In this interview with Dr Harriette Van Spall (McMaster University, Hamilton, CA) asks Dr Paul W Armstrong (Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, CA) about the VICTORIA trial. 
The objective of the Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction trial (VICTORIA) was to assess whether vericiguat reduced the primary composite outcome of cardiovascular (CV) death or first HF hospitalisation.

Transcription Below:

[Van Spall] I'm Dr. Harriette Van Spall, Associate Professor of Medicine at McMaster University, and I'm absolutely delighted to have with me Dr. Paul Armstrong, Professor of Medicine from the University of Alberta and principal investigator of the VICTORIA trial that was presented as a late-breaking clinical trial at the ACC in the last week, and published in The New England Journal of Medicine. Welcome, Paul.

[Armstrong] Good to be with you, thank you.

[Van Spall] So, the VICTORIA trial tested the efficacy of the soluble guanylate cyclase stimulator, vericiguat and heart failure with reduced ejection fraction. I wonder if you could start off by talking briefly about the mechanism of action of this drug.

[Armstrong] So vericiguat is, as you point out, a soluble guanylate cyclase stimulator, and the first in heart failure to be tested. It basically enhances the production of cyclic GMP which we know is diminished in heart failure based on the oxidative stress and endothelial dysfunction that surrounds the heart failure syndrome. We also recognise that it enhances nitric oxide pathway so that for those two reasons, we think that the enhancement of cardiovascular function and cardiovascular tone is enhanced with vericiguat.

[Van Spall] Wonderful. Why don't you tell us a little bit about the trial population and your methodology?

[Armstrong] Though we chose a high-risk population, and indeed ended up with a very high-risk population, these were patients who not only had heart failure with a reduced ejection fraction, as some of the more recent contemporary trials have, but they also had a recent worsening event. Usually associated with hospitalisation with a need for IV diuretics. And so at entry, we knew that because of, and they had very elevated natriuretic peptides, we expected that heart failure hospitalisation and cardiovascular endpoint, which was the composite of primary endpoint, would occur, and the trial was endpoint driven so we had a specific number of events that we needed before we concluded the trial, and we did that sooner than expected. In actually about 11 months. The trial was randomised, placebo-controlled, double-blind, and vericiguat was started in a dose of 2 and a half milligrammes and then titrated over just a few weeks to the target of 10 milligrammes. We achieved that dose, and in fact that dose was maintained at 12 months and close to 90% of both the placebo and the study drug population. And the... drug was well-tolerated, really no perturbations with electrolytes or renal function that required any modification of dosing.

[Van Spall] So you included patients with an EF of 45%, or less, and those with The New York Heart Association class 2 to 4 symptoms--

[Armstrong] Right.

[Van Spall] And they were a high-risk population, as you pointed out. Why don't you tell us some of the exclusion criteria because it's important that we bear that in mind as clinicians when we--

[Armstrong] Sure, so if they were on long-acting nitrates we excluded them or a phosphodesterase inhibitor, given the drug-drug interaction with the general pathway, but we actually enrol patients with diminished renal function, in fact, we went down to 15 mL of GFR, and of course the usual exclusion criteria, if there was impaired length of life because of comorbidities or correctable cardiac conditions, we excluded them. And we ended up then with actually 40%, as you point out, with function class 3, and a natriuretic peptide, the natriuretic peptide levels entry were higher in the atrial fib than in the sinus rhythm group but the 2,800 was the median natriuretic peptide at entry. So a high-risk population was what we sought and what we got.

[Van Spall] Right, higher risk than many of the contemporary trials in HFrEF. Why don't you share with us the results of your primary outcome?

[Armstrong] So, at about 12 months, the control, or placebo arm of the population had a combined event rate of over 38%, extraordinary, about double or triple of most heart failure trials. And we saw a relative reduction that was modest, 0.90 was the hazard ratio, p-value at 0.019. But when you look at the event rates, it actually translates into a 4.2 reduction in the primary composite event rate per 100 years treated, which is efficient in terms of 24 patients required to grant one endpoint. When we looked at the components of the primary endpoint, the heart failure hospitalisation was significant, the cardiovascular death did not reach significance, the actual number was 12.9 in the placebo group and 11.9 in the vericiguat group. We had expected a mortality rate of 11% and you can see we exceeded that by almost 2%. All heart failure hospitalisations were reduced and our secondary composite have all caused mortality in heart failure, hospitalisation was also reduced. So, we were pleased with the endpoint, and pleased that in terms of the vulnerability of the drug that we thought that this was a result that might help patients in the future.

[Van Spall] Can you speak about the rates of hypotension and anaemia in both groups?

[Armstrong] So, we saw about a 3 or 4% increase in anaemia compared to placebo. The anaemia was evident at about 16 weeks, and then stabilised. There was no evidence that we could see of hemolysis or blood loss, and the mechanism remains controversial and uncertain to be quite honest. There's been dilution suggested, other factors. It is in the label for riociguat, its country cousin that was approved for pulmonary hypertension.

[Van Spall] Right.

[Armstrong] And we're building into that. We have a very rich data set. But I don't know what the mechanism was. The hypotension and the syncope, which were our pre-specified safety endpoints, thank you for reminding me, tended towards being more frequent in the vericiguat than in the placebo group, but they were not significantly different. But certainly they were there and manageable and our investigators were told, of course, to maintain the evidence-based therapy on which these patients were on. I should've said that 60% were on triple therapy and 90% on double evidence-based therapy, and 14% on sacubitril/valsartan with a treatment effect that was not modified and there is one subgroup that's of particular interest that we're pursuing that is The New England Journal of Medicine didn't allow us to publish the interaction p-value on the brain natriuretic peptide, but in the upper quartile of natriuretic peptide, it was actually a high significant interaction term p-001 for those patients in the highest natriuretic peptide. Fascinating finding, one that we're pursuing and we hope to bring to light at future meetings and to publication soon.

[Van Spall] Wonderful, and a point about guideline directed medical therapy, in light of the timing of this trial relative to DAPA-HF is that I anticipate virtually no patients were on dapagliflozan.

[Armstrong] Absolutely, and if the audience is interested in looking at this, we've done a cross-trial comparison in a Circulation paper that was published simultaneously which tries to put in context DAPA-HF and PARAGON trial both in terms of the baseline features and the number needed to treat and the background therapy. What role SGLT2 inhibitor plays as a background therapy in this population and whether the worsening heart failure, which Dr. Stevens who commented on the trial talks about as a new issue in heart failure. These patients who seemed to have worsened despite excellent therapy. These people had 32% use of devices and ICDs. We think maybe one in four, one in five patients with chronic stable heart failure would fit into this category, but you're absolutely right, whether DAPA-HF or other gliflozin therapies will play a role here, we don't know.

[Van Spall] Right, and this brings me to my final question, we now have a five alive cocktail, so to speak. How do you see this class of medications fitting in with beta blockers, ACE inhibitors, ARNI, dapagliflozin, and ivabradine? Where do you see this coming in in terms of sequence of introduction to a patient's regimen, once it gets approved?

[Armstrong] So, we can say with assurance that these patients were exceedingly well-treated with guideline-based therapy. So I think setting the SGLT story aside for a moment, patients that either cannot tolerate or worsen with guideline-based therapy, I think this gives you a new option that was not previously available, and applies to a substantial fraction of patients, but this is not first-line therapy, for sure. This is the heavy artillery you bring out when things are not going well. But, of course, as you well know, they don't go well for a lot of proportion of patients of heart failure. If you look carefully at the DAPA study, and indeed you look at the thoughtful editorial, by Fong in that paper, you'll see with speculation that these patients were at low-risk and would that therapy work in a higher-risk population? I think DAPA, I think we don't know that question, but we do know that vericiguat works in that population, so I think it's in the eye of the beholder and we encourage people to look across trials and look at our work and others' and make an informed decision, but I think good that clinicians will have another arrow in their quiver.

[Van Spall] Right, and a large proportion of patients with HFrEF have ischemic heart disease. What can you say about the safety and efficacy in this population?

[Armstrong] Similar efficacy, similar safety in that population, which as you would guess, was probably about 2/3 of the population and we have a very talented executive committee and 42 national leaders that are all primed to begin to help us write on some of the subgroups that are pre-specified and some of the other data that we think will have more clinicians in terms of the use of the therapy and hopefully that'll be available by the time this drug is approved.

[Van Spall] Thank you so very much for joining me today. It was a pleasure to meet you and we're delighted on this successful trial that you led. Thank you, Dr Armstrong.

[Armstrong] Thank you very much. Good to be with you.