The VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) Trial

Educational Objectives

After completing the activity, the clinician will be better able to summarize the results of VICTORIA, comparing vericiguat to placebo in a very sick population of patients with worsening heart failure and reduced ejection fraction.

Summary

Interviewer: Spencer B. King III, MD, MACC, Atlanta, GA

Take-home Messages:

• Soluble guanylate cyclase (sGC) is an enzyme that is important for the function of the blood vessels and the heart. It is insufficiently stimulated in heart failure (HF) because of impaired nitric oxide availability and endothelial dysfunction.
• In the multinational randomized VICTORIA trial, vericiguat — an investigational sGC stimulator — reduced the risk of the composite endpoint of hospitalization for HF or cardiovascular (CV) death in a large high-risk patient population with worsening chronic HF with reduced ejection fraction (HFrEF) compared to placebo.
• The beneficial effect was consistent across the majority of prespecified subgroups, including patients receiving or not receiving sacubitril/valsartan. Patients with N-terminal pro–B-type natriuretic peptide (NT-proBNP) in the lower quartile and patients under 75 years of age seemed to show the greatest benefit.

Despite optimal guideline-based treatment, patients with chronic HF have a substantial risk of death or hospitalization after a recent worsening HF event. New therapies to alleviate this major health care burden have been slow to appear.

One approach under study is derived from the Nobel Prize-winning work of Furchgott, Ignarro, and Murad, who discovered that nitric oxide (NO) is an endothelial-relaxing factor that mediates its favorable CV actions with the effector molecule 3′,5′-cyclic guanosine monophosphate (cGMP). In a nutshell, the key target of NO is activation of soluble guanylate cyclase, which generates cGMP that is critical for normal cardiovascular and cardiac function.

Because of the importance of this pathway (technically, the NO — sGC — cyclic GMP pathway), the use of cGMP-augmenting drugs has emerged as a key treatment strategy in HF. Sacubitril/valsartan, for instance, augments natriuretic peptides through inhibition of neprilysin, illustrating the enormous potential of cGMP-augmenting therapy for heart failure.

Now comes the novel sGC stimulator vericiguat, which directly enhances the cGMP pathway but without the tolerance that develops with long-term administration of nitrovasodilators. It could be beneficial, given that the increased inflammation and vascular dysfunction of HF results in reduced NO bioavailability, with a resultant decrease in downstream cGMP synthesis. This cGMP deficiency causes systemic coronary and renal microcirculatory dysfunction, which may lead to progressive myocardial damage, further inflammation, and possibly worse outcomes.

Beyond the basic science, there are other important aspects of the drug. Vericiguat is a once-daily medicine, easy to titrate, generally safe and well tolerated, and does not require monitoring of renal function or electrolytes. In short, the scientific rationale is sound, and it may be an easy-to-add medication that could play a useful role in patients with a recent worsening HF event.

VICTORIA

VICTORIA was the first large contemporary outcomes study to focus exclusively on a population with worsening HFrEF and a recent episode of HF decompensation. That makes the study participants a particularly high-risk group — indeed, an older, sicker population with higher NT-proBNP levels than those enrolled in previous HF trials — susceptible to repeat hospitalizations and CV mortality.

Vericiguat or placebo was given to 5,050 patients with an ejection fraction <45% as add-on to guideline-directed medical therapy.¹ Over a median of 10.8 months, significantly fewer patients on active therapy experienced a primary-outcome event (HF hospitalization or CV death). The differences were not large, but they were clinically meaningful, driven by a reduction in rehospitalization for HF that, by itself, reached clinical significance. On the other hand, CV mortality did not reach statistical significance on its own, although it was “directionally congruent” (Table).

The study design was a double-edged sword. The high event rate in VICTORIA was an expected result of the study’s design; the decision was made, in conjunction with regulatory agencies, to enroll a very high-risk population to efficiently accrue the required number of events. It worked, but events happened so fast that investigators hit their targeted number of events fairly quickly, meaning that follow-up was quite short (11 months in VICTORIA vs. 27 months in PARADIGM-HF and 18 months in DAPA-HF). Consequently, it was more difficult to show a significant difference in CV mortality.²

The beneficial effect in the primary endpoint was consistent across the majority of prespecified subgroups, including patients receiving or not receiving sacubitril/valsartan. Levels of NT-proBNP at baseline and age seemed to correlate with treatment effect. Specifically, the majority of patients in the study with NT-proBNP in the lower quartile ranges and those under 75 years of age showed the greatest benefit.

Vericiguat generally had a favorable side effect profile, although, compared to placebo, active therapy was associated with numerically more symptomatic hypotension (9.1% vs. 7.9%; p = 0.12) and syncope (4.0% vs. 3.5%; p = 0.30).

In this era of precision medicine, one result of VICTORIA is to underscore the need for better information regarding which patients with HF might benefit most from sGC stimulation.

In an accompanying editorial, John C. Burnett, Jr., MD (Mayo Clinic, Rochester), notes that ≈25% of patients with HF lack activation of atrial natriuretic peptide and have low cGMP levels.³ He wrote that additional studies would help to better understand whether targeting both sGC and particulate guanylyl cyclase with combination therapy (such as vericiguat and sacubitril/valsartan) would be synergistic or would increase the incidence of adverse events such as hypotension and syncope.

The results of an ongoing study of vericiguat in patients with HF with preserved ejection fraction (NCT03547583) are anxiously awaited.

VICTORIA: Vericiguat in Patients with Heart Failure with Reduced Ejection Fraction

	Vericiguat (n = 2,526)	Placebo (n = 2,524)	HR (95% CI)	p Value
Primary outcome event*	35.5%	38.5%	0.90 (0.82-0.98)	0.02
Secondary outcomes
HF hospitalizations	27.4%	29.6%	0.90 (0.81-1.00)	0.048
Cardiovascular death	16.4%	17.5%	0.93 (0.81-1.06)	0.269
All-cause death or HF hospitalization	37.9%	40.9%	0.90 (0.83-0.98)	0.02

*Death from cardiovascular causes or first hospitalization for HF.

CI = confidence interval; HF = heart failure; HR = hazard ratio.

Readings

Disclosures

Paul Wayne Armstrong, MD, FACC, Edmonton, AB

Bayer AG (C); Merck & Co Inc (C)

Interviewer: Spencer B. King III, MD, MACC, Atlanta, GA

This author has nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC520821

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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