In a study published in the April 2005 issue of the Journal of the American Medical Association, a team of researchers assert that Natrecor users suffered from a higher death rate than cardiac patients on other drugs, such as diuretics and vasodilators, based on data from three past Natrecor clinical trials. In conclusion, Nesiritide may be associated with an increased risk of death within the first month after its use for the treatment of decompensated heart failure when compared to noninotrope-based therapies,the researchers wrote. The Natrecor study was conducted by researchers Dr. Jonathan Sackner-Bernstein, of the North Shore University Hospital in Manhasset, N.Y; Drs. Marcin Kowalski and Marshal Fox, of St. Luke’s-Roosevelt Hospital Center in New York; and Dr. Keith Aaronson, of the University of Michigan. Some of the researchers involved in the JAMA study also published a similar study in the medical journal Circulation in March 2005. In that analysis, the researchers said that Natrecor could hasten renal failure in some patients. On January 3, 2006, Johnson & Johnson informed U.S. regulators that a previously unreported two additional patients died 30 days after taking Natrecor, adding to uncertainty about the drug’s safety.
Natrecor (Generic: Nesiritide) was approved by the Food and Drug Administration in 2001 to treat a severe form of heart disease called decompensated heart failure, for which there are few available treatments. Many patients are treated with diuretics and vasodilators. Natrecor’s label already warns it can cause kidney problems in certain users. The drug is marketed by Scios Inc., a wholly-owned unit of Johnson & Johnson.
A Food and Drug Administration review of Natrecor in 2001 said the company’s data could not rule out a 50% increased risk of death among patients given Natrecor. Statements from Dr. Nissen at the FDA Advisory Committee hearing on Nesiritide.
Dr. Nissen: Jim, I have a series of sort of interrelated questions, and the hypothesis to be tested here was that this agent was effective in the background of standard of care, and so I’m interested in exploring with you this whole issue of standard of care. Now, as I understand this, these were Class IV patients, dyspneic at rest with acute decompensation; respiratory rates in the low to mid-20s; a pretty sick group.
In my experience, if a patient like that comes in the emergency room, before I’ve answered my page, someone has given them a big slug of IV furosemide, and I’m very troubled here by slide number 73, if you want to put that up, because it suggests something about this study was somehow biased toward not providing standard of care. I mean, here is only 30 percent of the Natrecor patients got an IV diuretic within six hours before they began these infusions, and only a little more than half got an IV diuretic within 24 hours before.
And so it looks to me like somebody was withholding diuretic therapy, withholding standard of care therapy in order to set these patients up for the drugs to be used, and I need to understand what happened here to be able to properly interpret the data.
Dr. Nissen: Yeah, I wonder if you could put up slide 112. I want to talk with you about that. the question I have relates to this issue of what I think is a somewhat narrow therapeutic index for this drug, and I was very struck by the fact that a dose increase from .01 to .015 is really associated with about a doubling of the risk of symptomatic hypotension, and then there’s even another large increase when the dose gets higher.
And so I had several questions that relate to this that I think are important, and let me make sure you understand why I am asking this question. You know, one of the reasons that IV nitroglycerine is very popular is that it has a very wide range of doses. We give as little as ten micrograms and I’ve certainly given as much a 1,000 or more micrograms.
So it’s a drug that we know we can use over a very broad range. So whenever I see a drug with a narrow therapeutic index, I worry. And so the next question I wanted to ask is given the fact that I assume you agree with me that it is a narrow therapeutic index, what do we know about the pharmacokinetics of this drug?
For example, how exactly is it metabolized or eliminated? What kinds of patients might we have to worry about as clinicians that might accumulate the drug at greater levels because if presumably a 50 percent increase in dose is associated with a big increase in risk of hypotension, then I’ve got to know more about the variability in the kinetics here to have comfort about this, and I wonder if you could address that for me.
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