With Greater Uptake, ARNIs Could Potentially Save the Lives of Nearly 30,000 Patients Each Year

Wide use of angiotensin receptor neprilysin inhibitor (ARNI) therapy by patients with heart failure and reduced ejection fraction could prevent more than 28,000 deaths a year, researchers have estimated.

The analysis, published online last week in JAMA Cardiology, comes out just 1 month after ARNIs were added to American and European guidelines for heart failure. ARNI therapy has been in the spotlight since 2014 when results of the PARADIGM-HF trial showed that the combination of a neprilysin inhibitor (sacubitril) and an angiotensin II receptor blocker (valsartan) was superior to enalapril at reducing the risks of death and of hospitalization for heart failure. Now sold as Entresto (Novartis), the therapy was approved by the US Food and Drug Administration the following year.

Gregg Fonarow, MD (Ronald Reagan UCLA Medical Center, Los Angeles, CA), lead author of the new study, says the pivotal trial’s positive findings are driving the growing interest in the ARNI therapy.

“In the clinical PARADIGM-HF, there was a 20% relative risk reduction in cardiovascular death on the order of about 3% in absolute terms over the 2 years of the trial,” Fonarow told TCTMD. “The level of the number of deaths [prevented], if fully applied to the US patient population with heart failure and reduced ejection fraction that was eligible, was a really striking finding.”

Fonarow and his colleagues projected that out of 2,736,000 patients with heart failure and ejection fraction < 40% in the United States, 84%—or nearly 2.3 million people—would be candidates for ARNI therapy after excluding those in hospice or receiving palliative care, on continuous inotropic agents and other advanced therapies, who had contraindications to the drugs, or had systolic blood pressure lower than 95 mm Hg.

Using data from PARADIGM-HF, they estimated the magnitude of the mortality reduction: 28,484 preventable deaths per year. Sensitivity analyses were also run, producing a range of preventable deaths from 18,515 to 41,017.

Barriers to Implementation

The analysis paints a bright picture for the future of heart failure treatment, but the scope of the outlook might be difficult to achieve in a clinical setting, according to Eiran Gorodeski, MD (Cleveland Clinic, OH).

“It seems like due to a variety of barriers it may be a bit more believable that the survival benefit would be on the lower end of their estimation, but I guess that's why they set out a range because of things that are not known,” he told TCTMD. “But it's definitely believable that in an ideal world where there are no cost barriers, a marked amount of people would have a survival benefit from [ARNI therapy], that's for sure.”

Fonarow agreed that there are a host of barriers to patients getting heart failure treatment, particularly one that is new on the market.

“There's a whole complex set of factors that are involved when new therapies become available,” he said, noting that it takes time for insurance to offer coverage. Additionally, Fonarow noted, experience has shown that “there was also clinical inertia with other new therapies that have come out for heart failure.”

Gorodeski agreed that physicians can be reluctant to prescribe ARNI therapy because it is still very new and the cost can be beyond reach for some. That cost amounts to $12/day for Entresto without insurance, according Gorodeski. Furthermore, inconsistencies in coverage contribute to difficulties in prescribing it to his patients. In Ohio where he practices, some payers, including Medicaid, cover the drug without co-pays while other insurance companies offer coverage with co-pays that are too high for many patients to afford, Gorodeski reported.

 “Another barrier is this drug needs to be titrated carefully,” he said. “Many patients have a hard time tolerating it because of blood pressure issues. It really causes hypotension.”

But the analysis looks mainly at potential—what would happen in terms of improved survival if adoption of ARNIs was quick and complete. Fonarow admits that the study’s projections would require changes in behavior on the part of physicians, patients, payers, and others in order to become reality, but he says that those necessary changes are already happening.

“It was really critical to get the recommendations of the professional societies and being integrated into a national guidelines,” he told TCTMD. “So it remains to be seen whether that will have an impact. We're hopeful that this study being published . . . will also be informative and really help quantitate the benefits that could occur should there be more timely and complete implementation of ARNI therapy into practice in the United States.”


  • Fonarow GC, Hernandez AF, Solomon SD, Yancy CW. Potential mortality reduction with optimal implementation of angiotensin receptor neprilysin inhibitor therapy in heart failure. JAMA Cardiol. 2016.1724.

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Michael H. Wilson is the recipient of the 2016 Jason Kahn Fellowship in Medical Journalism, working as a summer intern…

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  • Gorodeski reports having consulted for Novartis.
  • Fonarow reports receiving research grants from the National Institutes of Health and consulting fees from Amgen, Janssen, Medtronic, and Novartis.
  • Hernandez reports receiving research support from Amgen, AstraZeneca, Merck, and Novartis and receiving honoraria from Amgen, Luitpold, Merck, and Novartis.
  • Solomon reports receiving research grants from Novartis to Brigham and Women’s Hospital and consulting fees from Novartis, Amgen, and Bayer.