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Vericiguat Benefits Even With High Adherence to HFrEF Meds

Vericiguat (Merck/Bayer), among the latest drugs to gain cred in heart failure (HF) with reduced ejection fraction (HFrEF), significantly benefits patients who are highly adherent to standard-of-care (SOC) HF meds, suggests a new VICTORIA trial analysis.

The novel agent seemed to improve the primary endpoint on top of the entire slate of SOC agents, individually and when they were combined as guidelines recommend.

The research, reported earlier this week at the Heart Failure Society of America (HFSA) Virtual Annual Scientific Meeting 2020, also hinted at potential clinical-outcomes synergy between vericiguat and a drug class that is a cornerstone of HF medical management.

The findings argue against misgivings that recent and any future additions to the HF armamentarium could be therapeutically redundant or add to patients’ daily pill burden and potential for side effects without much incremental benefit.

There is as yet little evidence for such an effect; also, vericiguat and SGLT2 inhibitors — another rising drug class in HfrEF — don’t predominantly work by the same mechanisms underlying current SOC meds. But redundancy and drug-drug interactions remain potential concerns as the HFrEF guideline-directed medical therapy (GDMT) list grows.

Although vericiguat’s treatment effect was largely consistent across all HFrEF drugs used in the trial, regardless of how adherence was defined, there was one noteworthy outlier.

Virtually everyone in VICTORIA was on beta blockers, at least among patients who could tolerate the drugs and didn’t have a contraindication. But only about half of patients were beta-blocker “dosage-adherent,” that is, they had been successfully uptitrated to at least 50% of the prescribed dosage, the current analysis shows.

Those patients, compared with those who had not achieved such dose-corrected beta-blocker adherence, showed a pronounced effect of vericiguat on the primary endpoint of cardiovascular death or first HF hospitalization over about 11 months. 

“It looks like there is potential synergy” between vericiguat and good beta-blocker therapy in the VICTORIA data, Justin A. Ezekowitz, MBBCh, University of Alberta, Edmonton, Canada, told | Medscape Cardiology.

But the question remains, “Is it real and physiologic, or from confounding or a play of chance?”

The trial entered 5050 especially high-risk patients with a recent HFrEF exacerbation. Those assigned to vericiguat on top of SOC meds showed a 10% decline (= .019) in risk for the primary endpoint.

Although the relative benefit appears modest, the absolute effect was striking, according to the trial’s researchers and expert observers. They were impressed that only 24 patients needed treatment with the drug to prevent one event, as previously reported by | Medscape Cardiology.

Moreover, suggests the current report, adjusted risk for the primary endpoint fell 28% among patients who met criteria for beta-blocker dosage adherence and were on vericiguat compared with placebo. There was no risk reduction for actively treated patients who had not achieved that level of beta blockade.

But it’s only a signal. “We’re very cautious and concerned about our interpretation,” said Ezekowitz, who had earlier presented the new VICTORIA analysis at the HFSA sessions.

Stress Associated With HFpEF but Not HFrEF?

Stress was linked to higher long-term risk related to heart failure with preserved ejection fraction (HFpEF), researchers found from the large REGARDS cohort.

People who reported feeling more stress had more incident HFpEF-related death and hospitalization over a median follow-up of 10.1 years compared with peers scoring zero on the Perceived Stress Scale (PSS) assessment:

  • PSS score 1-2: adjusted HR 1.37 (95% CI 1.00-1.89)
  • PSS 3-4: adjusted HR 1.42 (95% CI 1.04-1.95)
  • PSS ≥5: adjusted HR 1.41 (95% CI 1.04-1.92)

In contrast, stress had no discernable relationship with incident HFrEF events, reported Lauren Balkan, MD, of Weill Cornell Medical Center in New York City, during her presentation at a moderated poster session at this year’s virtual conference of the Heart Failure Society of America.

HFpEF is thought to be a progressive systemic disorder influenced by aging and key comorbidities, such as chronic kidney disease and obesity. It is possible that psychological stress is another one of those comorbid conditions, Balkan suggested.

“We already know that lifestyle factors, including emotional and psychological stress, contribute to heart failure via increased oxidative stress and activation of inflammatory and neurohormonal pathways,” Balkan said.

The study was based on the REGARDS cohort of more than 30,000 U.S. study participants, originally examined to evaluate geographic and racial disparities in stroke mortality.

The ongoing longitudinal study enrolled patients in 2003-2007. Participants underwent a baseline physical examination and reported detailed sociodemographic information, dietary patterns, and medication use. Subsequently, they were contacted by phone every 6 months for updates on hospitalizations and mortality.

Balkan’s group analyzed the 25,785 REGARDS patients (45% men, 40% Black, mean age 64 years) who were free of heart failure and had the four-item PSS completed at baseline.

This cohort was divided into quartiles by PSS score.

People in higher stress categories were more likely to be female, Black, and have income below $35,000 per year. They also exhibited more unhealthy behaviors (e.g., current smoking, alcohol use, and no exercise), and had a higher prevalence of comorbidities such as atrial fibrillation.

But interactions for age, sex, and income were not significant.

Limitations of the observational study include its reliance on self-reported measures and the assessment of stress at a single time point, Balkan acknowledged.

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    Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow


The REGARDS study was sponsored by the NIH.

Balkan had no disclosures.

Study coauthors reported ties to Amgen and Novartis.

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