New Data Presented for Finerenone, Vericiguat, and SGLT2 Inhibitors at HF Session

Additional heart failure (HF) analyses from recent trials involving finereone and empagliflozin, and a cost-effectiveness study for vericiguat, were featured Monday during “From Failure to Success: Advances in Heart Failure,” during the 2021 American Heart Association (AHA) Scientific Sessions, which finished its virtual conference today.

Incident HF and finerenone. Gerasimos Filippatos, MD, professor at the National and Kapodistrian University of Athens Medical School, presented a subanalysis of the FIGARO-DKD study, which in August found that finerenone offered cardiovascular (CV) benefits in patients with mild to moderate chronic kidney disease alongside type 2 diabetes, while cutting HF hospitalization 29%. The aim of the subanalysis was to evaluate the onset of HF and outcomes in patients taking the drug, regardless of their HF history. Finerenone is sold as Kerendia by Bayer.

Filippatos explained that 7.8% of the patients in FIGARO-DKD had HF at baseline; these patients had a lower estimated glomerular filtration rate than patients without HF and were more likely to be taking beta-blockers or diuretics. This new analysis, which was published in the AHA journal Circulation,¹ showed that compared with placebo, new-onset HF—defined as death from HF or the first HF hospitalization (HHF)—declined 32% overall, with no difference between those with or without a HF diagnosis at baseline. A composite of all CV death and first HHF was similarly balanced, with a 16% reduced risk for those with HF and 17% for those without.

Of interest to payers, finerenone reduced the risk of a first HHF by 30% among patients with HF and by 28% for those without compared with placebo. Finerenone also fared better than placebo in a composite measure of CV death and total HHF, reducing overall risk by 31%. Patients with HF taking finerenone had a 27% reduced risk for total HHF, while those without HF reduced their risk of HHF by 30%. In addition, Filippatos said, finerenone was well tolerated; adverse events between the 2 groups were well balanced, although hyperkalemia was higher in patients without a history of HF than in those with HF.

In response to a question, Filippatos did not have a mean range for HF, but said patients with HF with reduced ejection fraction had been excluded. “So, we don't know the mean ejection fraction of those that have been included, but we know that the problem was above 40%.”

Cost-effectiveness of vericiguat. Derek Chew, MD, of the University of Calgary, presented results from a cost-effectiveness analysis completed with the Duke Clinical Research Institute (DCRI) on vericiguat. In the VICTORIA trial, patients who took the oral soluble guanylate cyclase stimulator were 10% less likely to experience the primary outcome, a composite of death from CV causes or first HHF. Merck received approval in January 2021 to market vericiguat as Verquvo for patients with left ventricle ejection fraction below 45% who are released from the hospital for HF or after they received outpatient diuretics.

For this analysis, Chew said, the “economic end points of interest included costs and measures of clinical effectiveness, including life expectancy and quality of life.” These end points are calculated into a recognized metric, the incremental cost-effectiveness ratio (ICER). As Chew explained, in the United States, an ICER that finds a drug comes in for less than $100,000 per quality-adjusted life-year (QALY), is generally considered cost-effective. For vericiguat, the metric for costs included inpatient care and cardiac procedures in a hospital, which were developed prospectively using recognized databases.

“We also mapped physician costs and medication costs to the Medicare fee schedule and national drug acquisition prices, respectively,” Chew said. Best practices call for an economic evaluation to project costs and benefits over a patient’s lifetime horizon, which he said required extrapolation beyond the limited empirical trial follow-up of 10.8 months. An age-based survival model allows the Duke group to scale life expectancy and benefits—including quality of life (QOL)—based on taking the medication. These calculations form a “base case” result.

To take vericiguat, the estimated lifetime costs in 2020 US dollars were $192,453 compared with $159,892 for taking placebo. However, both the life-years and QALYs were higher for vericiguat than placebo. In the end, the calculation put vericiguat at $71,538 per QALY gained, well within acceptable limits. Because VICTORIA subgroup results had revealed differences in outcomes based on patient levels of N-terminal pro-brain type natriuretic peptide (NT-proBNP), the analysis also calculated an ICER of $72,052 per QALY gained in the subgroups where VICTORIA found the drug to be most effective; no calculation was made for patients with the most elevated NT-proBNP, for whom benefits were not seen.

In a follow-up interview, Chew and Daniel Mark, MD, a professor of cardiology who is the director of the Outcomes Research Group at DCRI, discussed the results, in light of other findings presented during the AHA Sessions that call for starting HF therapy during hospitalization.

“I think the mode of initiation, regardless of whether it's in hospital vs out of hospital, shouldn't factor too much in terms of the overall cost-effectiveness,” Chew said. “What we're trying to show is value for money. With the VICTORIA population, [patients] tend to be a sicker population, with an elevated natriuretic peptide. So, the cost-effectiveness analysis is modeled on that specific patient population. Whether they're sick a lot can be generalizable to heart failure groups outside the inclusion criteria."

Mark said the movement to start HF therapy in the hospital, “is a strategic one, rather than a strictly scientific, medical one.” Starting patients on a new, more effective drug when an event has just occurred overcomes the therapeutic inertia that makes it more challenging to start therapies in the middle of a chronic HF visit, no matter how compelling the evidence might be.

Would such a strategy improve adherence?

“I think implicitly, if people can notice the benefits, I presume it would improve adherence,” Chew said. “Starting medications in the hospital and being able to improve clinically enough to be discharged from the hospital—that should represent a reasonable change in quality of life.”

One would think this would improve adherence, he said, at least in the short term, but “whether that extends more in the long-term setting outside hospital—that remains to be seen.”

QOL results in EMPEROR-Preserved. In August, investigators presented results for treatment of HF in patients with preserved ejection fraction (HFpEF), or those with an ejection fraction ≥ 40%, and found that empagliflozin produced a 27% drop in HHF risk in patients with HFpEF. Javed Butler, MBBS, MPH, MBA, of the University of Mississippi, presented an overview of results and new data on the impact of QOL. Improvements in QOL measures in these patients are “a major treatment goal,” he said.

Changes in patients’ Kansas City Cardiomyopathy Questionnaire score were a prespecified end point, said Butler who explained that the test is divided into 3 domains: the Total Symptom Score, the Clinical Summary Score, and the Overall Summary Score. Measures were taken at baseline and at 12, 32, and 52 weeks. He pointed out that those with a lower score at baseline have higher markers for disease severity and that women’s scores were lower overall, which is consistent with other studies. Although both the empagliflozin and placebo groups reported improvements across all 3 domains, patients taking empagliflozin saw early improvements well above those for placebo, and that difference was sustained at the 8- and 12-month marks. Data showed improvements regardless of baseline health status and across multiple measures; the biggest improvements were seen in symptom burden and symptom severity, and by the 12-month mark, larger improvements were seen in the measure for social limitations.

Empagliflozin is sold as Jardiance by Eli Lilly and Boehringer Ingelheim.

SGLT2s and atrial arrhythmia. Investigators continue to find new benefits for the sodium glucose co-transporter 2 (SGLT2) inhibitor class, including empagliflozin, dapagliflozin, and canagliflozin. A study from the University of Rochester in New York (UofR) featured data showing the drug class helps patients with atrial fibrillation (AF) who are using a cardiac implantable electronic device (CIED). The thinking behind the study, said Ilan Goldenberg, MD, director of the Clinical Cardiovascular Research Center at UofR, is that the multiple hemodynamic effects of SGLT2 inhibitors—lower intracardiac filling pressure, reduced arterial stiffness, reduced albuminuria, less hyperkalemia, modest weight loss, and reduced glucose levels—among others—would prove beneficial for the patients with AF.

The study measured results from 13,888 consecutive patients implanted with a CIED in tertiary medical centers in the United States and Israel from January 2015 to April 2020; of these, 898 took SGLT2 inhibitors. The primary end point was total atrial arrhythmia (AA); secondary end points were total ventricular arrhythmia (VA), total AA and VA, and death from any cause. A model was developed to allow propensity scoring of the study sample. The 3 major SGLT2 inhibitors sold in the United States were seen in the study drug arm: 39% took dapagliflozin, 35% took empagliflozin, and 26% took canagliflozin. During a follow-up of 24,442 patient-years, there were 19,633 AA events and 3231 VA events. In the total population adjusted propensity score analysis, those taking an SGLT2 inhibitor saw significant reductions in AA events and all-cause mortality:

• For patients taking SGLT2 inhibitors, the rate of AA burden was reduced 24%; with an HR of 0.76 favoring those taking the medication (95% CI, 0.68-0.84; P < .001); the combined burden of AA/VA was also reduced 24% (HR, 0.76, 95% CI, 0.70-0.83; P < 001)
• For all-cause death, the rate was reduced 42% (HR, 0.58, 95% CI, 0.40-0.82; P = .003)
• For VA, the trend favored SGLT2 inhibitors, but the results did not reach significance (HR, 0.93, 95% CI, 0.81-1.07; P = .33)

The propensity score matched analysis was only slightly less favorable to SGLT2 inhibitors; reduced AA burden was 23%, and reduced all-cause mortality remained at 42%. During questions, Goldenberg said the investigators are studying several possible mechanisms to explain the results, including a reduction in left atrial pressure. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” he concluded.