COMMENTARY

Nebulized Nitrite for HFpEF? Don't Hold Your Breath

An Interview With INDIE-HFpEF Investigator Barry Borlaug

Interviewer: Ileana L. Piña, MD, MPH; Interviewee: Barry A. Borlaug, MD

Disclosures

April 02, 2018

Ileana L. Piña MD, MPH: Hello. I'm Ileana Piña from Montefiore Medical Center and the Albert Einstein College of Medicine in the Bronx, and this is my blog. I am here at the 67th Sessions of American College of Cardiology (ACC) in the beautiful city of Orlando, where it's been sunny and nice.

Barry Borlaug from the Mayo Clinic is with me today. Barry is head of circulatory failure research and presented a very interesting paper that is hopefully soon to be published. Welcome to the show.

Barry A. Borlaug, MD: Thank you very much.

Piña: We've had a lot of discussions in this blog about heart failure (HF), particularly HF with preserved ejection fraction (HFpEF), which we know so little about. We had two very large trials that were totally negative (iPRESERVE and CHARM-Preserved),[1,2] and then we had TOPCAT,[3] which showed that giving an aldosterone blocker improved hospitalizations and perhaps even survival. Many of us are wondering, what's next? Tell us about your work and what is next.

Why Nitrite?

Borlaug: I started out being interested in HF just from a pathophysiologic perspective. I wanted to understand what causes it and how hemodynamics translate to the symptoms our patients experience every day. In more recent years, I've tried to extend my understanding to what we can do about it. That was the motivation for pursuing what ultimately became the INDIE trial.

Piña: How did you come to the idea of using nitrite?

Borlaug: We used to think that nitrite was just an inert byproduct of nitric oxide (NO) in the body, but it turns out it can be recycled back into NO in a one-step reduction reaction that is catalyzed by hemoglobin and myoglobin, common molecules in the body. That conversion of nitrite to NO is facilitated when there is low oxygen tension and when there is acidosis. When is that happening all the time? During exercise. We know from clinical observations of people with HFpEF that they most frequently have hemodynamic abnormalities when they are exercising, because that is when they are really stressing the heart.

We thought this might be a way to target delivery of NO—just at the time when patients need it the most. That was the idea.

Evidence suggests that one overarching process in HFpEF is an NO deficiency...

Piña: Why would you think NO would be a treatment for this population?

Borlaug: That is a great question. Evidence suggests that one overarching process in HFpEF is an NO deficiency[4] related to low-grade systemic inflammation from such things as obesity, hypertension, and metabolic syndrome—things we commonly see in people with HFpEF.

A lot of work, mostly from Walter Paulus's group in Europe, has shown that even without histomorphometry and elegant analysis, many of these people are NO deficient.[5] A lot of strategies and approaches have been and are being tested to try to restore that NO signaling.

Piña: How hard is it to get nitrite?

Borlaug: It is actually pretty easy. We use inhaled nitrite. Nitrate and nitrite are in foods we eat, such as green leafy vegetables and beetroot juice. But the amount that we administer with this inhaled nitrite, which was tested in the trial, leads to levels that are about an order of magnitude higher. It is a much more potent delivery, and in an acute invasive study,[6] we show that those levels could lead to favorable reductions in pulmonary artery pressure and left-heart filling pressures, especially during exercise.

INDIE Trial Design

Piña: Tell us about the INDIE trial.

Borlaug: The trial[7] has a crossover design and enrolled people with HFpEF. We define people with HFpEF the old-fashioned way, with an ejection fraction (EF) ≥ 50%. They all had to have objective evidence of HF: an HF hospitalization, a high B-type natriuretic peptide (BNP) or NT-proBNP level, significant echo Doppler diastolic dysfunction with treatment of a loop diuretic or a cath showing it. We were pretty rigorous. They also had to have an objective exercise disability; their peak VO2 had to be < 75% predicted.

Piña: That would be pretty easy with the HFpEF patients I'm thinking about.

Borlaug: We also had a four-point question. They had to answer that their symptoms were mostly limited by breathlessness and fatigue rather than hip or knee pain, orthopedic issues, or peripheral edema. They had to be limited mostly by breathlessness. We wanted to enrich the population with real HFpEF.

Piña: You were really serious about finding this population. What diastolic indices did you use on echo?

Borlaug: We ended up using an E/E' ratio > 15 or left atrial enlargement. We felt that those were the two easiest indicators of HFpEF that were also fairly robust. Again, patients also had to be on a loop diuretic.

Piña: At least for diagnosis, left atrium enlargement has been pretty consistent when you look across trials—even trials that have been negative. Then what happened?

Borlaug: We brought patients in. On their first visit, they did an exercise test to verify they had true impairment at baseline.

Piña: What was their peak VO2?

Borlaug: The average was 13.8 mL/kg/min.

Piña: That's interesting. In HF-ACTION,[8] it was 14.2 mL/kg/min.

Borlaug: Then they all received a single open label test dose of inhaled nitrate as a run-in. We wanted to make sure that they were able to tolerate it and would not have hypotension, intolerance, or headaches. If they tolerated it, they were randomized. Then there was a 2-week period where we just collected data. The primary endpoint of the study was peak exercise capacity—peak VO2.

We're also really interested in accelerometry, because if a medicine makes you feel better, we think you are going to move around more and be more willing to do stuff. In this first 2 weeks, patients wore the accelerometer but did not get any medicine, to establish a baseline.

Then they started treatment with a low dose of study drug. They got low-dose nitrite at 46 mg or placebo for 1 week, and then a target dose of 80 mg nitrite or placebo for 3 weeks. After 4 weeks of treatment, they returned and did another cardiopulmonary exercise test for an endpoint assessment, along with an echocardiogram and blood work.

Piña: How did they get the inhaled nitrite?

Borlaug: It's in a hand-held nebulizer device that they could take with them. They had to take it three times a day, so it's a bit of an undertaking. It was a bit of a commitment for them to do that, but they did. They returned, we did the endpoint assessment, and then they crossed over to the other side. If they got nitrate the first time, they got the placebo the second time. That way, the power is much better because each person is their own control.

Mirroring the first phase, we had another 2-week phase for washout so that the drug would not have any carryover effect into the second period. Then they did the same thing: 1 week at low dose and 3 weeks at high dose, for 4 weeks total.

Piña: Did you get another peak VO2 after the crossover and the cleanup for 2 weeks?

Borlaug: No, we did not do another baseline [measurement]. Baseline was done at their initial visit, and visit 2 was the initial treatment. After 4 weeks, they came back and did the same visit as the previous visit with exercise endpoints, quality-of-life questionnaire, bloodwork, and echocardiography.

Piña: What quality-of-life questionnaire did you use?

Borlaug: We used the Kansas City Cardiomyopathy Questionnaire (KCCQ).

INDIE Results

Piña: What did you find?

Borlaug: Unfortunately, and contrary to our hypothesis, we found that nitrite did not improve peak exercise capacity. There really was not any change. The mean change was -0.2, but it was not significantly different than zero. It was really nothing.

Piña: Did you give them any instructions on activity? The old nitrate story is that back from the V-HeFT trials, if the patients felt better, they were autorehabilitating themselves by doing more. I think some of those numbers were time-dependent.

Borlaug: That is exactly right, and we encouraged lots of activity in both groups throughout the trial. We encouraged them to do as much as they could. In retrospect, it's really hard to motivate people to do that. There was no structured exercise intervention. That is one potential problem why we did not see anything. Exercise training is really the key, I think.

Piña: What was the KCCQ score?

Borlaug: It didn't change at all. The average score was about 55.

Piña: In HF-ACTION, it was 59. Isn't that interesting? Everything ratcheted a little bit less than that. What else did you collect?

Borlaug: We did accelerometry data that give you highly granular data and average daily activity levels. These data did not change a lick at all with nitrate. Patients were not moving around more; they were not more active. We did physician-estimated New York Heart [Association] class, and that did not change at all. We did echocardiography, but that was performed at trough.

I should mention that the exercise tests were performed right after a single dose of the nitrite. It should have been a maximum pharmacodynamic effect, but the echos were done at trough before they got that, so we didn't see any effect on E/E', or PA systolic pressure estimated by echo or left atrial volume.

Piña: One of your colleagues, Maggie Redfield, had a paper on hydralazine and nitrates.[9] How does this fit into the picture?

Borlaug: We tested isosorbide mononitrate in the NEAT trial, and that actually decreased activity levels.

Piña: Everybody uses that because of the ease of giving it instead of the regular isosorbide dinitrate.

Borlaug: We're trying to stop it now. I think the latest guidelines[10] have suggested that we should actually be avoiding that and using dinitrate or just sticking with diuretics, unless there is another compelling reason. We are trying to avoid isosorbide mononitrate for sure.

Piña: Did you have enough African Americans in your group to make any comparisons?

Borlaug: We did not. The centers that ended up being the leading enrollers were not areas that had a lot of African American people. It was a mostly a study in Caucasians, and that is a limitation.

What Is HFpEF, Anyway?

Piña: What are we doing with this HFpEF business? What do you think it is?

Borlaug: It's breathlessness and fatigue due to some cardiac abnormality that I can measure. We can't measure things or do caths on everybody, but at least that provides a reference standard that we can use. The old Braunwald definition is the inability of the heart to pump blood to the body at a rate commensurate with its needs, or to do that pumping only at the expense of high filling pressures.

We can measure those things in the cath lab, and that is what we are doing. If I measure that they have symptoms and they have a high filling pressure, I'm calling that HFpEF.

There are obviously a lot of things that cause that constellation. How do we break those down and get more granular into those sub-endophenotypes of different people who would respond differently? That is where I think we need to go in the future.

Piña: Why do women have more of it later in life than the men? We see all these comorbidities, such as diabetes and hypertension. What are new diabetes drugs going to do in patients who are diabetic and have HFpEF? It's going to be very interesting.

Borlaug: It's a great point. About 40% of them have diabetes, and an even higher number have metabolic syndrome. Average body mass index in INDIE was over 35 kg/m2. It's really a disease of obesity, metabolic syndrome, and sedentariness. We need to get creative and think harder about what we can test next to get these people feeling better.

Piña: Did you get good respiratory exchange ratios (RERs) on the test?

Borlaug: We did. That was in the inclusion criteria. They had to be able to reach a RER > 1.

Piña: The ventilatory threshold didn't change either?

Borlaug: There was no difference in the oxygen consumption at anaerobic threshold. There was a trend toward an improvement in ventilatory efficiency; the V'E/V' CO2 slope went down a little bit (P = .11). With how congruent the other findings were in a neutral fashion, it's hard to read too much into it.

Piña: Yes, some of it may be just efficiency. I want to congratulate you, because these studies are so hard to do. This population is not easy, either. I'm hoping we're going to see this in the literature soon.

Borlaug: I hope so too. We're working on it.

Piña: We will fully support that. Thank you for joining me today, and thank you for joining our audience.

Borlaug: Thank you.

Piña: I hope this gets again to the conversations we have had about HFpEF, and what it is and what it isn't. I don't think we have a good definition yet. Every study has a little bit different definition and includes different patients. I think we're realizing that maybe it's a multitude of different syndromes, compiled into one.

I want to thank you for joining me today from the ACC in Orlando. Have a great day.

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