In the end everyone was wrong. After many years of controversy, we finally know the truth about nesiritide, and all the experts were wrong. Steve Nissen and Jonathan Sackner-Bernstein, who first raised concerns about the safety of nesiritide in decompensated heart failure, turned out to be wrong. But the defenders of nesiritide, including its manufacturer, Johnson & Johnson, and James Young, the principle investigator of the drug’s pivotal trial, also turned out to be wrong. In the end nesiritide turned out to be safe. But it also turned out that it didn’t have any significant benefit.
In response to the enormous enormous controversy, which began back in 2003, the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial) was eventually started. The trial randomized 7,141 patients with acute, decompensated heart failure to receive standard therapy and either continuous intravenous nesiritide or placebo.
Results of ASCEND-HF, presented as a late-breaking clinical trial at the AHA showed that there were no signficant differences in the pre-specfied endpoint of dyspnea. Shortness of breath improved in 15% of nesiritide patients and 13.4% of placebo patients. At 24 hours the pattern was similar: 30.4% of nesiritide patients and 27.5% of placebo patients had improved breathing function. At one month the rate of death and hospital readmission for heart failure was not statistically different (9.4% in the nesiritide group versus 10.1% in the placebo group).
On the other hand, the investigators found no evidence for an increase in mortality or renal injury, according to the investigators.
In an AHA press release study chair Robert Califf said:
“Nesiritide was marketed and widely used in the U.S. because of a perception that it had a major effect on dyspnea and then largely abandoned in clinical use because of concerns that it might increase rates of death and renal failure. Now that we finally have a proper clinical trial we know that both perceptions were incorrect; nesiritide is safe but has only a modest effect on dyspnea. This is a major signal that we must do a better job defining the biological effects of drugs early in development and conduct adequately powered outcomes trials much earlier to give doctors and patients the necessary information to enable appropriate use of the treatment in practice.”
Here is the AHA press release:
Large study of patients with severe heart failure confirms nesiritide safe, but shows no significant benefit on symptoms or mortality
- In a large clinical trial of the intravenous drug nesiritide in severe heart failure, the drug had no significant effect on 30-day hospital readmission or death.
- The drug had a small, non-significant improvement in breathing symptoms.
- The use of nesiritide did not increase the risk of kidney dysfunction or death.
CHICAGO, Nov. 14, 2010 – In a large clinical trial, the drug nesiritide proved to be safe but had little effect on breathing symptoms (dyspnea), and no significant effect on hospital readmission or death rates among patients with acutely decompensated heart failure, according to late-breaking clinical trial results presented at the American Heart Association’s Scientific Sessions 2010.
In the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND-HF), researchers randomized 7,141 patients with acute, severe heart failure to receive either continuous intravenous nesiritide or a placebo, both added to standard therapy, which includes diuretics, morphine and other medications.
Six hours after treatment, nesiritide slightly improved shortness of breath compared with placebo, with significant improvement occurring in 513 nesiritide patients (15.0 percent) and 460 placebo patients (13.4 percent). Similarly, 24 hours after treatment, more patients on nesiritide displayed markedly improved breathing function compared to placebo – 1,025 nesiritide patients (30.4 percent) compared to 935 placebo patients (27.5 percent). However, there was no significant difference in the pre-specified endpoint for dyspnea. At 30 days post-treatment, the rates of death from any cause and hospital readmission for heart failure were slightly lower with nesiritide compared to placebo. At 9.4 percent versus 10.1 percent, however, the difference in these rates was not statistically significant either.
Nesiritide is a manufactured drug derived from a naturally occurring protein known as human B-type natriuretic peptide. The drug helps to relax the blood vessels, which can improve circulation, and increase the body’s output of excess salt and water.
“Nesiritide was marketed and widely used in the U.S. because of a perception that it had a major effect on dyspnea and then largely abandoned in clinical use because of concerns that it might increase rates of death and renal failure, said Robert M. Califf, M.D., study chair and vice chancellor for clinical research at Duke University School of Medicine in Durham, N.C. “Now that we finally have a proper clinical trial we know that both perceptions were incorrect; nesiritide is safe but has only a modest effect on dyspnea. This is a major signal that we must do a better job defining the biological effects of drugs early in development and conduct adequately powered outcomes trials much earlier to give doctors and patients the necessary information to enable appropriate use of the treatment in practice.”
ASCEND-HF, a randomized double-blind trial, included participants from 400 international centers in 30 countries. Average age of patients studied was 67, 34 percent were female and 15 percent were African American. More than half (60 percent) had blockages or narrowing of the blood vessels supplying the heart. Treatment began within 24 hours of hospitalization for worsening symptoms and continued for between one to seven days. The study ran from May 2007 to September 2010; patients were followed for 30 days.
Previous studies have shown that nesiritide can relieve shortness of breath if given within three hours of the onset of worsening heart failure, but it was unclear whether this improvement persisted. Also unknown was whether nesiritide caused kidney (renal) impairment or increased the risk of death, which previous, much smaller studies have indicated. An important finding from this trial is that the drug did not increase these risks.
“I think the main message is that we need to do adequately powered studies to really understand the balance of safety and effectiveness,” said Adrian F. Hernandez, M.D., co-investigator of the trial and associate professor of medicine at Duke University School of Medicine. “Now that we’ve done an adequate trial, we know that nesiritide can be used safely, but there is no mandate to use it because of its modest effects.”
“ASCEND-HF represents an important milestone in our understanding of acute heart failure care as this is the first robust drug safety study completed in this difficult to treat patient population,” said Christopher M. O’Connor, M.D., the study’s co-principal investigator and director of the Duke Heart Center. “Given the complexities of heart failure, there is a significant need for better medications for use in treatment,” said Randall C. Starling, M.D., study co-investigator and head of the section of Heart Failure and Cardiac Transplant Medicine and vice chairman of Cardiovascular Medicine at Cleveland Clinic. “With the safety questions related to nesiritide having now been addressed, it could be an option for physicians depending on their interpretation of clinical benefit.”
The trial was led by an international executive committee which also included Paul W. Armstrong, M.D.; Kenneth Dickstein, M.D.; Daniel Gennevois, M.D.; Vic Hasselblad, Ph.D.; Michael Komajda, M.D.; Barry Massie, M.D.; John J.V. McMurray, M.D.; Markku Nieminen, M.D.; Jean L. Rouleau, M.D.; and Karl Swedburg, M. D. ASCEND-HF was coordinated by the Duke Clinical Research Institute led by Craig J. Reist, Ph.D. Author disclosures are on the abstract.
Johnson & Johnson funded the study.
Here is the press release from Johnson and Johnson:
Scios Announces Results of ASCEND Heart Failure Study at the Scientific Sessions of the American Heart Association
Study Provides Valuable Safety Information; Demonstrates No Additional Efficacy Beyond Existing Label
CHICAGO–(EON: Enhanced Online News)–Scios Inc. announced today that the landmark investigational study of NATRECOR®(nesiritide) for the treatment of acutely decompensated heart failure (ADHF), ASCEND-HF, demonstrated no statistically significant difference from placebo in the co-primary endpoints of dyspnea, measured at six and 24 hours, or in the composite of heart failure re-hospitalizations and death during the first 30 days following treatment. Importantly, the study reinforced the safety profile of NATRECOR®, revealing no excess adverse effects on renal function or mortality.
“The ASCEND-HF trial has answered many scientific questions and has increased our understanding of the safety profile of NATRECOR®”
NATRECOR® is approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of patients with acutely decompensated heart failure who experience dyspnea (shortness of breath) at rest or with minimal activity with proven efficacy impact at three hours.1Scios initiated the 7,141 patient ASCEND-HF study (Acute Study of Clinical Effectiveness ofNesiritide in Decompensated Heart Failure) in 2007 after first seeking the guidance of an expert panel of cardiology and heart failure clinicians chaired by Eugene Braunwald, M.D., Harvard Medical School, in response to questions raised in the medical literature about mortality and impaired renal function of patients treated with NATRECOR®.
“The ASCEND-HF trial has answered many scientific questions and has increased our understanding of the safety profile of NATRECOR®,” said Peter M. DiBattiste, M.D., Vice President of Cardiovascular Development at Johnson & Johnson Pharmaceutical Research and Development, L.L.C. “This is the largest trial ever conducted in patients with ADHF, and affirms our commitment to patients and physicians who have limited treatment options to fight this life-threatening disorder.”
The results from ASCEND-HF will be submitted to the FDA as part of the standard collection of post-marketing drug experience.
Adrian F. Hernandez, M.D. MHS, Associate Professor, Duke Clinical Research Institute, presented the results during a late-breaking clinical trial presentation during the Scientific Sessions of the American Heart Association.
Review of Clinical Trial Results
In ASCEND-HF, NATRECOR® did not show a statistically significant reduction in either of the composite co-primary endpoint measures: reduction of re-hospitalization due to heart failure or all-cause mortality during the first 30 days following treatment compared to placebo plus standard of care, (9.4% vs. 10.1%, respectively, p=0.313), or a reduction of heart failure symptoms as measured by subject self-assessment on a dyspnea scale at six and 24 hours after initiation, (p=0.030 at 6 hours and p=0.007 at 24 hours; p<0.005 is the pre-specified requirement for significance for this measure in ASCEND-HF).
Safety measures from ASCEND-HF showed that patients treated with NATRECOR® plus standard care had a comparable mortality rate to patients treated with placebo plus standard of care at 30 days (3.6% vs. 4.0%, p=NS). Furthermore, there was no statistically significant or clinically relevant evidence of kidney function impairment in NATRECOR®-treated patients with ADHF during the first 30 days based on a 25% decrease in glomerular filtration rate (31.4% vs. 29.5%, p=NS). Incidence of a known side effect, hypotension (a decrease in blood pressure), was statistically significantly increased with the use of NATRECOR® compared to placebo (26.6% vs. 15.3%, p<0.0001); however, the majority of these episodes were asymptomatic.
An estimated 5.7 million people around the globe are diagnosed with heart failure each year, and for most causes there is no known cure.2 The condition can worsen over time, or decompensate, to the point where hospitalization is required, a change that physicians refer to as ADHF. Symptoms and signs of ADHF include extreme fatigue and shortness of breath, worsening kidney function, severe swelling, sudden weight gain and a distended jugular vein along the side of the neck.3 It is the leading cause of hospitalization in Americans over age 65.4
About NATRECOR® (nesiritide)
NATRECOR® is the only approved treatment for ADHF that has shown improvement in breathing and a reduction of elevated pressures in the lungs and heart in controlled clinical trials. NATRECOR® has previously been studied in 16 prospective clinical trials involving 2,012 patients treated with the drug, and has been used to treat more than 800,000 acutely decompensated heart failure patients. NATRECOR® is indicated for the intravenous treatment of patients with ADHF who have dyspnea at rest or with minimal activity. In this population, the use of NATRECOR® reduced pulmonary capillary wedge pressure and improved patient reported dyspnea.
For full Prescribing Information, visit http://www.natrecor360.com.