Dr Javed Butler on Key Takeaways of Vericiguat Found in VICTORIA Trial Participants With HFrEF

March 28, 2020

Results from VICTORIA show vericiguat produced a 10% relative risk reduction in the highest-risk patients with heart failure. Study patients had about 3 times the health risk seen in recent heart failure trials, which showed higher relative risk reductions. However, VICTORIA saw a 4% absolute risk reduction, which is the same as the others, said Javed Butler, MD, MPH, MBA, chairman for the Department of Medicine at the University of Mississippi.

The result for the primary endpoint of VICTORIA was statistically significant. There was a 10% relative risk reduction among patients who were much higher risk on average than those in recent heart failure trials that produced larger relative risk reductions. However, there was an absolute risk reduction of 4% which is the same or better than those recent trials, said Javed Butler, MD, MPH, MBA, professor of physiology and chairman for the Department of Medicine at the University of Mississippi.

Transcript

Can you discuss the burden of heart failure in the US population? Do some groups have a greater burden than others?

So, there are about 6 million people in the US that have heart failure—the annual incidence is about 3 quarters of a million or a little bit higher than that. So, the burden is quite extensive, and unfortunately, the hematologic trends are such that this will increase by about 25% by the year 2030. So, not only is the burden quite high right now, it is expected to go up pretty substantially as well; but there are subgroups of people who are at a particularly higher risk for developing heart failure. So, those people who have diabetes, obesity, high blood pressure, valvular heart disease, these are the people that have a higher risk of developing heart failure, but I think probably the biggest reason why the incidence and the prevalence of heart failure is increasing is because of the aging of the population as most heart failure cases are older patients–older patients are at a higher risk.

Can you describe the mechanism of action for vericiguat? What is the potential to address an unmet need?

So, heart failure is a state in which you have generalized endothelial dysfunction and decrease nitric oxide production. Naturally, nitric oxide is the molecule that goes into the cell and then binds to this enzyme called soluble guanylate cyclase. After binding that, that leads to increased production of cyclic GMP. So, cyclic GMP (CGMP) signaling further down in multiple organs of the body, and has a lot of beneficial effects but in terms of cardiovascular system—causes vasodilation to improve endothelial function, decrease fibrosis of the heart, remodeling of the heart.

So, there are all these beneficial effects that occur in the cardiovascular system; but in the presence of oxidative stress, there is substantial reduction in nitric oxide and subsequently the action of the soluble guanylate cyclase. So, what vericiguat does—it's a novel medication that sort of bypasses that nitric oxide step and just directly binds and stimulates the soluble guanylate cyclase–directly increasing the solid CGMP production and all the downstream beneficial effects on the cardiovascular system.

As the results met their primary endpoint, in your view, what are the most important takeaways?

So there is currently an unmet need in patients with heart failure reduced ejection fraction. If you look at over the past 3 decades or so, there's been a lot of good medications that have come out to show benefits and outcomes for these patients, but remember, we started at such a bad point, people had 30-35% 1-year mortality that even with all those therapies, the reduction in mortality even in disabled patients, we're talking about 10% or so, and low mortality.

Now there's a special high risk group of patients called worsening heart failure. These are the patients who have been stable sort of in the outpatient setting on whatever the medication that you were giving them, but now that therapy is not enough for them, and now they're developing worsening heart failure symptoms requiring escalation of therapy or hospitalization in many, many cases. These patients, once they get hospitalized, we're talking about 25-30% 1-year mortality, so a much higher risk group of patients. So, that's where this medication vericiguat was tested in the VICTORIA trial, and what we found was that the primary endpoint for combined heart failure hospitalization and cardiovascular mortality was a benefit that was beneficial.

Now, what is the magnitude of benefit? It has to be sort of looked at in both relative risk reduction and absolute risk reduction because the amount of benefit is actually related. Not only to how efficacious the drug is, but as well as what is the baseline patient population, which was admitted in the clinical trial, with the inclusion exclusion criteria. So, as mentioned, this was a high risk group of patients.

The primary endpoint was statistically significant, it was a 10% relative risk reduction, but it was a very short follow up of about 10 months on average, because these patients had such a high risk—about 3 times a higher risk than some of the recent heart failure trials that we have seen. So therefore, the event emulation was much faster, and as I said, the average follow-up was about 10 months or so. So, if you actually look at the absolute risk reduction, there was about a 4% absolute risk reduction, which is the same or better than some of the recent trials that we’ve seen.