT2 inhibitors. So, those are really the foundation for HFrEF treatment.

But you asked about novel and emerging therapies. So, let's get back to soluble guanylate cyclase. So, nitric oxide-dependent soluble guanylate cyclase stimulation triggers the production of cyclic GMP. So, in turn, cyclic gMP has a lot of favorable properties that promotes vasodilation, it inhibits smooth muscle proliferation, and a number of other favorable vascular effects. And this really helps regulate vascular tone cardiac remodeling and cardiac contractility. However, soluble guanylate cyclase pathway is disrupted in heart failure. In heath failure, there's endothelial dysfunction, so that results in decreased production of nitric oxide, reactive oxygen species, ROS, are associated with inflammation that also bind to nitric oxide. And so, nitric oxide stimulation of guanylate cyclase is reduced in heart failure and this results in insufficient GMP or the lack of cyclic GMP associated with cardiac dysfunction and exacerbates endothelial dysfunction.

So, this is where it comes in these new therapies, these soluble guanylate cyclase stimulators. So, they increase the activity of guanylate cyclase and that leads to more production of cyclic GMP. But what's really important or notable is that the soluble guanylate cyclase stimulators actually enhance soluble guanylate cyclase activity independent of nitric oxide. They also can help increase sensitivity of soluble guanylate cyclase to endogenous nitric oxide, but kind of works independently of nitric oxide, which may be, you know, low in the heart failure state. So, these agents lead to more cyclic GMP. And as I mentioned, cyclic GMP has these potential beneficial effects in heart failure, like vasodilation, improving endothelial function, decreasing fibrosis, and improving remodeling of the heart that can help with cardiac function.

Host: So, you're saying even if nitric oxide production is low, that by addressing the SGC that we can still stimulate the cGMP, which is necessary for a healthy function.

Erin D. Michos, MD: Absolutely. You summarized that much more succinctly than I did.

Host: No, it's phenomenal because it's novel to think of it in that pathway.

Erin D. Michos, MD: Yeah. So, we actually have a first in class guanylate cyclase stimulator. It's vericiguat. And so, this is a once daily oral guanylate cyclase stimulator, and it was improved back in 2021 after the VICTORIA trial, which I could talk about that trial. But it's indication is for patients who have chronic heart failure despite guideline-directed medical therapy, who have an ejection fraction less than 45%, who have been hospitalized for heart failure or being treated as an outpatient with IV diuretics. So, this is sort of more of the more advanced or worsening heart failure.

Host: So, you already made mention of the VICTORIA trial. So, let's talk about that clinical trial and the evidence that supports the use of vericiguat in worsening heart failure.

Erin D. Michos, MD: Yeah. So, the VICTORIA trial compared vericiguat to placebo in patients with HFrEF, so they all had worsening heart failure, an ejection fraction less than 45%, and they had elevated natriuretic peptide levels. There was about 2,500 patients in each arm. Like a lot of cardiovascular trials, 75% of the patients were male. The average ejection fraction in the trial, baseline was 28%. It was a relatively short trial. It was only around 11 months. The primary outcome was the composite of either cardiovascular death or first hospitalization for heart failure. And the vericiguat, it met the primary endpoint. There was significantly lower of the primary outcome, which was, again, death from cardiovascular cause of first hospitalization in the vericiguat arm; about 10% lower, hazard ratio 0.90, which was statistically significant. It was a short trial, so it didn't quite meet statistical significance for cardiovascular death, although that trended favorably. It was significantly reduced, you know, the heart failure for hospitalization outcome, which overall drove the primary outcome. Overall adverse events, even serious adverse events, were similar between the two groups. Actually rates of hypotension and syncope were similar between the groups without a statistical significance.

One thing that was a little surprising to me, was anemia was a little bit more common in the vericiguat group than placebo. But I mean, I would be more worried by the mechanism for hypotension, because of the vasodilatory effects and that wasn't different between the two groups.

Host: Right. No, got it. Okay. So, let's shift gears a little bit. Let's talk about some monitoring devices. What's been some interesting developments around monitoring devices? You know, first, what are some baseline stuff and what are some new stuff?

Erin D. Michos, MD: Okay, great. One more thing about vericiguat just to let you know what the current guidelines say. So, the 2022 AHA/ACC Heart Failure Society guideline did give it a class 2B indication saying that it can be used in selective high-risk patients with HFrEF and worsening heart failure already on guideline-directed medical therapy to reduce heart failure, hospitalizations, cardiovascular death. So, it's in the guidelines as a 2B indication. So hopefully, more to come on that.

But you brought up another kind of emerging innovative area, and that's the use of monitoring devices for worsening heart failure. So, I think we talked about in episode one that heart failure is a chronic condition that's punctuated by periods of instability. So, medical devices potentially can be useful monitoring devices and identifying worsening symptoms as quickly as possible, maybe even before symptoms clinically manifest. And these devices that continually monitor patient, hopefully can catch them earlier than intermittent clinical analysis, like when patients come in for office visits. So, they're both invasive devices and non-invasive devices. We can talk about both of them, but the invasive implantable device is a small sensor that's implanted in the pulmonary artery. And the sensor measures and records pulmonary artery pressures, and then that information is transmitted back to the patient's cardiologist. And hopefully, that can be actionable to act on that data, and we can talk about the data supporting that, such as from the COMPASS trial.

Host: Yeah. Again, the technology advances, we kind of made mention of that in episode one. But the technology advances are just really coming to fruition and being applied to patients in need. And it's great to see what we thought was novel actually being used therapeutically and diagnostically. I just think it's great. So, what do you think about the potential of wearable monitoring devices for detecting worsening heart failure?

Erin D. Michos, MD: I think I mentioned to the audience about the COMPASS trial, so let me just go back, finish up about the implantable, and then we can talk about what's happening with wearables. Yeah, because the implantable actually does have an FDA indication. So, the COMPASS heart failure trial was a single blind but randomized trial. It was relatively small, 274 patients who all had class III or class IV heart failure that were being treated for worsening heart failure over the previous six months. And as I mentioned, this is a implantable continuous hemodynamic device.

Now unfortunately, it was a small trial, the primary efficacy endpoint was not met. So, that should be taken into consideration. But when they did a retrospective analysis, they showed there was a 36% reduction in first hospitalizations for heart failure in the monitored group and that adjustments in medications, you know, meaning that people were acting on them from the data and adjusting medications, that was also more common in the monitored group. So, the FDA initially approved one of these devices, CardioMEMS, in class III heart failure. And it then recently expanded, the FDA now has expanded the indication to even use in class II heart failure who's had worsening symptoms.

But, you know, again, there still needs to be more data about the clinical utility of this. And the 2022 AHA/ACC Heart Failure Society guidelines just gave a 2B indication for these devices. So, that's, you know, a relatively weaker indication, but can be used selectively. They said in select adults who have class III heart failure and have had a heart failure hospitalization in the past year, who've had elevated BMP despite maximally tolerated guideline-directed medical therapy and who've already been optimized with devices such as CRT devices, that the usefulness of these wireless pulmonary artery monitors may possibly reduce the risk of subsequent heart failure hospitalization, but warrants further study.

Host: Yeah, exactly. It warrants further study. You said retrospectively, they kind of went back and looked at the data and 30% reduction in first hospitalization, potentially because people are making decisions and doing some outpatient adjustment to medications and therapy to keep them out of the hospital, which is a great thing in and of itself. So, I think it's a cool study. I'm looking forward to hearing more about what comes next in further research. So, now let's get over to the wearable devices. What are your thoughts on wearable monitoring devices for worsening heart failure?

Erin D. Michos, MD: Yeah. So, you know, one of the limitations of what we were talking about before is that that device was implantable in the pulmonary artery, so that's, you know, invasive. So, can you wear something to be able to detect worsening heart failure? Well, wearable devices are in development and have the advantage of being convenient. They can be placed at a patient's home. They're not invasive. A pilot study had previously shown that participants were able to be able to correctly attach the device and get reliable heart measurements.

So, there is one example of a newer wearable device is one that uses radiofrequency signals to assess the wearer's thoracic fluid index, and again, alert their clinician if needed. And so, last year at the American College of Cardiology 2023 meeting, the BMAD trial was presented. It's a small trial, a single trial looking at this device. But they did suggest that there was reduced hospitalizations within 90 days. It should be noted that this was not a randomized controlled trial, this sort of proof of concept. So, it really warrants further study and studied in different patient populations. But it's really encouraging that maybe something that they can wear can actually keep people out of the hospital.

But one thing that comes up with all of these kind of wearable devices, including things from smart watches that detect heart rates and arrhythmias is who manages all this data? Patients can send all this data in and do we have the infrastructure in our system to be able to, you know, interpret all this data, make actionable advice related on that, and how do you, you know, have the time and the effort and the staff to potentially... So, we really also need new models of healthcare to kind of incorporate these expanding uses of technology for health.

Host: Yeah, absolutely. And so, you know, a bright horizon, you and I talked about in the last episode as well, where is AI going to start fitting into that? You know, I'm drowning in data, but starving for information. Can AI help turn all of that data into useful information for us to make clinical decisions for our patients? So, it's just exciting in what's going to be next. And one of the things I've always loved about medicine, it's constantly advancing, constantly growing. So, thanks. We've reached the end of this episode. And Dr. Michos, thank you so much. We'd also like to thank Merck for their support of the program.

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