Thursday, July 30, 2015

Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year

The newest drug for congestive heart failure, Entresto, a fixed combination of valsartan and sacubitril, has just hit the market at an elevated price.  Like other drugs recently introduced as blockbusters, the high price does not seem clearly justified by clinical evidence about the drug's benefits and harms.  

Questions Raised by the One Big Published Controlled Trial

Last year, we discussed the hoopla around a study of a new drug for congestive heart failure (CHF),(1) a fixed combination of valsartan and sacubitril. Also, on the now defunct CardioExchange blog, Dr Vinay Prasad discussed the same study (look here, and scroll down.) We both concluded that the (apparently multiply flawed) design of the study left important questions unanswered.

Does Sacubitril Actually Work?

 The PARADIGM-HF study compared patients given valsartan plus sacubitril to patients given enalapril.  Valsartan, an angiotensin receptor blocker (ARB) and enalapril, an angiotensin converting enzyme inhibitor (ACEI) have both been shown separately to improve symptoms and function, decrease morbid events, and extend life for patients with systolic CHF.  However, the PARADIGM-HF study compared a high dose of valsartan, 160 mg twice a day, (plus sacubitril) to a medium dose of enalapril, 10 mg twice a day.  Apparently, no trial comparing just valsartan 160 mg to enalapril 10 mg twice a day has been done.  So it is quite possible that a high dose of valsartan is better than a medium dose of enalapril.  Thus, PARADIGM-HF could not prove that sacubitril has any benefit independent of high dose valsartan.

What are the Adverse Effects of Sacubitril (With or Without Valsartan) Likely to be in Practice?

The PARADIGM-HF design prevented any assessment of the adverse effects of sacubitril independent of those of valsartan.  Furthermore, the trial had an active run-in period which resulted in the exclusion of  patients who failed to tolerate valsartan-sacubitril in a pre-trial run-in period.  This effectively biased downward the prevalence of adverse effects due to the combination reported during the trial.  Finally, the trial, while big, was not big enough to discover rare but severe adverse effects.  Thus, one cannot easily tell how the benefits of valsartan-sacubitril compare to its harms, or how the benefits of sacubitril alone compare to its harms.

How Would Valartan-Sacubitril Work for Patients with Common Diseases in Addition to CHF?

The study excluded patients with common conditions that may afflict CHF patients, including relatively severe coronary artery disease, severe lung disease, ulcers and liver disease.  CHF patients are often elderly and often have other diseases, but how the drug might work for them is unclear.

Other Doubts and Questions

In a recent Medscape post, Dr John Mandrola noted additional problems with the study that raise doubts about its validity.  These included its early termination, the very large number (1000) of study sites raising doubts about quality control of implementation and data collection, and the finding, not emphasized by the authors, that valsartan-sacubril caused an apparent increase in hypotension, a significant issue for CHF patients.

As far as I can tell, there have been no other big trials of sacubitril, with or without valsartan, so there are no other source of clinical research data to address these questions.  As we noted here, one of the most prominent PARADIGM-HF investigators tried to rebut Dr Prasad, but did so mainly by employing logical fallacies.

So in my humble opinion, there is only weak, ambiguous data to show valsartan-sacubitril produces benefits that outweigh its harms for congestive heart failure patients seen in usual clinical practice.

More Enthusiasm and Hype about Entresto

These questions about the one big study of valsartan-sacubitril did not deter the US Food and Drug Administration (FDA) from approving it.  As soon as it was approved, the hype machine started up in a big way.

Per the NY Times,

'This is one of those once-in-a-decade kind of breakthroughs, to get a drug that extends life so substantially,' David Epstein, the head of Novartis’s pharmaceutical division, said in an interview.

Per the Wall Street Journal,

Clyde Yancy, chief of cardiology at Chicago’s Northwestern Memorial Hospital, said that Entresto is 'one of the few times that we have identified a medication that is better than the standard. It’s clearly superior to what we have.'

Per a Medscape news post, Dr Clyde Yancy also said,

A year later, I continue to feel that this is, in fact, a reflection of a new day—for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine.

And Dr Milton Packer (who had countered Dr Pradad's critique of PARADIGM-HF with logical fallacies, said,

I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.

The Medscape article did document some doubts.  Dr John G Cleland of Imperial College, London, UK allowed that the active run-in group was among "issues that have yet to be settled," Dr Marriell Jessup who had written a positive editorial in the NEJM when the trial was published(2) allowed that the lack of patients with co-morbities might be a problem.  Finally, Dr Yancy allowed that the early termination might be a problem.   Yet each focused on a single problem with the study, and none of these physicians seemed to acknowledge the totality of the study's problem.  Neither did any of them seemed to let these doubts dampen the enthusiasm, e.g., at the end of the article, quoting Dr Yancy,

Can we change the narrative?  I believe it's time to take the 'failure' out of heart failure and look at what we can do to generate success.
Note that the article disclosed Dr Cleland does research funded by Novartis, maker of Entresto, and Dr Packer is a consultant to Novartis.  Is is possible these commercial relationships tempered any concerns that might have had about the study design. 

I realize that CHF is a miserable problem for patients, and clearly leads to severe symptoms, multiple hospitalization, and sometimes early death.  So I understand why people may be enthusiastic about a new therapy for it, especially if their research or consulting is funded by the drug's manufacturer.  But is it crystal clear the latest innovation is that good?

Billions of Dollars in Play

But never mind those unanswered questions and the multiple problems with the PARADIGM-HF trial, Entresto, the trade name for valsartan-sacubitril will not be cheap.  Per the NY Times,

Novartis said Entresto would cost about $12.50 a day, or about $4,500 for a year....

Novartis wants to convince you that it's not really that expensive

Mr Epstein said the price was 'really quite reasonable,' given that some drugs for other diseases cost many times that amount and confer less benefit.

He is certainly right that some drugs are even more expensive. However, is argument is just an appeal to common practice.  Whether the prices of other drugs are justified by strong evidence about their benefits and harms may not be clear. The benefits conferred by Entresto, and the harms it may cause as we belabored above, are really not that certain either. 

In the financial news, you could almost imagine the salivation.  Per the WSJ,

Wall Street predicts Entresto will be a blockbuster, with Leerink Partners estimating that annual global sales could top $6 billion by 2024.

In Reuters,

Expectations for Entresto have been building since it won early U.S. approval and Novartis set a higher than expected price, with analysts now forecasting $4.7 billion of sales in 2020, according to Thomson Reuters Cortellis.

Chief Executive Joe Jimenez said Entresto sales would take time to ramp up but growth would accelerate in 2016. Reception to the new drug, which Novartis started shipping within 24 hours of U.S. approval this month, has been good and there was little resistance to the $12.50 daily cost.

'The average hospital stay for a heart failure patient in the United States is $11,000,' Jimenez told reporters. 'So we are not receiving pushback on the price because I think this is seen as good value.'

Compared to what? Again, it is not clear that Entresto would be better than generic enalapril dosed at 20 mg/day, which is a lot cheaper than $4,500 a year.  But could it be that visions of billions of dollars have clouded some peoples' thinking, at least people paid by or owning stock in Novartis?


We have posted frequently about the blockbuster drug Sovaldi promoted as a cure for deadly hepatitis C infections.  Yet while the evidence that Sovaldi and its competitors are really so good, really provide cures, and really will prevent many patients from dire consequences of hepatitis C is not so strong, the US price of these drugs is stratospheric.

Now we have Entresto, whose price is not so stratospheric, but still quite high, and whose benefits compared to its harms are not clearly supported by evidence from clinical research.

 Unfortunately, Entresto (valsartan-sacubitril) is now one of a long line of new drugs that are breathlessly hyped, often by people who should know better, despite weak evidence in their favor.  It is one of a long list of examples of drugs approved based on poorly designed studies whose design flaws seem likely to make their commercial sponsors' products look better.  As a recent post in Health Affairs by Christopher Robertson reminds us, while many industry supporter act like allowing drug and device manufacturers to support (and usually control) most of the clinical research meant to evaluate their own products in inevitable,

When one steps back from our current practices, it should appear rather odd that we rely on companies to test the safety and efficacy of their own products. It would be as if a litigant were allowed to choose and fund its own judge, or an athlete to hire her own referee.

To convince us that we live in the best of all possible worlds, however, the media is full of proclamations that we are in a new era of marvelous medical and health care "innovations" that will bring us all untold benefits.  The notion that physician-industry collaboration is necessary to continue to produce these wondrous "innovations" is a talking point used to counter those who criticize conflicts of interest affecting academic medicine (look here).   Yet the evidence supporting many game-changers and blockbusters is often weak and ambiguous.  This rarely seems to deter the drug, device and biotechnology industry from charging more and more for them.

The sober, evidence-based medicine approach is being lost in all the hoopla and hucksterism.  We are adopting treatments of unproven value, whose benefits may be much less, and harms may be much worse than we imagine, and paying unconscionsable prices for them.  The results for patients and society include our ever rising health care costs, ever challenged access, and no evidence that outcomes are better for patients.

True health care reform would encourage sober discussion of the evidence, of benefits and harms, and of fair pricing, and would challenge the hype, hucksterism, and conflicts of interest that all swirl around modern health care. 


1.   McMurray JJV, Packer M, Desai AS et al.  Angiotensin - neprilysin inhibition versus enalapril in heart failure.  N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077  Link here.

2.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.

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