How did this heart drug get approved in the first place?

In case you believe that the medicine you’re taking has been adequately tested on real live patients before being legally approved, you might want to consider research published recently in The New England Journal of Medicine*. A heart drug called nesiritide that for the past 10 years has been given to hospitalized patients with acute heart failure has failed to show any improvement compared to placebo.

But the drug had somehow received FDA approval in 2001 for use on these patients – after initial non-approval. Researchers in the largest study so far for nesiritide published their findings that the drug showed no effect on the primary end point of all-cause cardiovascular mortality, as well as no effect on heart failure re-hospitalizations. The results of this ASCEND-HF trial were presented at the annual American Heart Association scientific meeting.

In a scathing editorial in Journal Watch Cardiology this month, Dr. Harlan Krumholz criticizes the FDA’s actions in approving nesiritide in the first place:

“Well more than $1 billion was wasted on purchasing the drug. This study clearly demonstrates the importance of testing the effects of new drugs on patient outcomes before approving them for clinical use.”

As merely a dull-witted heart attack survivor, I have to say that I always figured that the sole purpose of the drug approval process was to ensure that “testing the effects of new drugs on patient outcomes” has already been done.

In an accompanying NEJM editorial, cardiologist Dr. Eric J. Topol (of the Scripps Translational Science Institute, and coincidentally also the first physician researcher to raise questions about the deadly cardiovascular risks of the Merck drug, Vioxx) wrote:

“It has taken a full decade to learn the truth about nesiritide’s lack of efficacy in acute heart failure. Nesiritide was approved by the FDA on the basis of a single trial in which surrogate end points** were assessed three hours after administration.

“But in cardiovascular medicine, we learned long ago that therapies directed at surrogate end points can be associated with excess deaths.

“In this time frame of 10 years of fuzziness and ambiguity regarding whether or how to use nesiritide, there was also legitimate uncertainty regarding the potential side effect of renal dysfunction and an increased mortality, simply because such a limited number of patients had been evaluated in controlled trials.”

“The FDA should be provided the full regulatory authority to require definitive trials and withdraw a drug if the sponsor does not promptly conduct a far-reaching clinical-end-point trial for a new molecular entity. Ideally, this trial would have been performed before approval.

But long before this new trial, back in 2005 Dr. Topol had also written this warning about nesiritide in the same journal:

“How can a drug that costs 50 times as much as standard therapies – and for which there are no meaningful data on relevant clinical end points – be given to more than 600,000 patients and be promoted  for serial outpatient use, an indication not listed on the label?

“Until a trial definitively proves that this drug reduces the risk of death or repeated hospitalization for heart failure, there will be questions about the appropriateness of the drug’s use or even commercial availability.”

And questioning whether nesiritide, manufactured as Natrecor by California’s Scios (one of over 230 subsidiaries of drug giant Johnson & Johnson), should even be on the market, Dr. Topol wrote at the time:

“In my view, nesiritide has not yet met the minimal criteria for safety and efficacy.”

The current trial’s lead author, Dr. Christopher M. O’Connor (of Duke Clinical Research Center, Durham, North Carolina) studied some 7,100 patients, newly hospitalized with acute heart failure, who were randomized to receive either a placebo or nesiritide.

This drug is the pharmaceutical form of a hormone naturally produced by the heart to enhance vasodilation (to help widen coronary arteries). It’s administered intravenously to hospitalized patients with acute decompensated heart failure. All 7,100 patients in this study received other standard cardiac therapies as well.

The trial’s conclusions:

“The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed.

“Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.”

Dr. Robert Califf (also of the Duke Clinical Research Institute), chair of the trial’s executive committee, added:

We constantly put drugs on the market without doing the right outcome trials. If this outcome trial had been done earlier, clinicians and patients would have had a much better idea of the potentially very limited role of this treatment.”

Dr. Patricia Salber, a board certified internist and emergency physician, proposes an intriguing analogy comparing the approval of nesiritide with Ford Motor Company executives who calculated the cost-benefit ratio of keeping quiet about the known flaw in the gas tank design of the then popular – and deadly – Pinto.

What do the drug’s manufacturer Scios and their research funding bosses over at Johnson & Johnson have to say about the damning conclusions of the ASCEND-HF trial on their drug?

Dr. Peter M. DiBattiste, M.D., Vice President of Cardiovascular Development at Johnson & Johnson Pharmaceutical Research and Development, offered this example of corporate bafflegab on Johnson & Johnson’s own online news coverage of the trial results:

“The ASCEND-HF trial has answered many scientific questions and has increased our understanding of the safety profile of NATRECOR® (nesiritide). This is the largest trial ever conducted in patients with acute decompensated heart failure, and affirms our commitment to patients and physicians who have limited treatment options to fight this life threatening disorder.”

As a person with over 30 years experience in the field of public relations, I’ll translate that stupefyingly meaningless PR-speak into plain English for you:

Blah, blah, blah…”

Funny, Dr. DiBattiste must have missed the most important part in this trial’s conclusions – the part where nesiritide failed to show any improvement compared to placebo  in both cardiovascular mortality and heart failure re-hospitalizations.

In other words, it may be relatively safe for patients to take – but it doesn’t work.

Consumers may well ask why it’s taken government a full decade to warn physicians and their most vulnerable patients about this reality.

© 2011 Carolyn Thomas,  The Ethical Nag: Marketing Ethics For the Easily Swayed


* O’Connor, CM.  New England Journal of Medicine 2011 Jul 7;365 (1):32-43. “Effect of nesiritide in patients with acute decompensated heart failure”.

This post was picked up by Better Health’s Grand Rounds on July 26, 2011.

See also:

10 thoughts on “How did this heart drug get approved in the first place?

  1. Carolyn:

    One could become cynical about Big Pharma (and about the FDA).

    Cynicism, no doubt, is bad for the heart.

    Can you please recommend a drug to reduce cynicism?

    • Personally, I have found that a nice 12-year old Macallan scotch tends to reduce my cynicism. Or a good red wine like an Italian Barolo, which of course has the added benefit of being heart-healthy . . .

      • I will do experimental research with both of them this evening.. Particularly looking forward to the Scotch. Glad to know there is an antidote for Big Pharma cynicism.

        (On the other hand, this could be proof that Big Pharma practices are driving me to drink. Can I sue? Do you know any good law firms that have no scruples that you can recommend?)

  2. Back in the 1980s I was an RN, working in a cardio-thoracic unit. The thing which makes my blood boil – and my spirit despair – when I read this kind of story is that Doctors at the bedside who prescribe drugs such as this, are effectively selling hope and some kind of future to patients who face a potentially life-limiting condition.

    Why have Doctors become so trusting and reliant upon the ‘blah blah’ fed to them by Big Pharma and whatever it is we call the checks and balances which should exist in the FDA – and here in Australia, the TGA?

    What has become of simple, good ol’ fashioned medical ethics and a healthy dose of scientific caution and skepticism?

    I swear, in the past 20 years, the practice of medicine has become some kind of mass-delusional belief system, captivated by so-called innovation, paying homage to the costly and the unique, its adherents in the thrall of the distorted dogma of Evidence-Based Medicine [EBM].The foundation stones of EBM are in fact, the objective experiences and observations of multitudes of individual practitioners, not the meta-analyses of randomly controlled trials [RCTs].

    Where are all the cardiologists who administered this drug, and saw no real benefit in the men and women – beloved by others – who received it? Where is their evidence? What were their experiences, and those of their patients? Why has this evidence not been gathered, collated and openly discussed before now? Or if it was, why were those voices unheard and unnoticed?

    The meta-analysis of multiple RCTs – merely the pointy tip of the pyramid of evidence – is no tool for revealing truth, safety, or efficacy, and RCT’s are too easily corrupted by slick statistical manipulation, lack of external validity, artfully crafted conclusions which play loosely with the truth, the machinations of Big Pharma and the people in its pay etc etc.

    It must surely be time to rethink how we gather medical information [evidence], who should be gathering it, and how this information is used.

    • Well said, Margi. Your excellent questions deserve answers. This study was undertaken, for example, due to years of safety concerns about this drug – which is why J&J’s response is so ludicrous (“…increased our understanding of the drug’s safety profile…”). ?!?!

  3. Sounds to me like more of the same. Let’s push this drug through quickly before they notice. Dr. Battiste should be ashamed of himself being bought by the big giants and Johnson & Johnson keeps getting bigger and bigger because they have deep pockets to dangle that carrot in front of the right noses. They are no fools. What happened to honest research to help real people’s needs? The mighty bottom line. MONEY, POWER and GREED.

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