New Vericiguat Shine May Not Brighten Heart Failure With Preserved LVEF

June 15, 2020

Although a drug therapy shown to improve clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remains as elusive as ever, an agent offering functional or quality-of-life (QoL) gains would also be welcome. 

But vericiguat (Merck/Bayer), a novel agent with newfound fame on another stage in the HF arena, doesn't appear to be that drug, suggests a new randomized, controlled trial with a broadly defined HFpEF population.

Still, even a "negative" or "neutral" HFpEF trial may still have something to teach about the syndrome, researchers say.

Patients who received vericiguat uptitrated to either of 2 dosage levels for 24 weeks, compared with a placebo, showed no improvements in 6-minute walk distance (6MWD) or their daily-living activities (DLA) scores in a widely used QoL questionnaire.

The trial, called VITALITY-HFpEF, with more than 800 high-risk patients with HF in 21 countries, was neither designed nor powered to assess clinical outcomes on the drug, an oral soluble guanylate-cyclase (sGC) stimulator.

Rather, it aimed to explore a vericiguat QoL signal observed in a HFpEF trial published 2 years ago called SOCRATES-PRESERVED, which had failed to show a benefit for primary endpoints based on natriuretic peptides and left-atrial volume, said Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada.

Side effects were another focus of the new study. Symptomatic hypotension and syncope were more common on vericiguat in VITALITY-HFpEF, and appeared dose-dependent. The trial had entered "fairly typical" patients with HFpEF who tended to be on multiple antihypertensive medications already, Armstrong said in his June 12 presentation of the study.

His report capped a Late-Breaking Science Session held during HFA Discoveries, the online substitute for the annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology. The traditional HFA sessions had been dropped this year due to the COVID-19 pandemic.

Vericiguat has already impressed the cardiology community by showing a modest but significant effect on cardiovascular death or first HF hospitalization in the VICTORIA trial, with its more than 5000 high-risk patients with HF and reduced ejection fraction (HFrEF).

In VICTORIA, the drug had been given at an uptitrated dosage of 10 mg/day and was not associated with excess symptomatic hypotension. Vericiguat in VITALITY-HFpEF was uptitrated to 10 mg/day and, in a separate randomization arm, a newly explored 15 mg/day dosage.

Once again, a drug therapy that has shown some success in HFrEF disappointed when extended to HFpEF, observed Brenda Moura, MD, Hospital Regional Militar, Porto, Portugal. She added vericiguat to a list with recent additions that include an SGLT2 inhibitor and sacubitril/valsartan (Entresto, Novartis).

The current study may offer opportunities to guide exploration of HFpEF drug management in the future, she proposed. "I do think we can learn from neutral trials." Are these agents being tested in too broad an HFpEF population, she asked, or are the wrong endpoints being used?

Patients with HFpEF "have a much higher burden of noncardiac comorbidities and higher noncardiac death rate" compared to those with HFrEF, Moura pointed out. "So it's much more difficult for a drug to show benefit of reduced mortality in HFpEF patients."

But also, "We know that a primary focus of patients with HFpEF is having the ability to perform their daily activities." So, she said, "I totally feel that exercise tolerance is a very important endpoint to evaluate in the trials."

As for the VITALITY-HFpEF target population, "I guess the idea was to have a very good representation of all HFpEF patients," who in reality are quite heterogeneous. Vericiguat and other drugs in its class address some abnormalities that are common in the syndrome, such as left ventricular (LV) hypertrophy and vascular resistance, Moura observed.

So the results might potentially have been different had the entry criteria been based on "clinical phenotyping," with a focus on patients with more severe LV hypertrophy, for example, or exclusion of patients with exercise limitation due to chronotropic incompetence, she speculated.

The trial collected "extensive biomarkers," responded Armstrong. "We're hopeful that the biomarker profiling might add value in discriminating within this complicated disorder, for which treatments seem to be so challenging, to unravel the mysteries around distinctive phenotypes."

VITALITY-HFpEF entered patients with an LV ejection fraction (LVEF) of at least 40%, elevated natriuretic peptide levels, either LV hypertrophy or left-atrial enlargement or both, and a decompensation event within the prior 6 months.

Of the 788 patients ultimately randomized, about 48% were women, 45% had coronary disease, 41% were in NYHA functional class 3, and slightly more than one third had atrial fibrillation; their mean LVEF was 56%.

Patients in all three arms showed "modest" improvements in PLS scores on the Kansas City Cardiomyopathy Questionnaire, the primary endpoint, but there were no significant differences at 24 weeks. Change in 6MWD, a secondary endpoint, showed the same pattern.


Selected Adverse Events (AE) in VITALITY-HFpEF by Treatment Group

Endpoint Placebo, n=262 10 mg, n=262 15 mg, n=264
Any AE, % 65.6 62.2 65.2
AE leading to treatment discontinuation, % 2.7 3.4 4.5
Symptomatic hypotension, % 3.4 4.2 6.4
Syncope, % 0.4 0.8 1.5
Cardiovascular death, % 1.5 4.6 3.0
Death from any cause, % 2.7 5.7 3.8


Adverse events "were similar and common across all three groups," Armstrong said. Syncope and symptomatic hypotension became increasingly common with rising vericiguat dosage, as did study discontinuation due to adverse events.

"There was also some imbalance in the number of cardiovascular deaths and overall mortality," Armstrong observed. But there are so few events in the small trial, "I'm reluctant to say that anything other than the play of chance is likely operational here."

VITALITY-HFpEF was supported by MSD and Bayer. Armstrong has disclosed receiving research grants from Merck and Bayer; and consulting fees from Merck, Bayer, AstraZeneca, and Novartis. Moura had no disclosures.

HFA Discoveries 2020. Late-Breaking Science Session 3. HFpEF

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