Study Supports Controversial Heart Failure Drug
MONDAY Oct. 29, 2007 -- A new study supporting the safety of Natrecor, a widely used heart failure medication, is another volley in the ongoing battle over the drug.
Critics have charged that Natrecor, which costs about $500 a dose, adds little to patient outcomes and, in fact, may raise their risk of kidney failure and death.
However, the new study of 75 patients -- the first prospective trial of its kind -- showed no such trend during the week after the drug was given to patients hospitalized with heart failure. The study found Natrecor to be safe when given to those patients it was developed for: people with acute decompensated heart failure (ADHF).
"ADHF is really a broad definition," explained the study's lead author, Dr. Ronald Witteles, an instructor in cardiovascular medicine at Stanford University School of Medicine. "It encompasses anytime that patients with heart failure are hospitalized. They could be hospitalized for too much fluid and the so-called 'congestive' symptoms of heart failure. It could also be because their heart simply cannot pump enough blood to their organs."
The new finding, published in the Oct. 30 online edition of the Journal of the American College of Cardiology, isn't appeasing the drug's detractors, however.
"It's not enough to say, 'I have done a small study of 75 people, and [Natrecor] isn't heinous enough to see that it's bad, so how bad could it really be?' You actually have to show that it is safe," said Dr. Jonathan Sackner-Bernstein, associate chief of cardiology and director of the Heart Failure Program at St. Luke's-Roosevelt Hospital Center, in New York City.
He co-authored a 2005 retrospective analysis of data from three trials. It found that hospitalized heart failure patients who got Natrecor (nesiritide) faced an 81 percent higher risk of dying within 30 days, compared to patients who got a placebo.
More than 500,000 new cases of heart failure are diagnosed among Americans each year, but breakthroughs in treatment have remained elusive.
The usual first-line therapy is diuretics, drugs that flush water from the body, with nitroglycerine used as an alternative. Natrecor, approved by the U.S. Food and Drug Administration in 2001, is used to strengthen heart function.
The drug "was the first new treatment for decompensated heart failure in over a decade, and there is yet to be another one," Witteles noted.
Heart specialists welcomed any new weapon against ADHF, so Natrecor's annual sales soon soared into the hundreds of millions of dollars. But then reports like Sackner-Bernstein's began to surface, taking away some of the drug's luster.
Debate over Natrecor's safety and efficacy "became, certainly in the last five years, the biggest controversy I can think of in heart failure," Witteles said.
Critics quickly put the pressure on the drug's maker, Scios Inc., to initiate a large, prospective randomized controlled trial. Such a trial is already in the recruitment phase and organizers hope to gather 7,000 patients.
The Stanford study -- also funded by Scios -- was much smaller and was conceived before the controversy broke, Witteles said.
In the trial, 75 patients admitted to a hospital with ADHF received either Natrecor or a placebo within 12 hours of admission, for two days.
Since impaired kidney function was the main area of concern, the Stanford researchers used standard methods to assess each patient's kidney function during the first seven days of hospitalization. They also looked at rates of patient death or rehospitalization, or the need for dialysis or other care, over the following 30 days.
"The main findings were that nesiritide did not cause renal [kidney] dysfunction in high-risk patients who were hospitalized with heart failure," Witteles said. He stressed, however, that Natrecor also failed to prevent kidney trouble, so doctors should not use the drug in hopes of preserving kidney function.
Average length of hospital stay was similar for those on Natrecor or placebo -- four days. Four patients taking Natrecor died within 30 days compared to two on a placebo, but those numbers were far too small to represent any solid trend, Witteles said.
So, why do the Stanford results differ from those of prior studies?
According to Witteles, the patients in his team's study more accurately reflect those seen by doctors generally -- older patients whose situation when they arrive at the hospital is not so dire that they need the highly concentrated shot of Natrecor used in earlier trials.
"The lower dose [we used] is not associated with renal dysfunction the way that perhaps the higher dose is," Witteles reasoned. The lower dose is also the one approved for use by the FDA, he added.
Witteles also believes that Natrecor has both beneficial and detrimental effects on the kidneys. At the lower dose used in the study, "they simply cancelled each other out," he said, leading to a nil effect on kidney function.
The bottom line, according to Witteles: "I think [Natrecor] should be used in a particular context as well as in a particular fashion. I still believe that nesiritide is a very useful drug in the appropriate person."
That explanation doesn't satisfy Sackner-Bernstein, however, who called the new study "well-designed and well-executed" but also flawed.
The trial was too small to draw any firm conclusions, he said, and it also failed to address one important concern. The Stanford researchers "didn't look beyond hospitalization" when tracking the drug's effect on the kidneys, Sackner-Bernstein pointed out.
According to prior data, Natrecor-associated kidney problems only emerged in the weeks and months after a patient had been discharged from the hospital, Sackner-Bernstein said.
Witteles' team restricted their kidney tests to just the few days the ADHF patients were hospitalized. "Then they said, 'Look, there's no real risk,' " Sackner-Bernstein said. "Well, that's simply not the period of time in which the renal risk appears to exist. And, if you do not look for it, then, of course, you aren't going to find it."
Because of its small size and short follow-up, the Stanford study also failed to address the most important question of all: Does Natrecor increase patients' risk for death?
"Certainly this trial does not even attempt to answer mortality questions," Witteles agreed.
Those questions may only be answered by the large, prospective trial currently under development. "I think that that is the trial that will settle the matter," Sackner-Bernstein said. "That's the kind of trial I first asked for."
The results of that study will not arrive for at least four or five years, however. In the meantime, the debate over Natrecor continues.
Posted: October 2007
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