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Novel oral agent vericiguat modestly reduced mortality and hospitalization among recently decompensated heart failure with reduced ejection fraction (HFrEF) patients in the pivotal VICTORIA trial.

Once-daily doses of the soluble guanylate cyclase stimulator reduced the rate of death from cardiovascular causes or first hospitalization for heart failure by a relative 10% compared with placebo over a median of 10.8 months (35.5% vs 38.5%, P=0.02) -- an absolute reduction of 4.2 events per 100 patient-years with a number needed to treat for 1 year of 24.

The effect was driven by heart failure hospitalization (27.4% vs 29.6%, HR 0.90, 95% CI 0.81-1.00) Paul Armstrong, MD, of the University of Alberta in Edmonton, and colleagues reported at the virtual American College of Cardiology (ACC) annual and online in the .

Cardiovascular deaths leaned toward reduction with vericiguat but not significantly so in this population of patients who had recently been hospitalized or had received IV diuretic therapy (16.4% vs 17.5%, HR 0.93; 95% CI 0.81-1.06).

"Overall, the results of VICTORIA herald another 'win' for HFrEF and an important opportunity to modulate further the natural history of HFrEF," said ACC session discussant Clyde Yancy, MD, of Northwestern University in Chicago and a past president of the American Heart Association.

The heart failure hospitalization reduction was important, he said. "No prior therapies have attenuated this risk. These data are the first to indicate a singular intervention may lower the cardiovascular events after hospitalization or the need for IV diuretics."

Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, commented at the session that "it's not only a therapy for a new physiologic target, but it's also for a new population."

"Patients with a recent heart failure hospitalization for decompensation have been actively excluded from all the trials that showed benefit," she said. "The recent trials that have focused on this population have consistently shown no benefit. So VICTORIA finally addresses this population of decompensated patients. It's a unique population with longer disease duration, more severe disease, and narrow options."

The fact that it's a simple oral drug with no dose titration and a tolerable side effect profile makes it all the better, Yancy told attendees.

'Comparable Across Trials'

Armstrong defended the effect size as meaningful. In a , on which he was senior author, cautioned against misinterpreting comparisons across recent heart failure trials.

"While the HR may suggest the largest treatment effect in DAPA-HF followed by PARADIGM-HF and then VICTORIA, a comparison of annualized or 12-month event rates for the primary endpoint suggests that the outcome benefits are comparable across trials," he and two colleagues wrote.

"I would argue that any significant reduction in heart failure hospitalization risk in a contemporary heart failure trial should be taken seriously, given that our armamentarium consists of drugs that lower mortality," commented James Januzzi, MD, of Massachusetts General Hospital in Boston. "It's getting harder and harder."

"On the other hand, while it's very tempting to get excited about new drugs and new therapies in a high-risk population that continues to do not as well as we would like them to, we have to keep in mind that we have good therapies for these patients," commented Anu Lala, MD, of the Mount Sinai Hospital in New York City.

The showed, though, "that we're not really good at making sure that patients are on all these medications, and ...we're not good at optimizing them to the right dose. There's a large gap we have to fill with utilizing the therapies that we already have," she told 名媛直播.

Among the trial's 5,050 participants, 60% had concomitant guideline-based medical therapy that included a beta-blocker and a mineralocorticoid antagonist combined with either an ACE inhibitor, an angiotensin-receptor blocker (ARB), or sacubitril-valsartan (Entresto). Overall, only 15% received sacubitril-valsartan.

"So it's a little tricky to say what the incremental benefit of this drug would be in a totally optimized population," Lala added.

However, that's a level of sacubitril-valsartan prescribing that mimics real life, noted Januzzi.

"Understanding which patients benefit most is an important next step," Yancy said. "I encourage the investigators to remain diligent in their efforts to identify the target patient population."

1 in 4 HF Patients

The VICTORIA trial criteria would likely apply to one in four heart failure patients, Armstrong said at a press videoconference.

• Chronic New York Heart Association class II, III, or IV heart failure
• Ejection fraction of less than 45%
• Elevated natriuretic peptide level within 30 days before randomization
• Hospitalized within the prior 6 months for worsening heart failure

Notably, those with a systolic blood pressure under 100 mm Hg were excluded as were those on another drug in the class, long-acting nitrates, IV inotropes, or a left ventricular assist device.

Importantly, as with the sacubitril-valsartan trials, black participants represented less than 5% of the VICTORIA population, he noted. "Given prevailing concerns that nitric oxide bioavailability may be uniquely reduced, an opportunity emerges to study vericiguat in this special population."

Januzzi also pointed to prespecified subgroup analyses trending in the wrong direction for patients in the top quartile for NT-proBNP level (>5,314.0 pg/mL) with a hazard ratio of 1.16 (95% CI 0.99-1.35). "It raises the question if these people were too sick to benefit from any treatment," he said.

However, Armstrong noted that "It is tempting but dangerous to suggest that we could necessarily assert that the top quartile would not benefit." His group is working hard on understanding the natriuretic peptide story, he said.

Serious adverse events were similar between groups, but there were the expected albeit nonsignificant increased risks with vericiguat of symptomatic hypotension (9.1% vs 7.9%) and syncope (4.0% vs 3.5%).

While there were no adverse effects of vericiguat on electrolytes or renal function, there was more anemia with the drug (7.6% vs 5.7%), which Yancy said would be worth looking into further.

Cost is likely to be an issue if the only approved drug in this class -- , made by the same company (Bayer) -- is any clue, Lala noted.

Bayer and co-developer Merck said they plan to share the VICTORIA data with regulatory authorities worldwide for approval purposes.

Exactly how it fits into the armamentarium, as an add-on or replacement to existing therapies, remains to be seen, Januzzi said.

"Polypharmacy for HFrEF is now officially a problem (A good one to have!)," Yancy said. "The impetus for precision medicine is even more pressing."

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