Mitchel L. Zoler, PhD

NEW YORK – During the period 1996-2007, hospitalization rates for psychiatric disorders among American children aged 5-13 years rose dramatically, nearly doubling during that period.

Concurrently, psychiatric hospitalizations for U.S. adolescents (aged 14-19 years) also rose substantially, by 42%. During the same period, psychiatric hospitalizations rose modestly (by 8%) for adults aged 20-64 years, whereas psychiatric hospitalizations for Americans aged 65 or older fell dramatically, Joseph C. Blader, Ph.D., said while presenting a poster at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The reasons behind these changes and their implications for the quality of care American psychiatric patients receive remain unclear, said Dr. Blader, a researcher in the division of child and adolescent psychiatry at the State University of New York at Stony Brook. However, the shifts in hospitalization rates – especially the larger such shifts among children and adolescents – raise concerns that demand further analysis, he said.

"It’s not a good thing" that substantially more children and adolescents require hospitalization for psychiatric diagnoses, Dr. Blader said in an interview. The shifts "represent a significant development in mental health treatment in the United States," he said in the poster.

The data Dr. Blader analyzed came from the National Hospital Discharge Survey, and also showed that in 1996-2007, payment for the psychiatric hospitalizations underwent a significant shift away from private insurance coverage and toward an increased share of the hospitalizations paid for by government agencies, most typically Medicaid. Again, the implications of this – and how it might play into the increased hospitalization rates – remain unclear.

According to Dr. Blader, the questions now are, Does the rise in hospitalizations result from "problems in the level of services provided by community care," and has "more cost shifting" of patients into Medicaid from private insurance led to or resulted from the rise in hospitalizations?

"Beneficiaries of publicly funded inpatient care may have become disproportionately vulnerable to psychiatric emergencies," or perhaps the effect "indicates better outpatient care among the privately insured," he said in his poster. "In many states, privately insured patients with extended psychiatric hospitalizations become eligible for Medicaid coverage."

He noted that during the period studied, the psychiatric field has made a diagnostic shift: More children who engage in injurious behavior are being labeled with bipolar disorder. He also speculated that the increasingly complex polypharmacy treatment of psychiatric patients, including children, might be a factor boosting hospitalizations.

"When a child is on many medications and a crisis occurs, the physician may not be sure what to do, which drug to stop," and thus may feel it’s safer to hospitalize and manage the child or adolescent there, Dr. Blader said in an interview.

However, he dismissed the notion that clinical criteria for hospitalization shifted during the period examined. "It’s unlikely that there was a lower threshold for hospitalization" in 2007 compared with 11 years earlier, he said.

The National Hospital Discharge Survey, run by the Centers for Disease Control and Prevention, collected data from 366,000 U.S. hospitalizations in 2007.

Survey data showed that in 1996-2007, the rate of hospitalization for a primary diagnosis of a psychiatric disorder in children aged 5-13 years rose from 15.6 per 10,000 U.S. residents to 28.3. In adolescents aged 14-19 years, the rate rose from 68.4 per 10,000 to 96.9, while in those aged 20-64 years, the rate increased from 92.1 per 10,000 to 99.1. All of the changes were statistically significant. Dr. Blader’s poster did not report rates for patients aged 65 or older, but in his analysis, this number fell "dramatically" from 1996 to 2007, he said.

During the period studied, private insurance coverage of these psychiatric hospitalizations among children fell from 36% of cases to 23%, while government-based sources of payment rose from 63% of cases to 71%. Among adolescents, private payment fell from 52% of cases to 22% while government coverage rose from 44% to 62%. Among adults, private coverage fell from 36% to 23%, while government coverage was flat, at 58% in 1996 and 59% in 2007.

The impact of both increases in hospitalization rates as well as increased population levels also led to substantial boosts in total days hospitalized for primary psychiatric diagnoses among children and adolescents, but not in adults. For children, total hospitalized days soared from 644,461 in 1996 to 1,528,117 in 2007. Among adolescents, total days rose from 1,317,660 in 1996 to 2,115,905 in 2007.

Dr. Blader had no disclosures.

NEW YORK – During the period 1996-2007, hospitalization rates for psychiatric disorders among American children aged 5-13 years rose dramatically, nearly doubling during that period.

Concurrently, psychiatric hospitalizations for U.S. adolescents (aged 14-19 years) also rose substantially, by 42%. During the same period, psychiatric hospitalizations rose modestly (by 8%) for adults aged 20-64 years, whereas psychiatric hospitalizations for Americans aged 65 or older fell dramatically, Joseph C. Blader, Ph.D., said while presenting a poster at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The reasons behind these changes and their implications for the quality of care American psychiatric patients receive remain unclear, said Dr. Blader, a researcher in the division of child and adolescent psychiatry at the State University of New York at Stony Brook. However, the shifts in hospitalization rates – especially the larger such shifts among children and adolescents – raise concerns that demand further analysis, he said.

"It’s not a good thing" that substantially more children and adolescents require hospitalization for psychiatric diagnoses, Dr. Blader said in an interview. The shifts "represent a significant development in mental health treatment in the United States," he said in the poster.

The data Dr. Blader analyzed came from the National Hospital Discharge Survey, and also showed that in 1996-2007, payment for the psychiatric hospitalizations underwent a significant shift away from private insurance coverage and toward an increased share of the hospitalizations paid for by government agencies, most typically Medicaid. Again, the implications of this – and how it might play into the increased hospitalization rates – remain unclear.

According to Dr. Blader, the questions now are, Does the rise in hospitalizations result from "problems in the level of services provided by community care," and has "more cost shifting" of patients into Medicaid from private insurance led to or resulted from the rise in hospitalizations?

"Beneficiaries of publicly funded inpatient care may have become disproportionately vulnerable to psychiatric emergencies," or perhaps the effect "indicates better outpatient care among the privately insured," he said in his poster. "In many states, privately insured patients with extended psychiatric hospitalizations become eligible for Medicaid coverage."

He noted that during the period studied, the psychiatric field has made a diagnostic shift: More children who engage in injurious behavior are being labeled with bipolar disorder. He also speculated that the increasingly complex polypharmacy treatment of psychiatric patients, including children, might be a factor boosting hospitalizations.

"When a child is on many medications and a crisis occurs, the physician may not be sure what to do, which drug to stop," and thus may feel it’s safer to hospitalize and manage the child or adolescent there, Dr. Blader said in an interview.

However, he dismissed the notion that clinical criteria for hospitalization shifted during the period examined. "It’s unlikely that there was a lower threshold for hospitalization" in 2007 compared with 11 years earlier, he said.

The National Hospital Discharge Survey, run by the Centers for Disease Control and Prevention, collected data from 366,000 U.S. hospitalizations in 2007.

Survey data showed that in 1996-2007, the rate of hospitalization for a primary diagnosis of a psychiatric disorder in children aged 5-13 years rose from 15.6 per 10,000 U.S. residents to 28.3. In adolescents aged 14-19 years, the rate rose from 68.4 per 10,000 to 96.9, while in those aged 20-64 years, the rate increased from 92.1 per 10,000 to 99.1. All of the changes were statistically significant. Dr. Blader’s poster did not report rates for patients aged 65 or older, but in his analysis, this number fell "dramatically" from 1996 to 2007, he said.

During the period studied, private insurance coverage of these psychiatric hospitalizations among children fell from 36% of cases to 23%, while government-based sources of payment rose from 63% of cases to 71%. Among adolescents, private payment fell from 52% of cases to 22% while government coverage rose from 44% to 62%. Among adults, private coverage fell from 36% to 23%, while government coverage was flat, at 58% in 1996 and 59% in 2007.

The impact of both increases in hospitalization rates as well as increased population levels also led to substantial boosts in total days hospitalized for primary psychiatric diagnoses among children and adolescents, but not in adults. For children, total hospitalized days soared from 644,461 in 1996 to 1,528,117 in 2007. Among adolescents, total days rose from 1,317,660 in 1996 to 2,115,905 in 2007.

Dr. Blader had no disclosures.

NEW YORK – During the period 1996-2007, hospitalization rates for psychiatric disorders among American children aged 5-13 years rose dramatically, nearly doubling during that period.

Concurrently, psychiatric hospitalizations for U.S. adolescents (aged 14-19 years) also rose substantially, by 42%. During the same period, psychiatric hospitalizations rose modestly (by 8%) for adults aged 20-64 years, whereas psychiatric hospitalizations for Americans aged 65 or older fell dramatically, Joseph C. Blader, Ph.D., said while presenting a poster at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The reasons behind these changes and their implications for the quality of care American psychiatric patients receive remain unclear, said Dr. Blader, a researcher in the division of child and adolescent psychiatry at the State University of New York at Stony Brook. However, the shifts in hospitalization rates – especially the larger such shifts among children and adolescents – raise concerns that demand further analysis, he said.

"It’s not a good thing" that substantially more children and adolescents require hospitalization for psychiatric diagnoses, Dr. Blader said in an interview. The shifts "represent a significant development in mental health treatment in the United States," he said in the poster.

The data Dr. Blader analyzed came from the National Hospital Discharge Survey, and also showed that in 1996-2007, payment for the psychiatric hospitalizations underwent a significant shift away from private insurance coverage and toward an increased share of the hospitalizations paid for by government agencies, most typically Medicaid. Again, the implications of this – and how it might play into the increased hospitalization rates – remain unclear.

According to Dr. Blader, the questions now are, Does the rise in hospitalizations result from "problems in the level of services provided by community care," and has "more cost shifting" of patients into Medicaid from private insurance led to or resulted from the rise in hospitalizations?

"Beneficiaries of publicly funded inpatient care may have become disproportionately vulnerable to psychiatric emergencies," or perhaps the effect "indicates better outpatient care among the privately insured," he said in his poster. "In many states, privately insured patients with extended psychiatric hospitalizations become eligible for Medicaid coverage."

He noted that during the period studied, the psychiatric field has made a diagnostic shift: More children who engage in injurious behavior are being labeled with bipolar disorder. He also speculated that the increasingly complex polypharmacy treatment of psychiatric patients, including children, might be a factor boosting hospitalizations.

"When a child is on many medications and a crisis occurs, the physician may not be sure what to do, which drug to stop," and thus may feel it’s safer to hospitalize and manage the child or adolescent there, Dr. Blader said in an interview.

However, he dismissed the notion that clinical criteria for hospitalization shifted during the period examined. "It’s unlikely that there was a lower threshold for hospitalization" in 2007 compared with 11 years earlier, he said.

The National Hospital Discharge Survey, run by the Centers for Disease Control and Prevention, collected data from 366,000 U.S. hospitalizations in 2007.

Survey data showed that in 1996-2007, the rate of hospitalization for a primary diagnosis of a psychiatric disorder in children aged 5-13 years rose from 15.6 per 10,000 U.S. residents to 28.3. In adolescents aged 14-19 years, the rate rose from 68.4 per 10,000 to 96.9, while in those aged 20-64 years, the rate increased from 92.1 per 10,000 to 99.1. All of the changes were statistically significant. Dr. Blader’s poster did not report rates for patients aged 65 or older, but in his analysis, this number fell "dramatically" from 1996 to 2007, he said.

During the period studied, private insurance coverage of these psychiatric hospitalizations among children fell from 36% of cases to 23%, while government-based sources of payment rose from 63% of cases to 71%. Among adolescents, private payment fell from 52% of cases to 22% while government coverage rose from 44% to 62%. Among adults, private coverage fell from 36% to 23%, while government coverage was flat, at 58% in 1996 and 59% in 2007.

The impact of both increases in hospitalization rates as well as increased population levels also led to substantial boosts in total days hospitalized for primary psychiatric diagnoses among children and adolescents, but not in adults. For children, total hospitalized days soared from 644,461 in 1996 to 1,528,117 in 2007. Among adolescents, total days rose from 1,317,660 in 1996 to 2,115,905 in 2007.

Dr. Blader had no disclosures.

NEW YORK – Vitamin D deficiency was linked with an increased prevalence of psychotic symptoms in adolescents hospitalized for psychiatric reasons in a single-center study of 77 patients.

"The association of vitamin D deficiency with psychotic features warrants further investigation as a risk factor for both physical and mental health outcomes" in adolescents with serious mental illness, Dr. Barbara L. Gracious and her associates said in a poster presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

"The importance of vitamin D for brain development and function in both healthy and psychiatric populations is less well appreciated and understood, compared with its known role in bone health and emerging role in metabolic health," said Dr. Gracious, a psychiatrist at Nationwide Children’s Hospital in Columbus, Ohio, and her colleagues.

Prior study findings documented links between vitamin D levels and seasonal affective disorder, depression, and schizophrenia, observations that highlighted the potential for vitamin D levels to modulate vulnerability to mental disorders.

To explore a possible link between vitamin D and psychosis, Dr. Gracious and her associates studied 77 adolescents who presented at the University of Rochester (N.Y.) for inpatient or partial hospital mental health treatment during October 2008-June 2009. The patients averaged 15 years old, and underwent a psychiatric assessment at the time of their hospitalization by an emergency-room psychiatrist and by the attending child psychiatrist. Psychosis was defined as hallucinations, paranoia, or delusions. The researchers measured blood levels of 25-hydroxy vitamin D with an immunoassay.

The assays showed that 31 of the referred adolescents (40%) had vitamin D deficiency, defined as a blood level less than 20 ng/mL; 26 (34%) had vitamin D insufficiency, defined as a blood level of 20-30 ng/mL; and 20 (26%) had a normal vitamin D level, defined as greater than 30 ng/mL.

Overall, the researchers identified psychotic symptoms in 19 of the 77 patients (25%). The psychotic prevalence rate among vitamin D–deficient adolescents was 13 out of 31 (42%). Among 26 adolescents with vitamin D insufficiency, 3 (12%) had psychotic symptoms. In 20 adolescents with a normal vitamin D level, 3 patients (15%) showed psychotic symptoms.

In an unadjusted, odds ratio analysis, vitamin D–deficient adolescents had a significant, fourfold increased risk of psychosis, compared with patients with normal vitamin D levels.

On the basis of these findings, physicians should now consider clinical screening of vitamin D levels in severely mentally ill adolescents at high risk for chronic mental and metabolic illness, and supplementing those who are deficient or insufficient, Dr. Gracious and her associates concluded. Further research should explore the levels of vitamin D intake and sun exposure needed by these patients, and also explore the role that vitamin D plays in the severity of mental illness in patients of other ages, they said.

Dr. Gracious did not have any disclosures.

NEW YORK – Vitamin D deficiency was linked with an increased prevalence of psychotic symptoms in adolescents hospitalized for psychiatric reasons in a single-center study of 77 patients.

"The association of vitamin D deficiency with psychotic features warrants further investigation as a risk factor for both physical and mental health outcomes" in adolescents with serious mental illness, Dr. Barbara L. Gracious and her associates said in a poster presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

"The importance of vitamin D for brain development and function in both healthy and psychiatric populations is less well appreciated and understood, compared with its known role in bone health and emerging role in metabolic health," said Dr. Gracious, a psychiatrist at Nationwide Children’s Hospital in Columbus, Ohio, and her colleagues.

Prior study findings documented links between vitamin D levels and seasonal affective disorder, depression, and schizophrenia, observations that highlighted the potential for vitamin D levels to modulate vulnerability to mental disorders.

To explore a possible link between vitamin D and psychosis, Dr. Gracious and her associates studied 77 adolescents who presented at the University of Rochester (N.Y.) for inpatient or partial hospital mental health treatment during October 2008-June 2009. The patients averaged 15 years old, and underwent a psychiatric assessment at the time of their hospitalization by an emergency-room psychiatrist and by the attending child psychiatrist. Psychosis was defined as hallucinations, paranoia, or delusions. The researchers measured blood levels of 25-hydroxy vitamin D with an immunoassay.

The assays showed that 31 of the referred adolescents (40%) had vitamin D deficiency, defined as a blood level less than 20 ng/mL; 26 (34%) had vitamin D insufficiency, defined as a blood level of 20-30 ng/mL; and 20 (26%) had a normal vitamin D level, defined as greater than 30 ng/mL.

Overall, the researchers identified psychotic symptoms in 19 of the 77 patients (25%). The psychotic prevalence rate among vitamin D–deficient adolescents was 13 out of 31 (42%). Among 26 adolescents with vitamin D insufficiency, 3 (12%) had psychotic symptoms. In 20 adolescents with a normal vitamin D level, 3 patients (15%) showed psychotic symptoms.

In an unadjusted, odds ratio analysis, vitamin D–deficient adolescents had a significant, fourfold increased risk of psychosis, compared with patients with normal vitamin D levels.

On the basis of these findings, physicians should now consider clinical screening of vitamin D levels in severely mentally ill adolescents at high risk for chronic mental and metabolic illness, and supplementing those who are deficient or insufficient, Dr. Gracious and her associates concluded. Further research should explore the levels of vitamin D intake and sun exposure needed by these patients, and also explore the role that vitamin D plays in the severity of mental illness in patients of other ages, they said.

Dr. Gracious did not have any disclosures.

NEW YORK – Vitamin D deficiency was linked with an increased prevalence of psychotic symptoms in adolescents hospitalized for psychiatric reasons in a single-center study of 77 patients.

"The association of vitamin D deficiency with psychotic features warrants further investigation as a risk factor for both physical and mental health outcomes" in adolescents with serious mental illness, Dr. Barbara L. Gracious and her associates said in a poster presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

"The importance of vitamin D for brain development and function in both healthy and psychiatric populations is less well appreciated and understood, compared with its known role in bone health and emerging role in metabolic health," said Dr. Gracious, a psychiatrist at Nationwide Children’s Hospital in Columbus, Ohio, and her colleagues.

Prior study findings documented links between vitamin D levels and seasonal affective disorder, depression, and schizophrenia, observations that highlighted the potential for vitamin D levels to modulate vulnerability to mental disorders.

To explore a possible link between vitamin D and psychosis, Dr. Gracious and her associates studied 77 adolescents who presented at the University of Rochester (N.Y.) for inpatient or partial hospital mental health treatment during October 2008-June 2009. The patients averaged 15 years old, and underwent a psychiatric assessment at the time of their hospitalization by an emergency-room psychiatrist and by the attending child psychiatrist. Psychosis was defined as hallucinations, paranoia, or delusions. The researchers measured blood levels of 25-hydroxy vitamin D with an immunoassay.

The assays showed that 31 of the referred adolescents (40%) had vitamin D deficiency, defined as a blood level less than 20 ng/mL; 26 (34%) had vitamin D insufficiency, defined as a blood level of 20-30 ng/mL; and 20 (26%) had a normal vitamin D level, defined as greater than 30 ng/mL.

Overall, the researchers identified psychotic symptoms in 19 of the 77 patients (25%). The psychotic prevalence rate among vitamin D–deficient adolescents was 13 out of 31 (42%). Among 26 adolescents with vitamin D insufficiency, 3 (12%) had psychotic symptoms. In 20 adolescents with a normal vitamin D level, 3 patients (15%) showed psychotic symptoms.

In an unadjusted, odds ratio analysis, vitamin D–deficient adolescents had a significant, fourfold increased risk of psychosis, compared with patients with normal vitamin D levels.

On the basis of these findings, physicians should now consider clinical screening of vitamin D levels in severely mentally ill adolescents at high risk for chronic mental and metabolic illness, and supplementing those who are deficient or insufficient, Dr. Gracious and her associates concluded. Further research should explore the levels of vitamin D intake and sun exposure needed by these patients, and also explore the role that vitamin D plays in the severity of mental illness in patients of other ages, they said.

Dr. Gracious did not have any disclosures.

NEW YORK – Vitamin D deficiency was linked with an increased prevalence of psychotic symptoms in adolescents hospitalized for psychiatric reasons in a single-center study of 77 patients.

"The association of vitamin D deficiency with psychotic features warrants further investigation as a risk factor for both physical and mental health outcomes" in adolescents with serious mental illness, Dr. Barbara L. Gracious and her associates said in a poster presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

"The importance of vitamin D for brain development and function in both healthy and psychiatric populations is less well appreciated and understood, compared with its known role in bone health and emerging role in metabolic health," said Dr. Gracious, a psychiatrist at Nationwide Children’s Hospital in Columbus, Ohio, and her colleagues.

Prior study findings documented links between vitamin D levels and seasonal affective disorder, depression, and schizophrenia, observations that highlighted the potential for vitamin D levels to modulate vulnerability to mental disorders.

To explore a possible link between vitamin D and psychosis, Dr. Gracious and her associates studied 77 adolescents who presented at the University of Rochester (N.Y.) for inpatient or partial hospital mental health treatment during October 2008-June 2009. The patients averaged 15 years old, and underwent a psychiatric assessment at the time of their hospitalization by an emergency-room psychiatrist and by the attending child psychiatrist. Psychosis was defined as hallucinations, paranoia, or delusions. The researchers measured blood levels of 25-hydroxy vitamin D with an immunoassay.

The assays showed that 31 of the referred adolescents (40%) had vitamin D deficiency, defined as a blood level less than 20 ng/mL; 26 (34%) had vitamin D insufficiency, defined as a blood level of 20-30 ng/mL; and 20 (26%) had a normal vitamin D level, defined as greater than 30 ng/mL.

Overall, the researchers identified psychotic symptoms in 19 of the 77 patients (25%). The psychotic prevalence rate among vitamin D–deficient adolescents was 13 out of 31 (42%). Among 26 adolescents with vitamin D insufficiency, 3 (12%) had psychotic symptoms. In 20 adolescents with a normal vitamin D level, 3 patients (15%) showed psychotic symptoms.

In an unadjusted, odds ratio analysis, vitamin D–deficient adolescents had a significant, fourfold increased risk of psychosis, compared with patients with normal vitamin D levels.

On the basis of these findings, physicians should now consider clinical screening of vitamin D levels in severely mentally ill adolescents at high risk for chronic mental and metabolic illness, and supplementing those who are deficient or insufficient, Dr. Gracious and her associates concluded. Further research should explore the levels of vitamin D intake and sun exposure needed by these patients, and also explore the role that vitamin D plays in the severity of mental illness in patients of other ages, they said.

Dr. Gracious did not have any disclosures.

NEW YORK – Vitamin D deficiency was linked with an increased prevalence of psychotic symptoms in adolescents hospitalized for psychiatric reasons in a single-center study of 77 patients.

"The association of vitamin D deficiency with psychotic features warrants further investigation as a risk factor for both physical and mental health outcomes" in adolescents with serious mental illness, Dr. Barbara L. Gracious and her associates said in a poster presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

"The importance of vitamin D for brain development and function in both healthy and psychiatric populations is less well appreciated and understood, compared with its known role in bone health and emerging role in metabolic health," said Dr. Gracious, a psychiatrist at Nationwide Children’s Hospital in Columbus, Ohio, and her colleagues.

Prior study findings documented links between vitamin D levels and seasonal affective disorder, depression, and schizophrenia, observations that highlighted the potential for vitamin D levels to modulate vulnerability to mental disorders.

To explore a possible link between vitamin D and psychosis, Dr. Gracious and her associates studied 77 adolescents who presented at the University of Rochester (N.Y.) for inpatient or partial hospital mental health treatment during October 2008-June 2009. The patients averaged 15 years old, and underwent a psychiatric assessment at the time of their hospitalization by an emergency-room psychiatrist and by the attending child psychiatrist. Psychosis was defined as hallucinations, paranoia, or delusions. The researchers measured blood levels of 25-hydroxy vitamin D with an immunoassay.

The assays showed that 31 of the referred adolescents (40%) had vitamin D deficiency, defined as a blood level less than 20 ng/mL; 26 (34%) had vitamin D insufficiency, defined as a blood level of 20-30 ng/mL; and 20 (26%) had a normal vitamin D level, defined as greater than 30 ng/mL.

Overall, the researchers identified psychotic symptoms in 19 of the 77 patients (25%). The psychotic prevalence rate among vitamin D–deficient adolescents was 13 out of 31 (42%). Among 26 adolescents with vitamin D insufficiency, 3 (12%) had psychotic symptoms. In 20 adolescents with a normal vitamin D level, 3 patients (15%) showed psychotic symptoms.

In an unadjusted, odds ratio analysis, vitamin D–deficient adolescents had a significant, fourfold increased risk of psychosis, compared with patients with normal vitamin D levels.

On the basis of these findings, physicians should now consider clinical screening of vitamin D levels in severely mentally ill adolescents at high risk for chronic mental and metabolic illness, and supplementing those who are deficient or insufficient, Dr. Gracious and her associates concluded. Further research should explore the levels of vitamin D intake and sun exposure needed by these patients, and also explore the role that vitamin D plays in the severity of mental illness in patients of other ages, they said.

Dr. Gracious did not have any disclosures.

NEW YORK – Vitamin D deficiency was linked with an increased prevalence of psychotic symptoms in adolescents hospitalized for psychiatric reasons in a single-center study of 77 patients.

"The association of vitamin D deficiency with psychotic features warrants further investigation as a risk factor for both physical and mental health outcomes" in adolescents with serious mental illness, Dr. Barbara L. Gracious and her associates said in a poster presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

"The importance of vitamin D for brain development and function in both healthy and psychiatric populations is less well appreciated and understood, compared with its known role in bone health and emerging role in metabolic health," said Dr. Gracious, a psychiatrist at Nationwide Children’s Hospital in Columbus, Ohio, and her colleagues.

Prior study findings documented links between vitamin D levels and seasonal affective disorder, depression, and schizophrenia, observations that highlighted the potential for vitamin D levels to modulate vulnerability to mental disorders.

To explore a possible link between vitamin D and psychosis, Dr. Gracious and her associates studied 77 adolescents who presented at the University of Rochester (N.Y.) for inpatient or partial hospital mental health treatment during October 2008-June 2009. The patients averaged 15 years old, and underwent a psychiatric assessment at the time of their hospitalization by an emergency-room psychiatrist and by the attending child psychiatrist. Psychosis was defined as hallucinations, paranoia, or delusions. The researchers measured blood levels of 25-hydroxy vitamin D with an immunoassay.

The assays showed that 31 of the referred adolescents (40%) had vitamin D deficiency, defined as a blood level less than 20 ng/mL; 26 (34%) had vitamin D insufficiency, defined as a blood level of 20-30 ng/mL; and 20 (26%) had a normal vitamin D level, defined as greater than 30 ng/mL.

Overall, the researchers identified psychotic symptoms in 19 of the 77 patients (25%). The psychotic prevalence rate among vitamin D–deficient adolescents was 13 out of 31 (42%). Among 26 adolescents with vitamin D insufficiency, 3 (12%) had psychotic symptoms. In 20 adolescents with a normal vitamin D level, 3 patients (15%) showed psychotic symptoms.

In an unadjusted, odds ratio analysis, vitamin D–deficient adolescents had a significant, fourfold increased risk of psychosis, compared with patients with normal vitamin D levels.

On the basis of these findings, physicians should now consider clinical screening of vitamin D levels in severely mentally ill adolescents at high risk for chronic mental and metabolic illness, and supplementing those who are deficient or insufficient, Dr. Gracious and her associates concluded. Further research should explore the levels of vitamin D intake and sun exposure needed by these patients, and also explore the role that vitamin D plays in the severity of mental illness in patients of other ages, they said.

Dr. Gracious did not have any disclosures.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

CHICAGO – Five years of uncertainty about nesiritide’s safety for treating acute decompensated heart failure came to an end, as results from a multicenter trial with more than 7,000 patients proved the drug does no harm.

The results also showed that nesiritide had, on average, a marginal beneficial effect for improving patients’ dyspnea, with no apparent benefit at all for reducing 30-day mortality or need for rehospitalization.

But the findings provided enough evidence to allow the drug to regain a place in the otherwise skimpy armamentarium for treating acute decompensated heart failure, a second-line agent to fall back on when more standard agents,

diuretics and vasodilators, fail to give patients adequate relief, experts said. They also speculated that somewhere in the varied mix of acutely ill heart failure patients lies a patient subgroup that stands to gain significant benefit from nesiritide treatment. The only problem will be how to find those patients.

"Nesiritide can now be considered a safe therapy in patients with acute heart failure," Dr. Adrian F. Hernandez said at the annual scientific sessions of the American Heart Association. Further analysis of the study findings "is likely to permit better understanding of ... patient profiles that may potentially benefit from nesiritide," added Dr. Hernandez, a cardiologist at Duke University in Durham, N.C.

"I think there will be a wide divergence of opinion on the role of this drug," said Dr. Mariell L. Jessup, professor of medicine and medical director of the Heart and Vascular Center at the University of Pennsylvania in Philadelphia. "If physicians want a drug that will fundamentally change the outcome of their patients’ acute decompensated heart failure, then there is no role for nesiritide. However, if a patient is suffering and continues to be very dyspneic there may be a role for adding nesiritide to current treatment. If the patient does not respond to the traditional drugs, diuretics and vasodilators, then physicians may very well reach for nesiritide to see if it will benefit the patient," she said in an interview.

"The question was: Is nesiritide safe? Does it increase mortality or cause renal failure? Now that we know it’s safe, the focus will be on [determining which] are the right patients to get it. The study showed a small average benefit, and somewhere in there is probably a smaller population who benefits," commented Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia and immediate past president of the American College of Cardiology.

The cloud that hung over nesiritide dated back to a pair of meta-analyses published by Dr. Jonathan D. Sackner-Bernstein 5 years ago (JAMA 2005;293:1900-5 and Circulation 2005;111:1487-91). Those analyses suggested that nesiritide treatment of heart failure patients linked with an excess risk for death and renal failure. The reports led to a "meteoric" drop in the drug’s use, said Dr. Robert M. Califf, professor of cardiology at Duke University, who collaborated with Dr. Hernandez in running the new study. It also led the company that markets nesiritide, Scios, to form a panel of experts to review the evidence.

The panel recommended a pair of studies to test the drug’s safety and efficacy. Results from the first of those studies, the Second Follow-Up Serial Infusions of Nesiritide (FUSION II), failed to find any evidence that regular infusions of nesiritide helped heart failure patients (Circ Heart Fail 2008;1:9-16). Dr. Hernandez’s new report results from the second of those studies, designed to test nesiritide’s safety and efficacy for treating acute decompensated heart failure.

The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomized 7,141 patients at 398 sites in 30 countries, including 214 centers in North America. It enrolled patients hospitalized for acute decompensated heart failure within 24 hours of when they began intravenous therapy. Patients had dyspnea at rest or with minimal activity, and either a respiratory rate of at least 20 breaths per minute or rales at more than a third of bases. Patients also needed at least one objective measure of their disease severity, such as elevated brain natriuretic peptide or a history of a left ventricular ejection fraction of less than 40% within the past year. The study exclusions included patients with hypotension at baseline and those with acute coronary syndrome.

The researchers randomized patients to receive either an intravenous bolus of 2 mcg/kg nesiritide or placebo, followed by a continuous intravenous infusion of nesiritide at 0.01 mcg/kg per minute or placebo for up to 7 days. Each treating physician determined the exact duration of the continuous infusion. All patients also received usual care with diuretics and a vasodilator such as intravenous nitroglycerin or nitroprusside. Patients’ average age was 67, and 80% had an ejection fraction of less than 40%. Average respiratory rate was about 24 breaths/min, and average systolic blood pressure was about 124 mm Hg.

At 30 days after the start of treatment, the combined rate of all-cause death or rehospitalization for heart failure, one of the study’s two primary end points, was 10.1% in the 3,511 evaluable placebo patients and 9.4% in the 3,496 evaluable patients who received nesiritide, a nonsignificant difference. Thirty-day mortality was 4% in both arms of the study.

The study’s second primary end point was the change in dyspnea severity at 6 and 24 hours after treatment began. At 6 hours, 15.0% of patients on nesiritide and 13.4% of patients on placebo were "markedly better;" at 24 hours 30.4% of the nesiritide patients and 27.5% of the placebo patients were markedly better. The percentage of patients whose dyspnea was either markedly or moderately better at 6 hours was 45% with nesiritide and 42% with placebo, and at 24 hours it was 68% with nesiritide and 66% with placebo. Although these between-group differences fulfilled usual definitions of statistical significance at both time points, the study prespecified a higher standard for statistical significance that was not met.

A series of subgroup analyses failed to identify any smaller group of patients who received a significant dyspnea or mortality and rehospitalization benefit from nesiritide, except for the roughly 10% of patients who had not been on diuretic treatment at the time of their entry into the study, who did show a significant dyspnea benefit from nesiritide.

The results also showed no suggestion whatsoever of an adverse renal effect from nesiritide, with no change in patients’ creatinine levels or in their glomerular filtration rate through the 30 days after treatment. Nesiritide-treated patients had a 7% rate of symptomatic hypotension compared with 4% in the placebo group, a statistically significant difference.

"We run out of [treatment] options really fast for patients with acute decompensated heart failure if patients don’t get better with diuretics, morphine, and vasodilators," commented Dr. Jessup. "People will use [nesiritide] when patients fail to respond" to the standard agents. "We now know it’s relatively safe." But nesiritide is not a first-line drug that should be used first, she said.

"The problem with acute decompensated heart failure is that it is a vast array of different patients and different pathologic entities. Some patients have normal ejection fractions, some patients have renal insufficiency, some have

severe hypertension. No single treatment will work. Everyone in heart failure who you talk to says some patients really respond to nesiritide. Who are those patients, and how can we identify them? I don’t know," Dr. Jessup said.

Acute heart failure patients who may benefit most from nesiritide may be those who are sicker, have a low ejection fraction, or present to the hospital sooner, but more data are needed to get a clearer profile of who these patients are, Dr. Hernandez said.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). Dr. Hernandez is a consultant to Corthera, Medtronic, and AstraZeneca, and has received research grants from Johnson & Johnson, Merck, and Proventys. Dr. Califf is a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Heart.org, and Kowa research. He received research grants from Amlin and Johnson & Johnson-Scios. Dr. Jessup is a consultant to Medtronic, a speaker on behalf of Boston Scientific, and has received research funding from Scios. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems.

Dr. Gordon F. Tomaselli, chief of the Division of Cardiology at Johns Hopkins University School of Medicine, says that for the first time there are other options besides warfarin for treating patients at risk of thromboembolic complications of atrial fibrillation.

In this interview with Michel L. Zoler, he discusses the clinical and cost implications of dabigatran and the new rivaroxaban data.

Watch the interview conducted at the American Heart Association annual scientific sessions here.

Dr. Gordon F. Tomaselli, chief of the Division of Cardiology at Johns Hopkins University School of Medicine, says that for the first time there are other options besides warfarin for treating patients at risk of thromboembolic complications of atrial fibrillation.

In this interview with Michel L. Zoler, he discusses the clinical and cost implications of dabigatran and the new rivaroxaban data.

Watch the interview conducted at the American Heart Association annual scientific sessions here.

Dr. Gordon F. Tomaselli, chief of the Division of Cardiology at Johns Hopkins University School of Medicine, says that for the first time there are other options besides warfarin for treating patients at risk of thromboembolic complications of atrial fibrillation.

In this interview with Michel L. Zoler, he discusses the clinical and cost implications of dabigatran and the new rivaroxaban data.

Watch the interview conducted at the American Heart Association annual scientific sessions here.

TORONTO – The stronger a patient's bones are when bisphosphonate treatment is stopped, the less likely the bones are to fracture later, based on an analysis of 437 patients.

In contrast, changes in bone mineral density following the end of bisphosphonate therapy had no significant link with subsequent fracture risk, Dr. Douglas C. Bauer said at the meeting.

The finding calls into doubt the common practice of running annual dual-energy x-ray absorptiometry examinations on patients who have withdrawn from bisphosphonate treatment.

Routine BMD measurement “1-2 years after stopping prolonged alendronate therapy may not be useful for predicting the patient's fracture risk,” said Dr. Bauer, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. BMD at the time of alendronate discontinuation “was highly predictive of who was going to fracture.”

Patients who stopped alendronate therapy with a total hip BMD T score of −1.4 or greater had a 9% rate of clinical fracture during 5 years of follow-up. Patients with a T score of −2.1 to −1.5 when they stopped bisphosphonate treatment had a 23% fracture rate during 5 years of follow-up, and those who stopped with a T score lower than −2.1 had a 33% fracture rate over the next 5 years. The between-group differences were statistically significant.

These data “are helpful as I try to decide which of my patients I should leave on a bisphosphonate,” commented Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York. “Patients below −2.1 were at very high risk of fracture, but even those in the middle tertile, with less than −1.5, were at a risk almost as high.” Dr. Bauer's study “provides me with some comfort [on whom] I can stop safely.”

The investigators used data collected in the FLEX (Fracture Intervention Trial Long-Term Extension) study, which randomized 1,099 postmenopausal women who had completed 5 years of treatment with alendronate to either continue on alendronate for another 5 years or switch to placebo (JAMA 2006;296:2927-38). They focused on the 437 patients who switched to placebo, and assessed the BMD measures that were associated with fracture risk during follow-up.

Even among patients who had relatively substantial bone loss during 1 year of follow-up, the amount of lost BMD did not significantly correlate with their follow-up fracture rate. The researchers saw no significant link to fracture rate among the 21% of patients who lost at least 3% of their BMD during the first year of follow-up, or among the 8% of patients who lost at least 5% of their BMD during 1 year of follow-up.

When a patient starts bisphosphonate treatment, the BMD typically rises sharply for a couple of years, and then plateaus and remains stable, Dr. Bauer said. After patients stop bisphosphonate treatment, their BMD usually declines gradually. Prior analysis of the FLEX data showed that patients who failed to reach a BMD of at least −2.5 usually benefited with fewer fractures when they remained on bisphosphonate treatment. The new findings suggest that patients with T scores of less than −1.5 may also benefit from continued treatment, On the other hand, when patients reach an adequate BMD (greater than −1.5), “it's not unreasonable to talk with the patient about the potential risks and benefits of a drug holiday,” Dr. Bauer said.

The FLEX study was funded by Merck, the company that markets alendronate (Fosamax). Dr. Bauer said that he has received research funding from Amgen, Merck, and Novartis.

Measurement of BMD '1-2 years after stopping prolonged alendronate therapy may not be useful.'

Source DR. BAUER

TORONTO – The stronger a patient's bones are when bisphosphonate treatment is stopped, the less likely the bones are to fracture later, based on an analysis of 437 patients.

In contrast, changes in bone mineral density following the end of bisphosphonate therapy had no significant link with subsequent fracture risk, Dr. Douglas C. Bauer said at the meeting.

The finding calls into doubt the common practice of running annual dual-energy x-ray absorptiometry examinations on patients who have withdrawn from bisphosphonate treatment.

Routine BMD measurement “1-2 years after stopping prolonged alendronate therapy may not be useful for predicting the patient's fracture risk,” said Dr. Bauer, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. BMD at the time of alendronate discontinuation “was highly predictive of who was going to fracture.”

Patients who stopped alendronate therapy with a total hip BMD T score of −1.4 or greater had a 9% rate of clinical fracture during 5 years of follow-up. Patients with a T score of −2.1 to −1.5 when they stopped bisphosphonate treatment had a 23% fracture rate during 5 years of follow-up, and those who stopped with a T score lower than −2.1 had a 33% fracture rate over the next 5 years. The between-group differences were statistically significant.

These data “are helpful as I try to decide which of my patients I should leave on a bisphosphonate,” commented Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York. “Patients below −2.1 were at very high risk of fracture, but even those in the middle tertile, with less than −1.5, were at a risk almost as high.” Dr. Bauer's study “provides me with some comfort [on whom] I can stop safely.”

The investigators used data collected in the FLEX (Fracture Intervention Trial Long-Term Extension) study, which randomized 1,099 postmenopausal women who had completed 5 years of treatment with alendronate to either continue on alendronate for another 5 years or switch to placebo (JAMA 2006;296:2927-38). They focused on the 437 patients who switched to placebo, and assessed the BMD measures that were associated with fracture risk during follow-up.

Even among patients who had relatively substantial bone loss during 1 year of follow-up, the amount of lost BMD did not significantly correlate with their follow-up fracture rate. The researchers saw no significant link to fracture rate among the 21% of patients who lost at least 3% of their BMD during the first year of follow-up, or among the 8% of patients who lost at least 5% of their BMD during 1 year of follow-up.

When a patient starts bisphosphonate treatment, the BMD typically rises sharply for a couple of years, and then plateaus and remains stable, Dr. Bauer said. After patients stop bisphosphonate treatment, their BMD usually declines gradually. Prior analysis of the FLEX data showed that patients who failed to reach a BMD of at least −2.5 usually benefited with fewer fractures when they remained on bisphosphonate treatment. The new findings suggest that patients with T scores of less than −1.5 may also benefit from continued treatment, On the other hand, when patients reach an adequate BMD (greater than −1.5), “it's not unreasonable to talk with the patient about the potential risks and benefits of a drug holiday,” Dr. Bauer said.

The FLEX study was funded by Merck, the company that markets alendronate (Fosamax). Dr. Bauer said that he has received research funding from Amgen, Merck, and Novartis.

Measurement of BMD '1-2 years after stopping prolonged alendronate therapy may not be useful.'

Source DR. BAUER

TORONTO – The stronger a patient's bones are when bisphosphonate treatment is stopped, the less likely the bones are to fracture later, based on an analysis of 437 patients.

In contrast, changes in bone mineral density following the end of bisphosphonate therapy had no significant link with subsequent fracture risk, Dr. Douglas C. Bauer said at the meeting.

The finding calls into doubt the common practice of running annual dual-energy x-ray absorptiometry examinations on patients who have withdrawn from bisphosphonate treatment.

Routine BMD measurement “1-2 years after stopping prolonged alendronate therapy may not be useful for predicting the patient's fracture risk,” said Dr. Bauer, professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. BMD at the time of alendronate discontinuation “was highly predictive of who was going to fracture.”

Patients who stopped alendronate therapy with a total hip BMD T score of −1.4 or greater had a 9% rate of clinical fracture during 5 years of follow-up. Patients with a T score of −2.1 to −1.5 when they stopped bisphosphonate treatment had a 23% fracture rate during 5 years of follow-up, and those who stopped with a T score lower than −2.1 had a 33% fracture rate over the next 5 years. The between-group differences were statistically significant.

These data “are helpful as I try to decide which of my patients I should leave on a bisphosphonate,” commented Dr. Elizabeth Shane, a professor of medicine at Columbia University in New York. “Patients below −2.1 were at very high risk of fracture, but even those in the middle tertile, with less than −1.5, were at a risk almost as high.” Dr. Bauer's study “provides me with some comfort [on whom] I can stop safely.”

The investigators used data collected in the FLEX (Fracture Intervention Trial Long-Term Extension) study, which randomized 1,099 postmenopausal women who had completed 5 years of treatment with alendronate to either continue on alendronate for another 5 years or switch to placebo (JAMA 2006;296:2927-38). They focused on the 437 patients who switched to placebo, and assessed the BMD measures that were associated with fracture risk during follow-up.

Even among patients who had relatively substantial bone loss during 1 year of follow-up, the amount of lost BMD did not significantly correlate with their follow-up fracture rate. The researchers saw no significant link to fracture rate among the 21% of patients who lost at least 3% of their BMD during the first year of follow-up, or among the 8% of patients who lost at least 5% of their BMD during 1 year of follow-up.

When a patient starts bisphosphonate treatment, the BMD typically rises sharply for a couple of years, and then plateaus and remains stable, Dr. Bauer said. After patients stop bisphosphonate treatment, their BMD usually declines gradually. Prior analysis of the FLEX data showed that patients who failed to reach a BMD of at least −2.5 usually benefited with fewer fractures when they remained on bisphosphonate treatment. The new findings suggest that patients with T scores of less than −1.5 may also benefit from continued treatment, On the other hand, when patients reach an adequate BMD (greater than −1.5), “it's not unreasonable to talk with the patient about the potential risks and benefits of a drug holiday,” Dr. Bauer said.

The FLEX study was funded by Merck, the company that markets alendronate (Fosamax). Dr. Bauer said that he has received research funding from Amgen, Merck, and Novartis.

Measurement of BMD '1-2 years after stopping prolonged alendronate therapy may not be useful.'

Source DR. BAUER

TORONTO – Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, in a controlled study with more than 1,200 patients.

Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the meeting.

“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. “These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.

On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said. It may be possible to identify women who would benefit from a drug holiday.

With the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment. In a prior report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38). The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.

The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).

Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo. Their average age was 76, and about 55% had a femoral neck T score of less than −2.5.

At the end of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients treated with zoledronic acid, a statistically significant difference in the study's primary end point. Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over their baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, also a statistically significant difference.

Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo.

The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen Inc. and Nycomed, and that he has received research contracts from Amgen, Merck & Co., Novartis, and Roche/Genentech.

The decision to continue bisphosphonate treatment long term must be individualized.

Source DR. BLACK

TORONTO – Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, in a controlled study with more than 1,200 patients.

Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the meeting.

“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. “These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.

On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said. It may be possible to identify women who would benefit from a drug holiday.

With the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment. In a prior report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38). The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.

The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).

Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo. Their average age was 76, and about 55% had a femoral neck T score of less than −2.5.

At the end of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients treated with zoledronic acid, a statistically significant difference in the study's primary end point. Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over their baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, also a statistically significant difference.

Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo.

The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen Inc. and Nycomed, and that he has received research contracts from Amgen, Merck & Co., Novartis, and Roche/Genentech.

The decision to continue bisphosphonate treatment long term must be individualized.

Source DR. BLACK

TORONTO – Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, in a controlled study with more than 1,200 patients.

Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the meeting.

“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. “These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.

On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said. It may be possible to identify women who would benefit from a drug holiday.

With the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment. In a prior report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38). The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.

The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).

Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo. Their average age was 76, and about 55% had a femoral neck T score of less than −2.5.

At the end of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients treated with zoledronic acid, a statistically significant difference in the study's primary end point. Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over their baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, also a statistically significant difference.

Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo.

The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen Inc. and Nycomed, and that he has received research contracts from Amgen, Merck & Co., Novartis, and Roche/Genentech.

The decision to continue bisphosphonate treatment long term must be individualized.

Source DR. BLACK

BRUSSELS – Statin therapy may exert yet another beneficial clinical effect – preventing the development of knee osteoarthritis and slowing its progression – based on an analysis of more than 3,000 people who were enrolled in a prospective cohort study.

In an analysis of people in the Rotterdam Study, statin use was linked with a more-than-50% reduced rate of knee osteoarthritis (OA) incidence, and a more-than-50% reduced rate of knee OA progression after adjustment for baseline risk factors, Dr. Stefan Clockaerts said at the congress. In contrast, statin use had no impact on hip OA.

The findings suggest knee OA may be at least partly a metabolic disease, said Dr. Clockaerts of the orthopedics department at Erasmus University, Rotterdam, the Netherlands, and at the University of Antwerp (Belgium).

“We think that there is a difference in the pathogenesis of hip and knee osteoarthritis, and that several systemic factors – such as cholesterol, body mass index, and diabetes – appear to influence knee osteoarthritis” but not deterioration of the hip, Dr. Clockaerts said in an interview.

Another hypothesis is that vascular pathology may contribute to the OA disease process, and that statins' benefits on atherosclerosis may also link statins and knee OA. The anti-inflammatory effect of statins most likely also plays a role.

The Rotterdam Study began in 1990 and enrolled 7,983 men and women aged 55 years or older into a longitudinal cohort study. The analysis by Dr. Clockaerts and his associates focused on participants with knee and hip x-rays that were available from baseline and follow-up and were evaluable for scoring on the Kellgren-Lawrence (KL) scale.

Information on statin use came from computerized pharmacy records. The analysis considered anyone to be a statin user who received a statin prescription for at least 100 days for at least 50% of the drug's recommended daily dosage.

Among 3,056 people who were evaluable for incident knee OA, statin users had a significant, 57% reduced rate of knee OA, vs. nonusers, after adjustment for baseline age, diabetes, BMI, total cholesterol:HDL cholesterol ratio, and bone mineral density (BMD), said Dr. Clockaerts at the congress, which was presented by the Osteoarthritis Research Society International. (See box.)

Progression of knee OA among 1,412 people with a baseline KL score of 1-3 occurred 53% less often in the statin users, compared with nonusers after adjustment for age, BMI, and BMD, which was a significant difference.

Dr. Clockaerts said that he had no disclosures.

Elsevier Global Medical News

BRUSSELS – Statin therapy may exert yet another beneficial clinical effect – preventing the development of knee osteoarthritis and slowing its progression – based on an analysis of more than 3,000 people who were enrolled in a prospective cohort study.

In an analysis of people in the Rotterdam Study, statin use was linked with a more-than-50% reduced rate of knee osteoarthritis (OA) incidence, and a more-than-50% reduced rate of knee OA progression after adjustment for baseline risk factors, Dr. Stefan Clockaerts said at the congress. In contrast, statin use had no impact on hip OA.

The findings suggest knee OA may be at least partly a metabolic disease, said Dr. Clockaerts of the orthopedics department at Erasmus University, Rotterdam, the Netherlands, and at the University of Antwerp (Belgium).

“We think that there is a difference in the pathogenesis of hip and knee osteoarthritis, and that several systemic factors – such as cholesterol, body mass index, and diabetes – appear to influence knee osteoarthritis” but not deterioration of the hip, Dr. Clockaerts said in an interview.

Another hypothesis is that vascular pathology may contribute to the OA disease process, and that statins' benefits on atherosclerosis may also link statins and knee OA. The anti-inflammatory effect of statins most likely also plays a role.

The Rotterdam Study began in 1990 and enrolled 7,983 men and women aged 55 years or older into a longitudinal cohort study. The analysis by Dr. Clockaerts and his associates focused on participants with knee and hip x-rays that were available from baseline and follow-up and were evaluable for scoring on the Kellgren-Lawrence (KL) scale.

Information on statin use came from computerized pharmacy records. The analysis considered anyone to be a statin user who received a statin prescription for at least 100 days for at least 50% of the drug's recommended daily dosage.

Among 3,056 people who were evaluable for incident knee OA, statin users had a significant, 57% reduced rate of knee OA, vs. nonusers, after adjustment for baseline age, diabetes, BMI, total cholesterol:HDL cholesterol ratio, and bone mineral density (BMD), said Dr. Clockaerts at the congress, which was presented by the Osteoarthritis Research Society International. (See box.)

Progression of knee OA among 1,412 people with a baseline KL score of 1-3 occurred 53% less often in the statin users, compared with nonusers after adjustment for age, BMI, and BMD, which was a significant difference.

Dr. Clockaerts said that he had no disclosures.

Elsevier Global Medical News

BRUSSELS – Statin therapy may exert yet another beneficial clinical effect – preventing the development of knee osteoarthritis and slowing its progression – based on an analysis of more than 3,000 people who were enrolled in a prospective cohort study.

In an analysis of people in the Rotterdam Study, statin use was linked with a more-than-50% reduced rate of knee osteoarthritis (OA) incidence, and a more-than-50% reduced rate of knee OA progression after adjustment for baseline risk factors, Dr. Stefan Clockaerts said at the congress. In contrast, statin use had no impact on hip OA.

The findings suggest knee OA may be at least partly a metabolic disease, said Dr. Clockaerts of the orthopedics department at Erasmus University, Rotterdam, the Netherlands, and at the University of Antwerp (Belgium).

“We think that there is a difference in the pathogenesis of hip and knee osteoarthritis, and that several systemic factors – such as cholesterol, body mass index, and diabetes – appear to influence knee osteoarthritis” but not deterioration of the hip, Dr. Clockaerts said in an interview.

Another hypothesis is that vascular pathology may contribute to the OA disease process, and that statins' benefits on atherosclerosis may also link statins and knee OA. The anti-inflammatory effect of statins most likely also plays a role.

The Rotterdam Study began in 1990 and enrolled 7,983 men and women aged 55 years or older into a longitudinal cohort study. The analysis by Dr. Clockaerts and his associates focused on participants with knee and hip x-rays that were available from baseline and follow-up and were evaluable for scoring on the Kellgren-Lawrence (KL) scale.

Information on statin use came from computerized pharmacy records. The analysis considered anyone to be a statin user who received a statin prescription for at least 100 days for at least 50% of the drug's recommended daily dosage.

Among 3,056 people who were evaluable for incident knee OA, statin users had a significant, 57% reduced rate of knee OA, vs. nonusers, after adjustment for baseline age, diabetes, BMI, total cholesterol:HDL cholesterol ratio, and bone mineral density (BMD), said Dr. Clockaerts at the congress, which was presented by the Osteoarthritis Research Society International. (See box.)

Progression of knee OA among 1,412 people with a baseline KL score of 1-3 occurred 53% less often in the statin users, compared with nonusers after adjustment for age, BMI, and BMD, which was a significant difference.

Dr. Clockaerts said that he had no disclosures.

Elsevier Global Medical News