VICTORIA: Vericiguat reduces events in high-risk HF
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Vericiguat, a novel oral soluble guanylate cyclase stimulator, reduced the incidence of HF hospitalization or CV death compared with placebo in patients with high-risk HF, according to data from the VICTORIA trial presented at the American College of Cardiology Scientific Session.
Results from this trial were also published in The New England Journal of Medicine.
“Because vericiguat (Merck/Bayer) is a once-daily medicine, easy to titrate, generally safe and well tolerated without the need for monitoring renal function or electrolytes, it may play a useful role in patients with recent worsening heart failure,” Paul W. Armstrong, MD, cardiologist and distinguished university professor of medicine at the Canadian VIGOUR Centre at University of Alberta, said during a presentation.
Patients with chronic HF
Researchers analyzed data from 5,050 patients (mean age, 67 years; 24% women) with chronic HF after a worsening event.
After a 30-day screening period, patients were assigned 2.5 mg of vericiguat (n = 2,526) or placebo (n = 2,524). The dose for vericiguat was increased in a stepwise fashion to 5 mg and then to the target dose of 10 mg once per day based on clinical symptoms and BP. Patients were followed up at 2 weeks and 4 weeks and then every 4 months thereafter.
The primary outcome was a composite of first HF hospitalization or CV death. Secondary outcomes included components of the primary outcome, a composite of all-cause death or first HF hospitalization, first and subsequent HF hospitalizations, and all-cause death. Prespecified safety outcomes of interest were syncope and symptomatic hypotension.
The primary outcome occurred in 25.5% of patients assigned vericiguat vs. 38.5% in those assigned placebo during a median of 10.8 months (HR = 0.9; 95% CI, 0.82-0.98), which led to an absolute event reduction of 4.2 per 100 patient-years.
“Importantly, as one looks at these curves, the curves separate around 3 months,” Armstrong said during the presentation. “You can see that the placebo event rate is already strikingly at 12 months such that we reached our prespecified target event rates at a median follow-up of about 10.8 months.”
HF hospitalization was observed in 27.4% in the vericiguat group compared with 29.6% in the placebo group (HR = 0.9; 95% CI, 0.81-1). CV death occurred in 16.4% of patients assigned vericiguat and in 17.5% of those assigned placebo (HR = 0.93; 95% CI, 0.81-1.06).
The prespecified secondary outcome of all-cause death or HF hospitalization occurred in 37.9% in the vericiguat group vs. 40.9% in the placebo group (HR = 0.9; 95% CI, 0.83-0.98).
Patients assigned vericiguat tended to have higher rates of symptomatic hypotension (9.1% vs. 7.9%; P = .12) and syncope (4% vs. 3.5%; P = .3) compared with those assigned placebo.
The number needed to treat for 1 year to prevent one primary outcome event is approximately 24 patients based on the absolute event reduction.
‘We have another win’
During the discussion portion of the presentation, Clyde W. Yancy, MD, MSc, vice dean of diversity and inclusion, Magerstadt Professor of Medicine, professor of medical social sciences and chief of the division of cardiology at Northwestern University Feinberg School of Medicine; associate director of Bluhm Cardiovascular Institute at Northwestern Memorial Hospital; and past president of the American Heart Association, said, “I think we need to sit back and acknowledge that we have another win in the treatment of heart failure, and that’s a good thing. We have a really wonderful background now of guideline-directed medical therapy for reduced ejection fraction heart failure. Previously, it was fairly straightforward with inhibitors of the RAS system, evidence-based beta-blockers, mineralocorticoid antagonists and implantable devices, but now we know that, that portfolio has been expanded to include the ARNI compound (sacubitril/valsartan (Entresto), Novartis), ivabradine (Corlanor, Amgen), the SGLT2 inhibitors both for prevention and now for treatment perhaps, and now to this we can add vericiguat.”
Lynne Warner Stevenson, MD, Lisa M. Jacobson Professor of Cardiovascular Medicine at Vanderbilt Heart and Vascular Institute, said the VICTORIA trial promises help to those patients who need more than the traditional triad of HF medications.
“It’s not only a therapy for a new physiologic target; it addresses a new population,” she said. “Patients with recent heart failure hospitalization with decompensation have been actively excluded from all the trials that have shown sustained benefit to reduce decompensation. Recent trials that do focus on this population have consistently shown no benefit, so VICTORIA finally addresses this large population of decompensated patients with unmet need.”
“VICTORIA builds on Merck’s strong legacy of conducting larger cardiovascular outcomes studies designed to answer meaningful questions,” Roy Baynes, MD, senior vice president and head of global clinical development and chief medical officer of Merck Research Laboratories, said in a press release from the company. “By enrolling patients receiving heart failure therapy following intervention for a worsening event such as rehospitalization or urgent outpatient treatment, VICTORIA was designed to study a serious medical problem not studied in any other recent heart failure outcomes study.” – by Darlene Dobkowski
References:
Armstrong PW, et al. Joint American College of Cardiology and Journal of American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Armstrong PW, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1915928.
Disclosures: The trial was funded by Merck Sharp & Dohme, a subsidiary of Merck, and Bayer. Armstrong reports he received grants from Bayer, Boehringer Ingelheim, CSL Limited, Merck and Sanofi-Aventis Recherche & Développement and personal fees from AstraZeneca, Bayer, Merck and Novartis. Stevenson reports she serves on a data safety monitoring board for LivaNova. Yancy reports his spouse is a nonclinical employee of Abbott Vascular. Baynes is an employee of Merck. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Radha Gopalan, MD
Overall, this is exciting in the sense that for the first time, a trial of this magnitude with about 5,000 patients looked at the nitric oxide pathway in very sick patients with HF who are symptomatic.
The nitric oxide pathway is something that we have been aware of since the 1980s from the very first HF trials. We knew that if patients were on nitric oxide treatment in the initial trials, they did not show a significant benefit with ACE inhibitors.
That was a subject of discussion for the past 25 years. In 2005, the A-HeFT trial was released looking at the nitric oxide pathway — isosorbide dinitrate — in combination with hydralazine in an African-American population, and it showed that there was an additional 15% benefit in mortality.
That was exciting, but the VICTORIA trial patient population is different in that these are very sick patients who have required a hospitalization for decompensated HF. This is an important trial in the timeline of HFrEF. Overall, I would categorize this as exciting and a win with modest results.
With regards to symptomatic hypotension and syncope, this is an area that HF physicians struggle with daily. Yes, it should be carefully looked at because this could become a problem with regard to uptitrating the medication to the target dose of 10 mg daily.
In the VICTORIA trial, about 60% of patients were on triple therapy, which is a good thing. Most patients with HF when they are on triple therapy already have hypotension. When the angiotensin receptor-neprilysin inhibitor came out, we struggled to uptitrate the ARNI to target dose because of the development of hypotension, and this is still an issue. Now we are going to add an additional medicine. While an additional drug is very exciting and encouraging, it also poses difficulty for the clinician to uptitrate and comanage these coexisting medications.
One of the things we would like to see is more of a major impact on mortality benefit. Most of the benefits were derived from a reduction in HF hospitalizations.
Importantly, there is a gender disparity in the patients included in the trial. Only about a quarter of the patients were females, so it’s very hard for us to extrapolate the results. I’m sure the researchers will do some subgroup analyses from this trial in the future. That will give some direction, but it would be nice to have more studies in female patients.
One of the most important areas is that only about 5% of the patients were African Americans. This is a population where the nitric oxide pathway might have a good impact. Future studies probably should examine the effect of vericiguat in the African American population with regard to the influence of the nitric oxide pathway.
One of the good things about this trial is the fact that it was a global trial. About 50% of the patients were from Europe and another quarter from Asia. It was a global study with about 5,000 patients included within a reasonably good period of time. In addition, comorbidities that existed in these patients are similar to what we see in the real world. A fair number of patients had atrial fibrillation, diabetes and hypertension. As a result, this population of patients resembles the patients that I see in the HF clinic, so it’s much easier to adapt the treatment.
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