St Louis, MO - When reports in two prominent journals raised red flags on giving nesiritide (Natrecor, Scios/Johnson & Johnson) to patients with acute decompensated heart failure (ADHF) last year, physicians cut back on its use right away, suggests an analysis of hospital records from before and after their publication [1].

The March 29, 2005 issue of Circulation contained a pooled analysis of nesiritide trials that raised the possibility of renal toxicity from treatment with the drug [2]. A few weeks later, in the April 20 issue of the Journal of the American Medical Association (JAMA), a report from the same group suggested that the drug's use in the trials had may have increased 30-day mortality compared with treatment with noninotropic drugs [3].

As covered in detail by heartwire over the past 18 months, some prominent clinicians came to nesiritide's defense by criticizing how the two analyses were conducted, while others took them as a warning and urged restraint in using the drugs pending additional trials. Some also questioned the strength of evidence that had supported the drug's FDA approval and called for its removal from the market [4].

In the October 18, 2006 issue of JAMA, Dr Paul J Hauptman (St Louis University Hospital, MO) and associates report that the second of the two 2005 nesiritide articles marked a turning point in the drug's use by clinicians treating patients admitted for ADHF. Using a prospectively compiled database of such admissions at 491 acute-care hospitals in the US, the group compared the use of nesiritide and other treatments during the four months from January to April 2005 and over the subsequent May to December.

During the latter eight months, Hauptman explained to heartwire, "There was a very modest reduction throughout the period in the use of inotropic therapy and a very slight uptick in the use of vasodilators—nitroglycerin and nitroprusside. But the clear overwhelming change was with nesiritide." Its usage peaked in March, at 16.6% of 14 167 admissions, and had fallen significantly to 5.6% of 10 822 admissions by December (p<0.001), according to the analysis.

If you were going to get vasoactive therapy, you were more likely to get nitroglycerin, sodium nitroprusside, or an inotrope than you were to get nesiritide. Which is a huge change."

"In this particular case, physicians appear to have responded very quickly to a perceived safety problem," Hauptman said, noting that the prominence of the two involved journals and heightened safety consciousness in the wake of the Vioxx controversy and defibrillator recalls may have had something to do with how fast practice changed.

"This thorough analysis shows that the system works," the principal author of the two cautionary reports, Dr Jonathan Sackner-Bernstein (CliniLabs, New York, NY), said to heartwire. "Physicians are concerned about the association between the use of nesiritide and risk enough to markedly reduce its use and send the message that the medical community wants a definitive clinical trial, as is planned for nesiritide."

As recently reported by heartwire, nesiritide's maker, Scios, publicly announced plans for a large randomized controlled trial that would address any concerns about the drug's safety and efficacy. Although the company had drawn criticism for what seemed like a long delay in planning such a trial, nesiritide's critics and supporters welcomed the announcement.

Some nesiritide proponents have expressed concern that reduced nesiritide use in ADHF would be accompanied by greater reliance on dobutamine and other inotropic agents, which temporarily improve contractile function but at a substantial cost. Hauptman observed that the evidence for an increased mortality risk from inotropic drugs is "stronger and more complete" than the data suggesting any harm from nesiritide.

Although the analysis suggests that inotrope use overall actually fell slightly as nesiritide use declined, inotropes were used more often among ADHF patients who received intravenous vasoactive drug therapy, defined as any use of nitroglycerin, nitroprusside, dobutamine, dopamine, milrinone, or nesiritide. Among that subgroup, the rate of inotropic therapy rose from 21.5% before the cautionary nesiritide reports were published to 29.6% afterward (p<0.001).

"Certainly there wasn't an increase in inotrope use," Hauptman said. But after the reports came out, "if you were going to get vasoactive therapy, you were more likely to get nitroglycerin, sodium nitroprusside, or an inotrope than you were to get nesiritide. Which is a huge change."

One could argue that papers like those from Sackner-Bernstein can profoundly affect practice and that there could be, at least theoretically, downstream effects that we haven't anticipated.

Clinicians gave shorter nesiritide infusions after the articles were published, according to the analysis. Their average duration went from 2.3 days to 2.1 days (p<0.001). The infusions were also started later after presentation; the average time to infusion went from 1.9 days to 2.0 days (p<0.02). Mean hospitalization time among those getting the drug also fell, slightly but significantly, from 8.0 days to 7.6 days (p<0.005).

Those differences are small and may or may not be clinically meaningful. But if they are, Hauptman speculates, perhaps they mean physicians are trying to avoid using nesiritide, but when they do, they start it later than previously and withdraw the infusion sooner.

"One could argue that papers like those from Sackner-Bernstein can profoundly affect practice and that there could be, at least theoretically, downstream effects that we haven't anticipated," Hauptman said. "And the next time it happens, I have a feeling people will pay very close attention to what the effects are on the marketplace."

He observed that once the reports came out, clinicians hustled away from using nesiritide much faster than they adopted some of the currently recommended drug therapies for chronic HF. "It took a long time for the ACE inhibitors to be used, and it's taking some time to get the beta blockers on board.

"This [report] is the flip side that hasn't really been looked at before. We're living in an era of safety [consciousness], and our antennae appear to be up. Here you had papers that were retrospective analyses, a pooling of data that posited the possibility of increased mortality and worsening renal failure with the drug. But they were in prominent journals, it was covered in the press, and physicians reacted very quickly to the news."