VICTORIA PIs See Vericiguat as 'A Win' for High-Risk HFrEF

This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña, professor of medicine at Wayne State University, and this is my blog. We're living in interesting times, but the American College of Cardiology still did part of the meeting [virtually] by WebEx and Webcams. Today I'm joined by two principal investigators of the VICTORIA trial: Dr Chris O'Connor from Inova in Virginia, and Dr Paul Armstrong from the University of Alberta in Canada. I love the name of the trial because that is the name of my daughter. Welcome, gentlemen, and thank you for joining me today.

I loved your presentation, Paul. It was extremely well done. For our viewer audience, can you give me a very brief overview of the results?

Benefit of Vericiguat in High-Risk Heart Failure

Paul W. Armstrong, MD: Thanks, Ileana. It's good to be with you, and best wishes to everybody at this challenging time. VICTORIA was a team effort. Research is a team sport and this was a global initiative of which you were a part with 42 national leaders, 616 sites, and 5050 patients randomized to either [placebo or] vericiguat. Vericiguat is a novel guanylate cyclase stimulator, which opens a new pathway to heart failure because we believe that nitric oxide in that pathway is diminished because of the oxidative stress and endothelial dysfunction associated with heart failure.

Bottom line is that we've got a new therapy and a new pathway in a very high-risk population.

Patients were randomized to the target dose of 10 mg of vericiguat against placebo with excellent background standard of care, which you are great at reminding me about in terms of the importance. Of the participants, 60% were on triple therapy, 90% were on double therapy, 32% had devices. The primary endpoint was the conventional composite of cardiovascular mortality and heart failure hospitalization. We did achieve our principal endpoint with a 10% relative risk reduction—but importantly, 4.2% absolute benefit—on our primary endpoint, largely because of the extraordinarily high event rate within about 12 months. Our median follow-up is just around that. A 4.2% absolute benefit per 100 patient-years translates to a number needed to treat of about 24 patients to prevent one composite endpoint.

There is a lot of interesting additional information, including an interaction with natriuretic peptide that, no doubt, Chris will want to reflect on and that we're working hard to understand. The bottom line is that we've got a new therapy and a new pathway in a very high-risk population that previously has been underserved and has an unmet need. This occurred against a background of excellent standard care: 14% of patients were on sacubitril/valsartan and the treatment effect seemed to exist in those patients as well. We're pleased with the results. We reckon that this may help as many as 1 of 4 or 1 of 5 patients with heart failure, so we're hopeful that as we move forward, this will have a meaningful impact on the care of our patients.

Vericiguat vs Nitrates

Piña: Thank you, Paul. That was an excellent summary. Chris, for my audience of whom many are primary care docs, what is the difference between this drug and a nitrate? I've been using nitrates forever. What is so different about it?

Christopher M. O'Connor, MD: A lot of things about this drug are different from a nitrate. In the VICTORIA trial, this drug has been shown to be safe and effective. Nitrates have never really been shown in this population to be safe or effective. We know that people taking nitrates have problems with tolerance. We know that nitrates can cause hypotension. We have not seen the type of data that we need to change our practice with nitrates, even though they have been around a long, long time. [Vericiguat] has novel properties in its ability to stimulate and enhance the cyclic guanosine monophosphate pathway. Direct stimulation of guanylate cyclase is a mechanism that I think affords our patients and our practitioners a different pathway that provides benefit.

High Event Rate

Piña: I was really struck by the event rate. This is higher than just about every event rate that we've seen recently. Why do you think the event rate is so high? We're fighting this 30-day readmission rate, which you see at Inova as well, but that rate is usually about 25%. This is like a 32% event rate.

O'Connor: By design, over 60% of the patients were enrolled within 3 months of a hospitalization for heart failure, so we're enriching that population. This population event rate looks like what we saw in GUIDE-IT, EVEREST, and ASTRONAUT. What we know about those trials is that none of them were able to show a benefit. This trial was also enriched by having a high natriuretic peptide level for enrollment. Enriching the population to be a high-risk patient population that has not been studied in other large studies with other drugs provides an unmet need in an unmet area for our patients and our caregivers.

Piña: Paul, there was a simultaneous publication in Circulation comparing VICTORIA with some of the other trials, like PARADIGM-HF and DAPA-HF. Everybody has been very impressed with the results of DAPA-HF. Can you comment a little bit? There is a great table in that paper, and I recommend that my viewers look at it because it's very instructive.

Armstrong: Thanks, Ileana. We knew from the get-go that context was going to be very important in interpreting the results. If we look at the comparator arms in VICTORIA, DAPA-HF, AND PARADIGM-HF, primary endpoints (which were identical) were 37.8 [events per 100 patient-years] in VICTORIA, 15.6 events in DAPA-HF, and 13.2 events in PARADIGM-HF. The cardiovascular death rate in VICTORIA in the comparator arm was 13.9 [events per 100 patient-years]—we estimate that as 11%. It was 7.9% in DAPA-HF and 7.5% in PARADIGM-HF.

That high median natriuretic peptide, which was about double what it was in the other trials, was associated with 40% of participants being New York Heart Association functional class III or IV. Given that two thirds of the population had a hospitalization within the past 3 months, we captured then a very, very high-risk population on excellent standard of care. I think that tells us that even though the relative reduction was more modest than we anticipated, the absolute reduction is actually 4.2 events per 100 patient-years in VICTORIA, 4.0 in DAPA-HF, and 2.7 in PARADIGM-HF. You get the texture of how this translates into a public health perspective. We were delighted that Circulation published our context piece in conjunction with the New England Journal of Medicine paper because it gives people a bird's-eye view of the big picture in this population.

Signal of High NT-proBNP

Piña: Chris, I know a lot of papers will be coming out from this dataset because it's very rich and it's international. I will like to see the US data and this very interesting interaction with the very high N-terminal-pro B-type natriuretic peptides (NT-proBNP) > 5000 pg/mL. That to me was incredibly striking because patients do leave the hospital with very high NT-proBNPs. We saw that in GUIDE-IT, and not always are docs responding as they should. Can you comment on that interaction? What do you think that is?

O'Connor: We think it's a real signal because it makes physiologic sense that there could be a population of patients in which the degree of illness measured by the natriuretic peptide is so high that a drug may be less effective. We prespecified this analysis exactly like it came out. The P value and the strength of that interaction was high, so it does not look like it could be accounted for by a random fluctuation and multiple comparison of subgroups.

Piña: It will be very interesting to dive deep into that group and see who those patients are. Paul, do you want to comment on that?

Armstrong: Of course, we treat patients not by quartiles but on a grey scale of gradients of risk. We're working hard to elaborate with Chris, Justin Ezekowitz, and others like Richard Troughton, one of our New Zealand thought leaders who has been a world leader in natriuretic peptide pathophysiology. I think we're beginning to see a window that is quite broad in which the benefit of vericiguat may well extend not only to the primary composite [but] to both components of the primary composite. I encourage your listeners to stay tuned, because I think we'll have more to say about that in the months ahead as we peel back the layers of the onion in VICTORIA and learn about the richness of the data behind it.

Which Agent First?

Piña: I'm looking forward to that because we're going to learn a lot. These datasets always teach us. Chris, now we're going to have all of these drugs on the shelf. One of our biggest challenges as heart failure docs is, what do we go to first? Do you use dapagliflozin first? Patients leave the hospital with 13 drugs and we try to pare them down at their first visit. You can't live your entire life just trying to figure out what time to take your next medicine.

Armstrong: You are exactly right, and this is where the leadership in the heart failure community really needs to come together and help our broad community of colleagues and give them guidance. We have begun to have that conversation. Sacubitril/valsartan is a very good drug in chronic reduced ejection fraction heart failure. That is a drug that certainly has to be part of the equation. But as Paul pointed out nicely, this high-risk population proximal to a heart failure hospitalization really is an unmet need because they are often not treated with all the medicines out there, and there has not been this level of evidence, even with the exciting new therapies that you have talked about in this higher-risk population. I think it's going to be on us to come up with algorithms for treatment to help our practitioners and our patients get the best outcomes.

Heart Failure Trials -- Challenging and Changing

Piña: The Heart Failure Collaborative, of which you are the leader, is trying to improve clinical trial recruitment in this era. And now with all these trials, I think clinical trials are going to get even tougher to do. We finished VICTORIA at the right time because of other things that may be coming down the pike.

This horrible pandemic may allow us to think differently about clinical trial conduct.

O'Connor: That is a great point. COVID-19 influences so many aspects of our life and certainly has slowed down clinical trials and momentum for those that are enrolling and trying to complete their trials. But there could be an opportunity. This could disrupt the way we do trials, using more telehealth and remote monitoring and statistical monitoring, which can help reduce the cost of clinical trials and allow us to investigate more molecules, therapies, and devices in the long run. This horrible pandemic may allow us to think differently about clinical trial conduct that could be favorable for the ecosystem.

Piña: Either way, we have much to learn. Paul, do you want to give any final comments before we wrap it up?

Armstrong: Ileana, I would just say that we've now got a once-a-day medicine, which is easy to titrate. It's safe and well tolerated; 90% of people were on it at 1 year. You don't need to worry about electrolytes or renal function, which is a welcome relief for many clinical practitioners in terms of monitoring therapy. We're hopeful that it will be approved and provide a useful incremental role in patients with recent worsening heart failure events. I'm delighted for the opportunity to discuss this with you today, and I'm hopeful that we will learn more in the future and deliver better patient care.

Piña: We certainly look forward to that. Chris, any final words?

O'Connor: I think the bottom line is that this is a win for patients. Development programs for drugs and devices are very hard, and trying to get these completed is very difficult. This takes almost a decade of work, and to see this meaningful result is a win for patients. That is what I'm pleased about.

Piña: I want to thank Dr O'Connor and Dr Armstrong for joining me today. My viewers will really look forward to seeing more papers about this. We're going to learn a lot. It's a fascinating population. I want to thank my viewers. I wish for all of you to be well and be safe. Have a great day. This is Ileana Piña, signing off.

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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