The U.S. Food and Drug Administration (FDA) and Scios, Inc., have alerted healthcare professionals via letter of several published reports that suggest nesiritide (Natrecor) may have adverse effects on survival and kidney function compared with control agents such as nitroglycerin and diuretics, according to an alert sent from MedWatch, the FDA’s safety information and adverse event reporting system.
Nesiritide was approved by the FDA in 2001 for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.
The approval was based on the results of studies showing that nesiritide reduced pulmonary capillary wedge pressure and improved dyspnea in this population. Although the mortality rate associated with nesiritide therapy in these studies was somewhat greater than that of comparator groups, it was not clear at that time that the increase could be drug related.
The current revision of nesiritide safety information to include 30-day mortality data were based on an analysis of results from seven controlled studies involving 1,700 patients. Three of the studies were used in a meta-analysis that recently appeared in the April 20, 2005, issue of JAMA and in the March 29, 2005, issue of Circulation.
In the seven clinical trials, nesiritide was associated with an increased mortality rate compared with other standard medications (5.3% vs 4.3%). In the four trials that measured long-term mortality, the 180-day mortality rate was also increased in patients receiving nesiritide, relative to standard medications (21.7% vs 21.5%). None of the mortality differences reached statistical significance.
The FDA notes that due to the small number of deaths, confidence limits around the hazard ratios for mortality are wide. Furthermore, the small size of the studies allows the presence of potentially important baseline imbalances among the treatment groups of which the effects cannot be ascertained.
Nesiritide may also affect renal function and cause azotemia in patients with severe heart failure whose renal function is dependent on the activity of the renin-angiotensin-aldosterone system.
In clinical studies, initiation of nesiritide at doses more than 0.01 Âµg/kg per minute (0.015 and 0.03 Âµg/kg/minute) was associated with an increased rate of serum creatinine elevation to more than 0.5 mg/dL above baseline compared with other therapies. No increases were observed in rates of acute renal failure or dialysis requirements.
However, nesiritide was associated with a higher number of patients requiring first-time dialysis during a 30-day follow-up period compared with nitroglycerin therapy (9 [3%] vs 5 patients [2%]).
According to the letter, the company will be convening a panel of experts to review all available studies and advise the company on their clinical significance; additional information will be available pending the review.