Is Nesiritide Safe? A Prestigious Journal Wants That Question Asked
I have written about a concern that nesiritide (Natrecor TM) may not be a safe medicine. When asked, I will certainly acknowledge the benefits of the drug. These include improving symptoms and lower the pressure in the heart very quickly (both good things if you have bad heart failure). But these advantages don't exist much longer than 3-6 hours. By 24 hours of treatment, the medicine is not different than the established options.
The reason that I expressed my concern initially (early 2002) was that it seemed to me that there could be a risk associated with use of nesiritide. I spoke at a national meeting in the spring of 2003 to present data that suggested this risk to me and was given the "freeze." The data from our analysis suggesting risk associated with nesiritide leaked to the Wall Street Journal in advance of the publication, but perhaps because I did not speak with the reporter, the lay press paid little further attention (according to the policy of the meeting where I was scheduled to present the data, I was not permitted to discuss the results in advance).
Discussion amongst my peers, focusing on the scientific and medical implications, was also fairly absent. I was told (this is hearsay, I have no proof it happened) that Scios (manufacturer of nesiritide) devoted a significant part of a teleconference with key cardiology opinion leaders to try to figure out what my agenda was. It was as simple then as it is now, drugs used in clinical medicine should undergo rigorous safety analyses in formal studies wheneven feasible.
Besides that "discussion," I was treated more as a pariah than did the analyses lead to meaningful discussions about how to learn whether there was a risk associated with nesiritide. For the most part, a huge database was analyzed (ADHERE registry) to see if there were any associations of concern. This kind of analysis is even less meaningful than the pooled analyses I have performed with my colleagues.
I gave apresentation at another national meeting (fall 2004), and was greeted by both outright attacks and quiet encouragement. Finally, more practicing physicians are realizing how important it is to look cautiously at the rationale for using nesiritide, hopefully as a first step towards carefully considering the rationale for any test or treatment. Ideally, doctors will go even one step further, and look at the data.
This is what the cardiology journal Circulation has done. This spring, they will be publishing our analysis that shows an association between nesiritide use and worsening kidney function. As a colleague said to me recently abou this association, "that is not good."
My goal; to continue to push for rationale, data-driven medical care.
Perception of Safety
If I haven't made it clear enough, my attitude as a practicing cardiologist is pretty simple. If a treatment improves quality of life enough, it is worth considering even if, on average, it shortens life. I would apply this to the COX-2 inhibitors (Vioxx, Celebrex, Bextra) by using them for pain relief when other medicines don't work, IF a patient told me that it was worth the risk for them. That's a personal decision, based on my ability to explain the risks. Since there are now several studies that provide an estimate of risk, the discussion can be focused on risks compared to benefits.
Sometimes, I see other doctors have attitudes that are very different, and that's okay. But I am amazed by some of the attitudes displayed, which may apply to the use of drugs such as these.
Let's take the example of a medicine discussed in the medical journals but which is not currently approved for use. It's called ximelagatran and in theory, would replace the use of the blood thinner coumadin (warfarin). I like the idea of replacing coumadin. Most people are upset when they learn that their medicine is also a popular rat poison (rats eat it and bleed to death - rather brutal). I was on the FDA panel that reviewed the application for ximelagatran and I voted to reject it. Why? Aside from the fact that it seemed possible that it was far inferior in effectiveness relative to coumadin, meaning people would still have some risk of bleeding with this new blood thinner but not be as protected from the risk of strokes and heart attacks, it also may increase the risk, paradoxically, of having a heart attack. Then there's the possibility suggested by the data that it can cause liver failure. That's a big deal, as you can imagine.
So here's the amazing part. Some of the data was published in medical journals and in response, almost 2/3 of cardiologists surveyed (see lower left corner of the landing page of http://www.theheart.org) believe the drug should be approved.
Here's an example of the FDA doing the right thing, acting to protect the public, then publishing on their website several hundred pages of information from the company's application and the FDA analysis, yet doctors are unaware, uninformed and misguided in wanting access to a drug that appears likely to be dangerous and possibly less effective than the standard, coumadin.
Amazing that somehow, somewhere, there isn't a better way to disseminate information to patients and physicians.
Safety Issues Exist Beyond Vioxx and Celebrex
Check out the article on Forbes.com about our work on the relative risks of nesiritide, a medicine for the treatment of heart failure marketed by Scios/J&J. It is pretty impressive that somehow J&J has escaped the attention that this drug should be receiving. Although it is nowhere near the magical level of $1 billion in sales, nesiritide is used for about 10% of the one million heart failure hospitalizations annually.
I know why nesiritide was approved by the FDA; the drug does improve symptoms more quickly than other medicines that were already available. What I don't understand is why Medicare agreed to pay for it to be used in an unapproved setting, doctors' offices, when there was a lack of safety and effectiveness data in this setting.
Perhaps this press will help open people's eyes and minds. Merely because there is no evidence of danger associated with a medicine does not mean a medicine is safe, when, as is the case for nesiritide, no one has bothered to look.
Vioxx, Celebrex or Neither?
The debate has been raging for a while now. But it's no longer whether Vioxx, Celebrex or any other COX-2 inhibitior is safe or dangerous. The debate is focused on whether Merck did the right thing, and therefore, whether Pfizer is doing what's right.
Here's the recap. Vioxx is shown to increase risk of heart attacks, strokes and bad stuff like that, even in people who don't seem to be at risk. Merck, aware of the liability associated with such a discovery, pulls the drug from the market. While Pfizer initially said the there was no evidence at all for any such risk associated with Celebrex, with more data available, they seem to be admitting that there is some risk after all, althought not as much as with Vioxx. Lost by some is that another medicine of this type, Bextra, also made by Pfizer, probably does increase risks as much as Vioxx.
Nonetheless, Pfizer took a different approach. They chose not to remove the drug from the market, even though their sales will drop dramatically and they will face some serious liability when court cases start to move ahead.
I "know" who did the right thing. And it isn't Merck.
Thousands of people suffer from horrible pain, some so affected that they can't get out of their house, can't sleep, can't sit. For these people affected by arthritis and chronic pain syndromes, COX-2 inhibitors represent their only chance to feel better and have the ability to function at a level that gets close to normal. For such people, the data from all of these studies allows a decision to be made about the relative risks and benefits of taking Vioxx, Celebrex or Bextra. For many, it's an easy decision. They'd rather feel less pain and enjoy a bit of life (by taking the medicines) even if it means that they may live a year or two less.
Why did Merck do what they did? To be able to project more accurately their quarterly earnings. And Pfizer? While I am sure that they are thinking similarly, I interpret their commitment to continue to sell Celebrex as an indication that they are committed to help people with pain, even at the risk of feeling some significant financial pain themselves.
