New Heart Failure Drug Struggles To Find Its Footing

–Experts offer insight about Entresto at the ESC.

Despite its success in a large and widely praised clinical trial the novel heart failure drug Entresto (sacubitril/valsartan, Novartis) has been struggling to gain a substantial foothold in the marketplace. Now new papers and presentations and commentary from experts at the European Society of Cardiology meeting are helping to clarify the drug’s position in the real world.

Clyde Yancy says he is not terribly troubled by the slow uptake of Entresto. In an interview he said “a linear model is preferable to logarithmic growth.” Slow growth “is a reasonable path— we need to provide a lot of education— you can’t digest all the news in a soundbite.”

But Steve Nissen (Cleveland Clinic) has a  different view. He thinks Entresto should be adopted more readily by cardiologists. “I’m not a heart failure doctor but when a drug shows a 20% reduction in death in a very mortal disease you have to sit up and take notice. When I see heart failure patients I look to see how they match up with the patients in the PARADIGM-HF trial and if it’s appropriate I will discuss it with them.”

Nissen said he is unconcerned by questions over the drug’s value. “This question of value troubles me. Look at cancer. They pay hundreds of thousands of dollars for therapies that add a few weeks. But for a chronic disease like heart failure we have trouble getting reimbursement.”

Cost Effectiveness and Patient Population

Nissen can take comfort in the latest of a series of reports suggesting that Entresto is cost effective. In broad agreement with earlier reports, a new study published in Annals of Internal Medicine concludes that the drug is cost effective in patients with NYHA class II to IV heart failure at a cost of $47,000 per quality-adjusted life year.The evidence of efficacy is based on a single trial, but our findings were robust in sensitivity analyses across model parameters,” the authors wrote. The value of the drug is likely to be even greater than their calculations in the paper, they argued, since for most people the cost of the drug will be lower than the wholesale acquisition cost used in the study.

Another recurrent question is the patient population in whom the drug should be considered. Nissen’s decision to identify patients similar to those studied in the PARADIGM-HF study is likely a good starting point. But how many patients in the real world would have met the trial’s entry criteria?

Yuksel Cavusoglu (Eskisehir, Turkey) presented the results of an analysis of heart failure patients in Turkey estimating the number of patients who might be eligible for Entresto. Based on the drug’s label, with a broad indication for use in NYHA class II-IV patients with ejection fractions of 40 or below, more than 87% of heart failure patients in Turkey would be eligible for the drug. The more restrictive entry criteria in PARADIGM, which required that patients already be receiving an ACE or ARB and a beta blocker, would lower that percentage to 55%. But there are new, even more restrictive guidelines from the ESC that limit the use of Entresto to NYHA II and III patients, require that patients already be taking a mineralocorticoid receptor antagonist as well as the other drugs, and also have sufficiently elevated BNP of NT-proBNP levels. In Turkey this would limit use to less than 20% of heart failure patients.

However, the moderator pointed out that many people would likely give the drug in the absence of an MRA. Clyde Yancy said he agreed with that statement, and pointed out that adherence to guidelines requiring an ACE or an ARB, a beta-blocker, and a MRA is much higher in the US than in Europe.

Another problem, said Yancy, is that there are now “so many class 1 indications in heart failure that we may be coming to the point that most heart failure patients will need to be seen by a heart failure specialist.” He said that we may need to adopt a team approach to treating heart failure, especially in complex cases in which patients have additional conditions, such as diabetes. “We need to evolve a better process,” he said.

“Physicians would take the drug themselves if they had heart failure…”

Finally, in an editorial accompanying the Annals cost-effectiveness study, Milton Packer, one of the two leaders of the PARADIGM-HF trial, and colleagues at Baylor University Medical Center argue that most physicians are not aware of the magnitude of benefit Entresto can bring to most of their patients, including their younger patients. They write that most physicians underestimate the risk of death in their patients with mild to moderate heart failure. In their editorial they describe the survival benefits of switching patients to Entresto as “substantial.”

The PARADIGM-HF trial, they write, “found an incremental 20% reduction in cardiovascular death beyond that achieved with enalapril. This finding may not be persuasive if physicians believe that their patients are not at significant risk for death. However, physicians should recognize that patients with mild to moderate heart failure are at greater risk for dying than many patients with cancer. Using patient-level data, the PARADIGM-HF investigators estimated that treatment with sacubitril–valsartan prolongs life by an average of 1.0 to 2.0 years.”

“We believe that, when they consider these findings, physicians who previously never prescribed sacubitril–valsartan would take the drug themselves if they had heart failure— even if they were clinically stable and had minimal symptoms,” they concluded. “Yet, the plethora of articles and P values concerning sacubitril–valsartan published over the past 3 years have had minimal impact on prescribing behaviors.”


  1. I fail to see why this drug is not put forward as a hypertension medication. That’s basically how it acts. That could be the simple slippery slope that gets it into clinical practice.

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