Vericiguat Success in HFrEF May Not Apply to Sickest: VICTORIA

June 23, 2020

A natriuretic peptide assay could potentially identify patients with heart failure (HF) with reduced ejection fraction (HFrEF) who have either the most or the least to gain from add-on therapy with vericiguat (Merck/Bayer), suggests a post-hoc VICTORIA analysis.

It showed that patients with the highest levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), which track with HF severity and risk, missed out on the significant clinical benefit seen in the overall population. 

The modest but significant clinical advantage in patients taking the novel agent, an oral soluble guanylate-cyclase stimulator, compared with placebo, appeared to concentrate in the 86% who had baseline NT-proBNP levels 8000 pg/mL or lower.

In that group, the risk reduction for the primary endpoint of cardiovascular (CV) death or first HF hospitalization reached 15%, compared with 10% in the overall trial; there were similarly sized benefits for the composite endpoint's individual components.

Those risk reductions "were further amplified in patients with NT-proBNP of less than 4000 pg/mL, and that includes 65% of the VICTORIA population," Justin A. Ezekowitz, MBBCh, University of Alberta, Edmonton, Canada, said June 19 in an HFA Discoveries Late-Breaking Science Session.

Hazard Ratio (95% CI) for Outcomes by Baseline NT-proBNP in VICTORIA

Endpoints ≤4000 pg/mL, n=3100 >4000 to 8000 pg/mL, n=1033 >8000 pg/mL, n=672
Primary Endpoint* 0.77 (0.68-0.88) 0.85 (0.76-0.95) 1.16 (0.94-1.41)
CV Death 0.75 (0.60-0.94) 0.84 (0.71-0.99) 1.32 (1.01-1.71)
HF Hospitalization 0.78 (0.67-0.90) 0.84 (0.75-0.95) 1.16 (0.94-1.41)
*CV death or first heart failure hospitalization

The risk reduction for patients with the lowest NT-proBNP levels reached a "quite striking" 23%, "much like what we've seen in DAPA-HF and PARADIGM-HF," Ezekowitz said during the online sessions, a substitute for the traditional annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology, which had been canceled due to the COVID-19 pandemic.

Similar primary endpoints in those HFrEF trials fell by 26% with dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and by 20% with sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, as previously reported.

VICTORIA had entered 5050 patients with baseline NT-proBNP of at least 1000 pg/mL, a requirement more than twice as high as in DAPA-HF and PARADIGM-HF, Jelena Celutkiene, MD, PhD, Vilnius University, Lithuania, said as the invited discussant after Ezekowitz's presentation. All had experienced a prior and usually recent HF exacerbation, and the trial racked up clinical events faster than the predicted rate.  

They were, therefore, "a cohort of much sicker patients," she said. And those with the highest NT-proBNP levels were the sickest, based on the biomarker as well as some baseline features. Compared to those with lower levels, they had more severe HF symptoms by NYHA class, lower left ventricular ejection fraction, and worse renal function.

Vericiguat "lost its power" in VICTORIA above a baseline NT-proBNP threshold of 8000 pg/mL, which exceeded the median values observed in some acute HF trials, Celutkiene observed.

As such, she said, the current analysis may have demonstrated "the potential upper limit of medication benefit in the HFrEF population."

"In this way, the VICTORIA investigators identified a subgroup with the most advanced stage of the disease and probably the need for a nonpharmacological treatment or palliative care."

Ezekowitz is a member of the VICTORIA executive team. The trial was supported by Merck Sharp & Dohme Corp and Bayer AG. Celutkiene has reported no relevant financial relationships.

HFA Discoveries 2020 from the Heart Failure Association (HFA) of the European Society of Cardiology.

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