Matching Right Patients to Right Drugs Is Key With New Entrants to Heart Failure Market

Sessions, posters, and late-breaking trials at the American College of Cardiology’s 70th Scientific Session offer updates on vericiguat, SGLT2 inhibitors, sacubitril/valsartan, and heart failure therapies still in the pipeline.

The market for treating heart failure has become crowded of late. Since the start of 2021, the FDA has approved therapies to treat sicker patients with heart failure with reduced ejection fraction (HFrEF) and the first therapy for heart failure with preserved ejection fraction (HFpEF). Thus, much of the research presented at the American College of Cardiology (ACC) 70th Scientific Session has involved secondary analyses of earlier studies, which have zeroed in on exactly which patients would benefit most from each treatment.

Experts are also embracing a new “midrange” of heart failure, between 40% and 50% ejection fraction, and finding benefits for therapies by examining how they work in this previously ill-defined gray zone. From late-breaking research presented Monday to a Sunday evening session on new and emerging treatments, called “What’s New in HF Pharmacotherapies: The What, How, and Wow,”1 it’s clear there will be more choices than ever in heart failure.

But do clinicians know when to use which drug?

“Although the newest heart failure guidelines are still in development, clinicians need to be aware of the drugs available and which patients are likely to derive the most benefit,” said Alanna Morris, MD, associate professor of medicine at Emory University in Atlanta, Georgia, who chaired the session and opened with some startling statistics on disparities in heart failure.

Fortunately, a wave of new approvals—and some drugs in the pipeline—offer options in all stages of the condition, from “pre–heart failure” to very sick patients to some with rare conditions.

Some highlights:


Last year, the VICTORIA trial opened ACC with results that showed high-risk patients taking this oral soluble guanylate cyclase stimulator were 10% less likely to die from cardiovascular causes or be hospitalized for heart failure. Vericiguat has since received FDA approval to be marketed as Verquvo for patients with chronic heart failure in HFrEF below 45%, following a hospitalization or when there is a need for intravenous diuretics.

But to fully appreciate vericiguat’s value, it’s important to understand when it should be used, said Carolyn S.P. Lam, MBBS, PhD, a professor of Duke-National University of Singapore.1 She explained that even when patients with HFrEF take guideline-recommended treatment, some number of them will show signs that their heart failure is worsening. To address this, Lam said, vericiguat offers an alternative from the “blocking” mechanism of other drugs. Vericiguat, she said, “stimulates more production of cyclic GMP [guanosine monophosphate production], which exerts positive effects in the myocardium and vasculature, and these are effects that are needed in heart failure.”

It’s also important to understand how sick the population was that VICTORIA targeted—not just patients with chronic heart failure, but those who had already shown signs of worsening heart failure and thus have a 2-year mortality of 23%. Although comparable trials had an estimated glomerular filtration rate cutoff of ≥20 mL/min/1.73m2, VICTORIA went down to >15 ml/min/1.73m2. Median NT-proB type natriuretic peptide (BNP) levels, a measure of a hormone released as heart failure worsens, were much higher among VICTORIA patients than comparable trials. In VICTORIA, levels were 2816 pg/mL compared with 1971 pg/mL for the GALACTIC-HF trial studying omecamtiv mercarbil, 1437 pg/mL for DAPA-HF studying dapagliflozin, and 1887 pg/mL in the study drug arm of EMPEROR-Reduced for empagliflozin.

Lam pointed out some features about patients recruited to participate in VICTORIA.

“The highest-risk patients were the ones recruited in-hospital,” she said. “And that risk gradually reduced with another very-high-risk group, being those within 3 months of hospitalization.”

Where does vericiguat fit in among treatment options? Lam said it’s a good choice for patients who cannot tolerate other heart failure therapies and for those with NT-proBNP <8000.

To further pin down the best candidates for vericiguat, a poster presented during the sessions found an association between baseline levels of cardiac troponin T and the primary end point in VICTORIA: the higher the baseline level, the more like the patient was to experience cardiovascular death or hospitalization for heart failure. Thus, the authors concluded, cardiac troponin T appears to be an important biomarker in identifying patients with high-risk HFrEF, “and may influence treatment choices.”2

SGLT2 inhibitors

Gregg Fonarow, MD, of UCLA Health, discussed the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients who are at risk for heart failure and who have chronic heart failure. SGLT2 inhibitors, first developed to treat type 2 diabetes, have emerged as the fourth pillar of high-value treatment in heart failure, alongside beta-blockers, mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor-neprilysin inhibitors (ARNIs).

Dapagliflozin received the first approval to treat patients for HFrEF regardless of diabetes status, and the FDA is reviewing a similar approval for empagliflozin. Canagliflozin received an approval to treat diabetic kidney disease and to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes. Trials are expected to show that these same SGLT2 inhibitors offer benefits in HFpEF within the next year, and on Monday, a pooled analysis presented during ACC.21 showed a benefit in HFpEF for the SGLT1/2 inhibitor sotagliflozin.3

Once heart failure occurs, patients can lose up to 15 years of life.

“So really, we want to do everything we can to prevent heart failure,” he said.

The question has been whether the value of SGLT2 inhibitors is additive or whether they are duplicative of other things a patient may be taking. Fonarow said it’s clear that because of their unique mechanism of action—which helps patients excrete excess blood sugar out of the body through the urine—the drugs bring additional benefits. But the problem is, he said, is that not all doctors see it that way, and even when they do, not all patients can get access to the right drugs.

“What would happen if we applied all of our guideline recommended therapies optimally to patients in the United States—we could actually save 130,000 additional lives per year, with optimal implementation of our existing therapy,” Fonarow said, citing a series of papers he has published in recent years, including one in JAMA Cardiology in 2020. “There's compelling evidence for why this should be a routine part of our clinical care.”

By contrast, he said, moving slowly and selectively contributes to heart failure, hospitalizations, and deaths “that could have been prevented with earlier and more comprehensive use of guideline-directed medical therapy.”


This first-in-class ARNI, Scott D. Solomon, MD, of Harvard and Brigham and Women’s Hospital explained, is a crystal that is both an angiotensin II type 1 receptor blocker (valsartan) and sacubitril, which blocks the enzyme neprilysin, which breaks down peptides that include atrial natriuretic peptide, BNP, and C-type natriuretic peptide. Thus, Solomon explained, this combination therapy blocks the renin angiotensin system, “something that we're quite familiar with in heart failure,” while enhancing the vasoactive peptide system.

Sold as Entresto, this drug was already approved in HFrEF when Solomon led the PARAGON-HF trial, which in 2019 barely missed achieving statistical significance in its composite end point in HFpEF (P = .059). “If 7 events in 1 arm had simply gone in the other arm, we could have seen a reduction in P below .05)."

Solomon said when data are pooled with another study, PARADIGM, the number of patients passes 13,000, and “we would have seen significant benefit.”

Nonetheless, the FDA relied on PARAGON to grant approval for patients with HFpEF in February. Of note, Solomon explained, secondary end points revealed cut points and certain groups that fared especially well. In particular, Solomon said, ejection fraction of 57% emerged as a break point.

“We see that the patients with an ejection fraction below the median—at or below the median of 57%—have a much greater benefit than patients with an ejection fraction at above 57%,” he said. “We also saw greater benefit in women than in men.”

These issues will be important to follow as trials studying the use of SGLT2 inhibitors to treat HFpEF come out over the next year, Solomon said. Heart failure “is increasing in prevalence [and] is both ecologically and therapeutically heterogeneous. What we've learned over the past few years is that the therapies that improve outcomes in patients with heart failure with reduced ejection fraction also probably do so in patients with heart failure and mildly reduced ejection fraction.”

Omecamtiv mecarbil

The big news at ACC.21 on this investigational therapy, a novel selective cardiac myosin activator, came early Monday. John Teerlink, MD, of the University of California San Francisco, presented a secondary analysis from 8200 patients in the GALACTIC-HF trial that showed a relationship between ejection fraction and outcomes. The more severe the left ventricle ejection fraction (LVEF), the greater the potential for the drug to work.4

The original GALACTIC-HF studied patients with LVEF ≤35%. For this analysis, reseachers divided the patient population into quartiles based on LVEF. The cutoff points were LVEFs of ≤22%, 23% to 28%, 29% to 32%, and ≥33%. Patients in the lowest 2 quartiles saw a 15% to 17% reduction in the risk of cardiovascular death or hospitalization for heart failure compared with 8% for the overall population. In the lowest quartile, this calculated to treating 12 patients with omecamtiv mecarbil to prevent 1 cardiovascular death or heart failure hospitalization.

"That's a very important and clinically meaningful finding, particularly given that patients with low ejection fraction tend to be at the highest risk and the hardest to treat," Teerlink said.5 However, the study did not find a clear benefit for the drug once LVEF reached about 30%.

During Sunday’s session, Nasrien E. Ibrahim, MD, a cardiologist at the Inova Health Advanced Heart Failure and Transplant Program, included omecamtiv mecarbil in her discussion of drugs in the pipeline. She explained the condition of the patients in GALACTIC-HF:

“The mean time of a prior heart failure event was 3 months. Patients had a LVEF of less than 30%, and the majority of patients were (New York Health Association) class II or III heart failure. Half them had ischemic etiology, about 40% had diabetes, and their NT-proBNP was almost 2000."

This is a really sick cohort of patients,” she said, but nearly all were being treated on guideline-directed medical therapy—90% were on beta-blockers, 80% on MRAs, a few had started SGLT2 inhibitors, “which had only been on the scene very recently.”

Ibrahim noted the primary outcome was achieved, but was driven by time to the first heart event—there was no difference in cardiovascular death between the study drug and placebo. In a preview of the results that Teerlink released the following day, Ibrahim noted some differences in subgroups:

  • Patients had LVEF lower than the median of 28%
  • Those in the inpatient setting had a higher NT-proBNP than in the outpatient setting
  • Those with NYHA class III or IV symptoms did better with the drug

“So, do I think there's a place for omecamtiv mecarbil?” Ibrahim asked.I'm not sure if we can add it to the guidelines as of yet, but [there are] a specific group of patients, maybe sicker patients, who might benefit.”


  1. Morris AA, Fonarow GC, Lam CSP, et al. What’s new in HF pharmacotherapies: the what, how and wow. Presented at: the 70th Scientific Session of the American College of Cardiology; May 16, 2021; Virtual.
  2. DeFilippi CR, Alemayehu W, Voors A, et al. Baseline cardiac troponin T, clinical outcomes, and verciguat treatment effect in heart failure with reduced ejection fraction study: insights from the VICTORIA trial. Presented at: the 70th Scientific Session of the American College of Cardiology: May 16, 2021; Virtual. Abstract 1040-11.
  3. Bhatt DL, Szarek M, Steg G, Pitt B. Benefits of sodium glucose co-transporter 1/2 inhibition with sotagliflozin across the full spectrum of ejection fraction, including heart failure with preserved ejection fraction. Presented at: the 70th Scientific Session of the American College of Cardiology; May 17, 2021; Virtual. Abstract 21-LB-21288-ACC.
  4. Teerlink JR, Diaz R, Felker GM on behalf of the GALACTIC-HF Investigators. Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF. J Am Coll Cardiol. Published online May 17, 2021. doi:10.1016/j.jacc.2021.04.065
  5. Cytokinetics announces secondary analysis of GALACTIC-HF presented in late-breaking clinical trial session at the American College of Cardiology 70th Annual Scientific Session. News release. Intrado/GlobeNewswire. May 17, 2021. Accessed May 17, 2021.
Related Videos
Related Content
© 2023 MJH Life Sciences
All rights reserved.