A Win for Vericiguat in High-Risk Chronic HF Patients: VICTORIA

Treatment with the novel agent vericiguat (Merck Sharp & Dohme and Bayer), a drug that targets cyclic guanosine monophosphate (cGMP), significantly reduces the risk of cardiovascular mortality or hospitalization for heart failure in a high-risk heart failure population with reduced ejection fraction (HFrEF), according to the results of the VICTORIA trial.

Presenting today during the late-breaking clinical trial session at the “virtual” American College of Cardiology 2020 Scientific Session, VICTORIA’s investigators reported that this primary endpoint occurred in 35.5% of patients treated with vericiguat on top of guideline-directed medical therapy (GDMT) compared with 38.5% of patients in the placebo arm treated with GDMT alone (P = 0.02) over a median follow-up of 10.8 months.  The results were simultaneously published in the New England Journal of Medicine.

To TCTMD, lead investigator Paul Armstrong, MD (Canadian VIGOUR Centre/University of Alberta, Edmonton), said that even in the modern era of excellent GDMT for patients with HFrEF, roughly one in four will be hospitalized for worsening HF. “That’s where we think vericiguat adds value that didn’t previously exist,” he said. “We can say with assurance that we made a difference in a new population with a new drug.”

Roughly 24 patients with HFrEF and worsening disease would need to be treated to prevent one cardiovascular death or HF hospitalization, he said.

Clyde Yancy, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), one of the study discussants, said the VICTORIA trial is “another win in the treatment of heart failure, and that’s a good thing.” While there is excellent background therapy for patients with HFrEF, which typically includes inhibitors of the renin-angiotensin-aldosterone system, as well as implantable devices, the “portfolio” has been expanded to include the angiotensin receptor-neprilysin inhibitor (ARNI), ivabradine, and the sodium glucose co-transporter 2 inhibitors.

“To this we can now add vericiguat,” said Yancy. “This is really an important statement, because it allows us to focus on nitric oxide.” There are number of cardiovascular disease states, especially heart failure, where the bioavailability of nitric oxide is reduced, he said. Past attempts to target nitric oxide with exogenously administered long-acting nitrates, such as phosphodiesterase type-5 inhibitors, haven’t been very effective.

In heart failure, diminished nitric oxide and soluble guanylate cyclase (sGC) activity is precipitated by both endothelial dysfunction and oxidative stress, said Armstrong. Vericiguat stimulates sGC to produce cGMP and restore nitric oxide sensitivity. Increased cGMP production, said Armstrong, translates to decreased arterial constriction and arterial stiffness, as well as reduces myocardial thickening, ventricular remodeling, and fibrosis.

High-Risk Patients With Worsening HF

The VICTORIA study included 5,050 patients with chronic HF and an ejection fraction of less than 45%. All patients had a recent worsening event, which was defined as a hospitalization for HF/intravenous diuretic use and elevated natriuretic peptides (BNP or NT-proBNP). Baseline characteristics were well matched between the two study arms, with 60% of patients in both groups receiving triple therapy with a beta-blocker and a mineralocorticoid antagonist combined with either an ACE inhibitor, angiotensin receptor blocker, or angiotensin receptor/neprilysin inhibitor (ARNI). In total, 15% of patients were treated with an ARNI.

Treatment with vericiguat—which was started at 2.5 mg per day until the target dose of 10 mg daily was achieved—was associated with a 10% lower risk of cardiovascular death or first HF hospitalization (HR 0.90; 95% CI 0.82-0.98). “This translates into an absolute event reduction of 4.2 events per 100 patient-years,” said Armstrong. “Importantly, as one looks at the curves, the curves separate around 3 months, and the placebo event rate is strikingly high.” There was a trend toward a reduction in the risk of cardiovascular mortality but reductions in the composite primary endpoint appeared to be driven by the reduction in HF hospitalizations (HR 0.90; 95% CI 0.81-1.00).

Speaking with the media, Armstrong said the absolute rate reduction in the primary endpoint is comparable to that observed in the DAPA-HF and PARADIGM-HF trials. The VICTORIA trial, he noted, included a much higher-risk patient population, as demonstrated by the high rate of cardiovascular death/HF hospitalization in the placebo group.

Hospitalization for worsening HF represents a “major inflection point” in the natural history of the condition, which is characterized by a marked change in the risk of future hospitalizations and mortality, said Yancy. To date, no prior therapies have attenuated this risk, but vericiguat might be the first to alter the natural history of HF after a patient has had a worsening event. He pointed out, however, that despite the 10% reduction in the primary endpoint, the risk of death after HF hospitalization “appears recalcitrant to any of the current medical therapies—that is still an issue we have to address.”

Radha Gopalan, MD (Banner—University Medicine Heart Institute, Phoenix, AZ), a transplant and HF specialist who wasn’t involved in VICTORIA, called the results a win for patients. While the results are significant, the benefit of treatment was relatively modest, he said. But that doesn’t imply they won’t have a meaningful impact in clinical practice.

“In heart failure, we have very few therapies that are available for this particular population,” he told TCTMD. “In this particular group of patients who have been hospitalized or who have received intravenous diuretics as an outpatient, when they are seen in the hospital, we normally think about the next level of treatment, which is not continued medical therapy but tends to be mechanical circulatory support or heart transplant eligibility. When you think of it that way, you could consider this a game changer. It’s something heart failure specialists will try before committing a patient to transplant or mechanical circulatory support.”     

Both Gopalan and Yancy highlighted the characteristics of patients enrolled in the trial, with Gopalan pointing out that 75% were male and Yancy noting that just 5% were black. “That’s important because there are prevailing concerns that this unique patient population may exhibit exquisite nitric oxide bioavailability concerns,” said Yancy, referring to black patients. Gopalan made a similar point, adding, like Yancy, that further study of vericiguat in black HF patients will be warranted.

Side-Effect Profile

In VICTORIA, there was a significant interaction with baseline NT-proBNP levels, with investigators observing that patients with the highest levels (> 5,314 pg/mL) did not appear to benefit from vericiguat. Whether this is a play of chance or whether these patients might have HF too advanced to benefit from treatment is uncertain, they state.  Overall, the benefit of vericiguat was generally consistent across all subgroups, including patients taking an ARNI.

The rates of symptomatic hypotension and syncope tended to be higher with vericiguat, as was the rate of anemia, but the rates of serious adverse events were similar between the two treatment groups. There were no adverse effects of vericiguat on electrolytes or renal function. “Without the need for monitoring of renal function or electrolytes, [vericiguat] may play a useful role in patients with recent worsening heart failure,” said Armstrong.  

“Polypharmacy for heart failure with reduced ejection fraction is now officially a problem,” added Yancy, noting the plethora of drugs available for this population. “I think that’s a good one to have because we didn’t have that concern for many years and now we have to recognize there are multiple choices. With that recognition, we have to understand the time is now to be even more focused on precision medicine and understanding which patient under which circumstances should the current availability of treatments be administered.

Gopalan noted that HF patients tend to have low blood pressure and the struggle can be adding medications that can be tolerated with limited side effects. In VICTORIA, hypotension and syncope were numerically higher with vericiguat, which isn’t surprising given the drug’s mechanism of action on the nitric oxide pathway. If and when the drug becomes commercially available, tolerability of vericiguat will need to be established with each patient, he said.