This transcript has been edited for clarity.
Ileana L. Piña, MD, MPH: Hello. This is Ileana Piña, professor of medicine at Central Michigan University and adjunct professor at Case Western Reserve. This is my blog.
Today I am talking to you during the European Society of Cardiology (ESC) meeting, which is always an exciting time where we hear about a lot of new trials and new ideas. I am happy to have my good friend here, Dr James Udelson, who’s the chief of cardiology at Tufts University School of Medicine. Jim has dedicated his career to ventricular remodeling and heart failure (HF) and has published some of the seminal papers that have shown us that remodeling can be captured on nuclear scans and echocardiography. At ESC, he presented a late-breaking study called AVANTI.
We’ve talked before about the importance of the neurohormones, and today we’re going to be talking about vasopressin. The EVEREST trial of tolvaptan was conducted quite a few years ago. This trial included some of the sickest patients that were ever in a trial, and looked at improvements in hyponatremia and other outcomes. The results were kind of disappointing and the drug is now used for patients who are very hyponatremic and have been difficult to control otherwise. You can give them tolvaptan, recognizing that it’s not likely to change the outcomes. So, Jim, what’s so different about this trial? And tell us about this new drug.
James E. Udelson, MD: You set the stage very well. The issue with the previous vaptan drugs, and particularly tolvaptan, is that they predominantly involved antagonism at the V2 receptors. Vasopressin eventuates its effects through two receptors, the V1a and the V2. Tolvaptan was predominantly a V2 receptor antagonist and it consistently reduced weight, reduced dyspnea, caused an aquaresis or diuresis, and improved serum sodium in virtually every trial it was studied in. But in the long-term EVEREST trial, as you mentioned, outcomes were neutral. It’s conceivable that what happened — and this was supported by a couple of analyses from EVEREST — was that there was a reflexive increase in vasopressin levels as one of its receptors is antagonized. Thus, there was unopposed signaling to the V1a receptor, which is on vascular, smooth muscle cells in myocytes, leading to increased afterload, myocyte hypertrophy, etc., that may have balanced, in a negative way, any favorable effects that happened at the V2 receptor. So what’s novel in AVANTI is the drug, pecavaptan. In preclinical models, pecavaptan clearly had effects in a balanced way on the V2 receptor, like tolvaptan, but also on the V1 receptor.
Piña: How’s that different from conivaptan?
Udelson: Years ago, conivaptan was thought to be a dual receptor antagonist but, at least in the early human studies, you could not detect that signal. Systemic vascular resistance (SVR) didn’t go down and cardiac output didn’t go up. So it may have been a dual receptor antagonist, but the development was slowed down because it was an intravenous drug. Pecavaptan is an oral drug, and in animal models, SVR does go down and cardiac output does go up, so it seems very balanced. That was the basis for trying to develop this, to capture the good part that we know can happen from the V2 receptor, but then get the additional incremental benefit of the V1 receptor antagonism.
Piña: Who were the patients in the study ?
Udelson: This was meant to be an early phase 2 proof of concept in humans with disease study. For that kind of a trial, it was large, with about 450 patients, but we were trying to study multiple things. One of the novel aspects was that the patients enrolled were at the tail end of a decompensated HF hospitalization. There was no ejection fraction (EF) cut-off. It was across the spectrum of EF, and participants needed to have one of multiple signs of incomplete decongestion. As you know, that’s common at the end of an HF hospitalization; we don’t always have people tuned up so well. We wanted to capture people who needed additional decongestion over time. Those are the patients who were enrolled.
Piña: Did they stay in the hospital when they were enrolled or were they discharged?
Udelson: They could stay for another day or two after enrollment, but they could also be on the verge of discharge. The other novel aspect of this trial was that it was conducted in two sequential parts for 30 days each. In part A, patients were initially randomly assigned in the standard way to pecavaptan or placebo on top of standard of care for 30 days. The co-primary endpoints were weight loss and renal function. Our hypothesis was that weight would be better controlled by 1.5 kg; that was our target in the pecavaptan group. We also hypothesized that renal function would be improved.
Outcomes in that part of the trial were neutral. There was weight loss in the pecavaptan group but only about 0.25 or 0.3 kg lower.
Piña: Not what you were expecting.
Udelson: Not at all what we projected. And renal function was essentially unchanged and not improved. So we gained a lot of safety information, etc., but otherwise it was neutral — well, pinch-positive, but not to what we wanted to see. At the end of the first 30 days , patients were re-randomized. So, we randomly assigned the same patients to either pecavaptan as monotherapy — in other words, we withdraw loop diuretics — vs loop diuretics alone.
This idea goes back about 10 or 15 years. We did a 1-week-long trial with tolvaptan, taking away furosemide in a blinded way, and the patients remained stable. And it may very well be that a more physiologic volume control with a vaptan, and let’s say an MRA (aldosterone receptor antagonist), is a much better way to go than high-dose diuretics over time. AVANTI was an attempt to extend that concept out to 30 days of safety. The co-primary endpoints this time were noninferiority of weight loss. In other words, could you maintain that euvolemia for 30 days off a loop diuretic and improve renal function?
Piña: Whatever weight loss happened in part A, you wanted to maintain it in part B?
Udelson: That’s right. So that part of the trial was positive. There was noninferiority of weight loss between those two groups and renal function, measured as BUN: creatinine ratio, improved in the pecavaptan group. Another important feature was the major secondary endpoint, what’s called the augmentation index. It’s a measure of vascular stiffness. It was challenging, but we were trying to figure out whether we could identify the V1a effect, and we did see that in part B of the trial.
Piña: Do you think that happens also in the renal bed? Are those receptors in the renal bed?
Udelson: The V1a receptor is active in the renal medulla. So it may have had some impact on favorable renal function as well.
Piña: You would think that better renal blood flow could account for the improvement in BUN and creatinine.
Udelson: Potentially. As you know, it’s highly complex. The kidney is a complicated organ. The heart is a lot simpler in many ways. We did see positive effects based on very carefully defined parameters, all prespecified to the level of statistical significance we projected, for both weight loss and renal function. So that was really promising.
Piña: What is the next step now that you have these positive data? If you think about it, furosemide increases renin angiotensin, increases vasopressin. And here you’re trying to avoid getting that increase. I’ve been thinking this about diuretics forever. I always try to get patients off diuretics if I possibly can.
Udelson: That is one of the potential pathways forward in designing a trial. This was just a month of monotherapy, but I think one of the potential pathways is to see whether you could use a vasopressin antagonist, let’s say, in combination with an MRA. And many people will be on SGLT2 inhibitors and minimize or eliminate loop diuretic use — keep them at an absolute minimum or none in milder patients.
Piña: Wouldn’t that be wonderful not to have to give loop diuretics?
Udelson: That idea obviously resonates with you and would likely resonate with many of our colleagues. That is one potential next step. Another potential is more like part A, a standard add-on to everything-else therapy. Those are the two potential directions we may take now.
Piña: Is pecavaptan a once-daily drug?
Udelson: Once daily.
Piña: That’s always helpful. And does it have good bioavailability?
Udelson: Yes. As you implied with your comments about EVEREST, the vaptan drugs work pretty well, even at very low levels of renal function. EVEREST had the highest creatinine cutoff for inclusion. You could have a creatinine up to 3.5 and be enrolled.
Piña: And a high event rate, if I remember correctly.
Udelson: You’re exactly right.
Piña: Where will you publish this?
Udelson: We’re working on that right now. It was a very late-breaking study. We had the data only about a month before. One of the important questions is what happens to the background diuretic in the monotherapy group. We don’t actually have that pulled together this second. We’ll have that within the next week or so.
Piña: Your background drugs will be important because the HF with reduced ejection fraction group will likely be on renin angiotensin blockade, but the HF with preserved ejection fraction group could be on anything, including calcium blockers.
Udelson: We do know the baseline. What I think is important to help understand the endpoint results is what happened to the background loop diuretic dosing. In EVEREST, because the vaptans are very effective, the loop diabetic dosage went down.
Piña: The drug does produce aquaresis. I have used it quite a bit as far as a hyponatremia agent, and the patients do have aquaresis.
Congratulations, Jim. This is novel and it’s nice to hear that you’re thinking about another mechanism out of the box. We’ve been so focused on the SGLT2 inhibitors in the past couple of years.
Udelson: But there are other things going on too.
Piña: That’s right, and it’s nice to hear. Thank you for joining me today. We look forward to the paper. And to our audience, thank you for joining us. If you want to go back, take a look at the EVEREST paper. Mike Gheorghiade, rest his soul, is one of the primary authors. There’s a lot of important information that will help you understand this point about the V1 and V2 receptors.
Thanks for joining me today. Have a great day.
Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA’s Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.
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