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 theheart.org | 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 (P = .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 theheart.org | 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. The effect would have to be studied more carefully before it could be seen as possibly real.

“This finding of the interaction between vericiguat and beta-blocker therapy is interesting, but it remains unclear if the interaction is valid or a chance finding,” agreed James L. Januzzi Jr, MD, Harvard University and Massachusetts General Hospital, Boston, as invited discussant after the Ezekowitz presentation.

One interpretation, he added, doesn’t see the drug as interacting with achieved beta-blocker dosage targets per se. Rather, it may be that “vericiguat’s benefits are less obvious in those patients who could not receive higher-dose beta-blocker therapy, such as the more advanced heart failure patients, or patients with frailty.”

That would be consistent with a prior finding from VICTORIA, that more advanced heart failure as indicated by higher natriuretic peptide levels “was associated with less obvious benefit from vericiguat therapy,” Januzzi said.

As previously reported, a post-hoc analysis from the trial suggested that patients with the highest natriuretic peptide levels, presumably the sickest in the study, showed no vericiguat benefit for the primary endpoint. But such benefit was pronounced, the risk falling a significant 23%, among patients with the lowest natriuretic peptide levels.

So in the current analysis, Januzzi said, “it may be we’re seeing the same type of interaction manifesting here as intolerance to higher doses of beta blocker.”

Beta blockers, renin-angiotensin-system inhibitors (RASi), and mineralocorticoid receptor antagonists (MRAs) have long been the main GDMT platform in HFrEF; guidelines say patients should be on all three classes, as tolerated. In recent years, sacubitril/valsartan (Entresto), classified as an angiotensin-receptor/neprilysin inhibitor (ARNI), has joined ACE inhibitors and angiotensin-receptor blockers (ARBs) in the broad RASi category.

Vericiguat — an oral soluble guanylate-cyclase stimulator — works by mechanisms different from those of current SOC heart failure meds as well as the SGLT2 inhibitors, which are making their mark in HFrEF based on DAPA-HF, EMPEROR-Reduced, and other trials. But adherence to SGLT2 inhibitors wasn’t explored in the current analysis.

It looked at patient adherence to current SOC medications individually and when combined as triple therapy consisting of a RASi plus both a beta blocker and MRA.  

Adherence was defined three ways. Basic adherence, reflecting simply whether a patient was taking or not taking the drug or drug combination, was met by 87.4% for the three types of RASi collectively, by 93.1% for a beta blocker, by 70.3% for an MRA, and by 59.7% for triple therapy.Adherence was also corrected for indication, which considered whether patients avoided any SOC meds due to contraindications or intolerance; and for indication plus dosage, which also accounted for patients who achieved at least 50% of prescribed dosage targets.

In general, vericiguat benefit for the primary endpoint was consistent across adherence definitions and drug categories. However, the drug was associated with a lower hazard ratio (HR) for the primary endpoint of 0.72 (95% CI, 0.61 – 0.84) among patients meeting or exceeding 50% of prescribed target dose of beta blockers but 1.01 (95% CI, 0.88 – 1.15) for those not meeting that goal.

The HRs were adjusted for score on the MAGGIC mortality risk index for heart failure. The interaction between vericiguat benefit and achieved beta-blocker dosage was significant at P = .001.

“The trial design of VICTORIA adds an important new element to the design of clinical trials,” Januzzi said. “Tracking baseline doses of GDMT is not at all common in modern clinical trials in heart failure, and allows us to evaluate whether a novel therapy added to well-dosed GDMT provides a consistent benefit.”

As it happens, he added, the trial shows “vericiguat actually exerts benefit across the wide range of GDMT that is prescribed to our patients, providing reassuring information for clinicians who might be contemplating utilizing these agents.”

VICTORIA was funded by Bayer and Merck. Ezekowitz discloses receiving grants or research support or having a company relationship with Bayer, Merck, Servier, Amgen, Novartis, Cytokinetics, American Regent, Applied Therapeutics, and Sanofi; and consulting for Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Januzzi discloses receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on endpoint committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

Heart Failure Society of America Virtual Annual Scientific Meeting 2020: Late Breaking Clinical Trials II. Effect Of Vericiguat In Victoria According To Guideline-directed Medical Therapy. Presented October 5, 2020.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.