Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.