Mary Ann Moon

With longer half-lives than previously used imaging agents, florbetapir and flutemetamol can be used in PET scanning to detect and quantify amyloid levels in the brain, according to two separate reports published online July 11 in Archives of Neurology.

Radiolabeled with fluorine-18, 18F-florbetapir and 18F-flutemetamol may eventually make the use of PET scanning to detect Alzheimer’s disease via brain imaging more accessible in clinical practice, concluded both teams of investigators.

In one study, data from four phase I and II clinical trials of florbetapir PET scanning were pooled to permit assessment of beta-amyloid burden in a large combined cohort of patients with probable AD (68 subjects) or mild cognitive impairment (60 subjects), and healthy age-matched controls (82 subjects). "To our knowledge, our study presents the largest analysis of multicenter [18F-florbetapir] amyloid PET data currently reported," said Dr. Adam S. Fleisher of Banner Alzheimer’s Institute, Phoenix, and his associates.

The extent of florbetapir activity on PET scanning reliably distinguished the three groups of subjects, with the highest activity seen in AD patients, an intermediate level seen in patients with mild cognitive impairment (MCI), and the least activity seen in control subjects. For both AD and MCI patients, there was preferential uptake of 18F-florbetapir in the posterior cingulate, the parietal lobe, and the temporal and frontal cortex – all areas that were found to be involved during previous PET studies of amyloid deposition that used a different imaging agent.

Dr. Fleisher and his colleagues used these data to devise two sets of criteria for classifying florbetapir activity.

The first set of criteria uses a conservative cutoff threshold associated with the extensive amyloid presence that characterizes AD, which "might be used in the clinical setting to determine whether or not a person has neuropathologically significant cerebral amyloidosis." The second set of criteria uses a more liberal threshold associated with any degree of amyloidosis, which "might identify those individuals in the earliest stages of amyloid accumulation." The latter group "might be especially responsive to presymptomatic amyloid-modifying treatments for AD," they speculated (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.150]).

Using the conservative criteria, the researchers found that 81% of the AD patients, 40% of the MCI patients, and 21% of the control subjects were correctly classified by florbetapir PET scanning. When the liberal criteria were used, the technology correctly classified 85%, 47%, and 28%, respectively.

Approximately 19% of the patients who had clinical AD showed florbetapir activity below the cutoff, and 15% showed no florbetapir activity at all. These percentages correspond with the results of autopsy studies showing that 10%-30% of patients with clinical AD lack amyloid deposits.

Similarly, 21%-28% of the control group showed slightly elevated florbetapir activity rather than no activity, which corresponds with previous reports from imaging studies showing that 20%-51% of healthy elderly adults have elevated (but not pathologic) amyloid levels.

Interestingly, florbetapir activity also increased with normal aging in the control group. The same finding has been reported in previous PET studies using a different imaging agent, Dr. Fleisher and his associates noted.

In the second report, investigators used 18F-flutemetamol PET scanning in seven patients who had normal pressure hydrocephalus (NPH), a progressive disorder characterized by a classic triad of dementia, gait abnormalities, and urinary incontinence. A large proportion of patients with normal pressure hydrocephalus – 68% in one study – also show AD pathology on cortical biopsy.

The seven patients in this study, all older than 50 years, had undergone placement of a ventriculoperitoneal shunt 3-45 months earlier, with concomitant cortical biopsy in the area of the shunt. The biopsy specimens allowed immunohistochemical detection and quantification of beta-amyloid pathology, said Dr. David A. Wolk of the Penn Memory Center and the department of neurology, University of Pennsylvania, Philadelphia, and his associates.

Investigators who were blind to the subjects’ biopsy status assessed their flutemetamol PET scans and classified three of them as normal (with no or minimal amyloid pathology) and the other four as abnormal (with amyloid pathology). These scan assessments corresponded 100% with the presence or absence of amlyoid plaques in the biopsy specimens.

"These findings provide support for the use of 18F-flutemetamol PET in the detection of AD-related amyloid pathology," Dr. Wolk and his colleagues said (Arch. Neurol. 2011 July 11 [doi:10/1001/archneurol.2011.153]).

In particular, this technology "may play an important prognostic role in patients with mild cognitive impairment and, perhaps, in preclinical populations," they added.

In an editorial accompanying these two reports, Dr. William J. Jagust said that with their longer half-lives, these two radioimaging agents labeled with fluorine-18 may make PET imaging of brain amyloid levels more accessible and commercially viable.

But it is likely that clinical use of the technology will depend on highly trained readers to visually interpret scans and to convert quantitative scores into diagnoses. Even with reliance on such experts, "there will always be results that can be described as ‘borderline’ with visual reads or as ‘intermediate’ between liberal and conservative [numerical] thresholds," and clinicians won’t know how to classify such patients, said Dr. Jagust of the Helen Wills Neuroscience Institute and School of Public Health at the University of California, Berkeley.

As more patients are scanned, there will be more such "intermediate" cases. "How these radiotracers fare with larger samples along the full spectrum of both imaging and pathology will be very important for clinical applications to patients who express a wide range of dementia syndromes," he noted (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.152]).

Dr. Jagust reported serving as a consultant to GE Healthcare, which manufactures flutemetamol, and collaborating with Avid Radiopharmaceuticals, which manufactures florbetapir, through the Alzheimer’s Disease Neuroimaging Initiative. Dr. Fleisher’s study was supported by Avid Radiopharmaceuticals, which manufactures florbetapir and is owned by Eli Lilly. Dr. Fleisher and his associates reported numerous ties to industry sources. Dr. Wolk’s study was sponsored by GE Healthcare, which manufactures flutemetamol.

With longer half-lives than previously used imaging agents, florbetapir and flutemetamol can be used in PET scanning to detect and quantify amyloid levels in the brain, according to two separate reports published online July 11 in Archives of Neurology.

Radiolabeled with fluorine-18, 18F-florbetapir and 18F-flutemetamol may eventually make the use of PET scanning to detect Alzheimer’s disease via brain imaging more accessible in clinical practice, concluded both teams of investigators.

In one study, data from four phase I and II clinical trials of florbetapir PET scanning were pooled to permit assessment of beta-amyloid burden in a large combined cohort of patients with probable AD (68 subjects) or mild cognitive impairment (60 subjects), and healthy age-matched controls (82 subjects). "To our knowledge, our study presents the largest analysis of multicenter [18F-florbetapir] amyloid PET data currently reported," said Dr. Adam S. Fleisher of Banner Alzheimer’s Institute, Phoenix, and his associates.

The extent of florbetapir activity on PET scanning reliably distinguished the three groups of subjects, with the highest activity seen in AD patients, an intermediate level seen in patients with mild cognitive impairment (MCI), and the least activity seen in control subjects. For both AD and MCI patients, there was preferential uptake of 18F-florbetapir in the posterior cingulate, the parietal lobe, and the temporal and frontal cortex – all areas that were found to be involved during previous PET studies of amyloid deposition that used a different imaging agent.

Dr. Fleisher and his colleagues used these data to devise two sets of criteria for classifying florbetapir activity.

The first set of criteria uses a conservative cutoff threshold associated with the extensive amyloid presence that characterizes AD, which "might be used in the clinical setting to determine whether or not a person has neuropathologically significant cerebral amyloidosis." The second set of criteria uses a more liberal threshold associated with any degree of amyloidosis, which "might identify those individuals in the earliest stages of amyloid accumulation." The latter group "might be especially responsive to presymptomatic amyloid-modifying treatments for AD," they speculated (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.150]).

Using the conservative criteria, the researchers found that 81% of the AD patients, 40% of the MCI patients, and 21% of the control subjects were correctly classified by florbetapir PET scanning. When the liberal criteria were used, the technology correctly classified 85%, 47%, and 28%, respectively.

Approximately 19% of the patients who had clinical AD showed florbetapir activity below the cutoff, and 15% showed no florbetapir activity at all. These percentages correspond with the results of autopsy studies showing that 10%-30% of patients with clinical AD lack amyloid deposits.

Similarly, 21%-28% of the control group showed slightly elevated florbetapir activity rather than no activity, which corresponds with previous reports from imaging studies showing that 20%-51% of healthy elderly adults have elevated (but not pathologic) amyloid levels.

Interestingly, florbetapir activity also increased with normal aging in the control group. The same finding has been reported in previous PET studies using a different imaging agent, Dr. Fleisher and his associates noted.

In the second report, investigators used 18F-flutemetamol PET scanning in seven patients who had normal pressure hydrocephalus (NPH), a progressive disorder characterized by a classic triad of dementia, gait abnormalities, and urinary incontinence. A large proportion of patients with normal pressure hydrocephalus – 68% in one study – also show AD pathology on cortical biopsy.

The seven patients in this study, all older than 50 years, had undergone placement of a ventriculoperitoneal shunt 3-45 months earlier, with concomitant cortical biopsy in the area of the shunt. The biopsy specimens allowed immunohistochemical detection and quantification of beta-amyloid pathology, said Dr. David A. Wolk of the Penn Memory Center and the department of neurology, University of Pennsylvania, Philadelphia, and his associates.

Investigators who were blind to the subjects’ biopsy status assessed their flutemetamol PET scans and classified three of them as normal (with no or minimal amyloid pathology) and the other four as abnormal (with amyloid pathology). These scan assessments corresponded 100% with the presence or absence of amlyoid plaques in the biopsy specimens.

"These findings provide support for the use of 18F-flutemetamol PET in the detection of AD-related amyloid pathology," Dr. Wolk and his colleagues said (Arch. Neurol. 2011 July 11 [doi:10/1001/archneurol.2011.153]).

In particular, this technology "may play an important prognostic role in patients with mild cognitive impairment and, perhaps, in preclinical populations," they added.

In an editorial accompanying these two reports, Dr. William J. Jagust said that with their longer half-lives, these two radioimaging agents labeled with fluorine-18 may make PET imaging of brain amyloid levels more accessible and commercially viable.

But it is likely that clinical use of the technology will depend on highly trained readers to visually interpret scans and to convert quantitative scores into diagnoses. Even with reliance on such experts, "there will always be results that can be described as ‘borderline’ with visual reads or as ‘intermediate’ between liberal and conservative [numerical] thresholds," and clinicians won’t know how to classify such patients, said Dr. Jagust of the Helen Wills Neuroscience Institute and School of Public Health at the University of California, Berkeley.

As more patients are scanned, there will be more such "intermediate" cases. "How these radiotracers fare with larger samples along the full spectrum of both imaging and pathology will be very important for clinical applications to patients who express a wide range of dementia syndromes," he noted (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.152]).

Dr. Jagust reported serving as a consultant to GE Healthcare, which manufactures flutemetamol, and collaborating with Avid Radiopharmaceuticals, which manufactures florbetapir, through the Alzheimer’s Disease Neuroimaging Initiative. Dr. Fleisher’s study was supported by Avid Radiopharmaceuticals, which manufactures florbetapir and is owned by Eli Lilly. Dr. Fleisher and his associates reported numerous ties to industry sources. Dr. Wolk’s study was sponsored by GE Healthcare, which manufactures flutemetamol.

With longer half-lives than previously used imaging agents, florbetapir and flutemetamol can be used in PET scanning to detect and quantify amyloid levels in the brain, according to two separate reports published online July 11 in Archives of Neurology.

Radiolabeled with fluorine-18, 18F-florbetapir and 18F-flutemetamol may eventually make the use of PET scanning to detect Alzheimer’s disease via brain imaging more accessible in clinical practice, concluded both teams of investigators.

In one study, data from four phase I and II clinical trials of florbetapir PET scanning were pooled to permit assessment of beta-amyloid burden in a large combined cohort of patients with probable AD (68 subjects) or mild cognitive impairment (60 subjects), and healthy age-matched controls (82 subjects). "To our knowledge, our study presents the largest analysis of multicenter [18F-florbetapir] amyloid PET data currently reported," said Dr. Adam S. Fleisher of Banner Alzheimer’s Institute, Phoenix, and his associates.

The extent of florbetapir activity on PET scanning reliably distinguished the three groups of subjects, with the highest activity seen in AD patients, an intermediate level seen in patients with mild cognitive impairment (MCI), and the least activity seen in control subjects. For both AD and MCI patients, there was preferential uptake of 18F-florbetapir in the posterior cingulate, the parietal lobe, and the temporal and frontal cortex – all areas that were found to be involved during previous PET studies of amyloid deposition that used a different imaging agent.

Dr. Fleisher and his colleagues used these data to devise two sets of criteria for classifying florbetapir activity.

The first set of criteria uses a conservative cutoff threshold associated with the extensive amyloid presence that characterizes AD, which "might be used in the clinical setting to determine whether or not a person has neuropathologically significant cerebral amyloidosis." The second set of criteria uses a more liberal threshold associated with any degree of amyloidosis, which "might identify those individuals in the earliest stages of amyloid accumulation." The latter group "might be especially responsive to presymptomatic amyloid-modifying treatments for AD," they speculated (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.150]).

Using the conservative criteria, the researchers found that 81% of the AD patients, 40% of the MCI patients, and 21% of the control subjects were correctly classified by florbetapir PET scanning. When the liberal criteria were used, the technology correctly classified 85%, 47%, and 28%, respectively.

Approximately 19% of the patients who had clinical AD showed florbetapir activity below the cutoff, and 15% showed no florbetapir activity at all. These percentages correspond with the results of autopsy studies showing that 10%-30% of patients with clinical AD lack amyloid deposits.

Similarly, 21%-28% of the control group showed slightly elevated florbetapir activity rather than no activity, which corresponds with previous reports from imaging studies showing that 20%-51% of healthy elderly adults have elevated (but not pathologic) amyloid levels.

Interestingly, florbetapir activity also increased with normal aging in the control group. The same finding has been reported in previous PET studies using a different imaging agent, Dr. Fleisher and his associates noted.

In the second report, investigators used 18F-flutemetamol PET scanning in seven patients who had normal pressure hydrocephalus (NPH), a progressive disorder characterized by a classic triad of dementia, gait abnormalities, and urinary incontinence. A large proportion of patients with normal pressure hydrocephalus – 68% in one study – also show AD pathology on cortical biopsy.

The seven patients in this study, all older than 50 years, had undergone placement of a ventriculoperitoneal shunt 3-45 months earlier, with concomitant cortical biopsy in the area of the shunt. The biopsy specimens allowed immunohistochemical detection and quantification of beta-amyloid pathology, said Dr. David A. Wolk of the Penn Memory Center and the department of neurology, University of Pennsylvania, Philadelphia, and his associates.

Investigators who were blind to the subjects’ biopsy status assessed their flutemetamol PET scans and classified three of them as normal (with no or minimal amyloid pathology) and the other four as abnormal (with amyloid pathology). These scan assessments corresponded 100% with the presence or absence of amlyoid plaques in the biopsy specimens.

"These findings provide support for the use of 18F-flutemetamol PET in the detection of AD-related amyloid pathology," Dr. Wolk and his colleagues said (Arch. Neurol. 2011 July 11 [doi:10/1001/archneurol.2011.153]).

In particular, this technology "may play an important prognostic role in patients with mild cognitive impairment and, perhaps, in preclinical populations," they added.

In an editorial accompanying these two reports, Dr. William J. Jagust said that with their longer half-lives, these two radioimaging agents labeled with fluorine-18 may make PET imaging of brain amyloid levels more accessible and commercially viable.

But it is likely that clinical use of the technology will depend on highly trained readers to visually interpret scans and to convert quantitative scores into diagnoses. Even with reliance on such experts, "there will always be results that can be described as ‘borderline’ with visual reads or as ‘intermediate’ between liberal and conservative [numerical] thresholds," and clinicians won’t know how to classify such patients, said Dr. Jagust of the Helen Wills Neuroscience Institute and School of Public Health at the University of California, Berkeley.

As more patients are scanned, there will be more such "intermediate" cases. "How these radiotracers fare with larger samples along the full spectrum of both imaging and pathology will be very important for clinical applications to patients who express a wide range of dementia syndromes," he noted (Arch. Neurol. 2011 July 11 [doi:10.1001/archneurol.2011.152]).

Dr. Jagust reported serving as a consultant to GE Healthcare, which manufactures flutemetamol, and collaborating with Avid Radiopharmaceuticals, which manufactures florbetapir, through the Alzheimer’s Disease Neuroimaging Initiative. Dr. Fleisher’s study was supported by Avid Radiopharmaceuticals, which manufactures florbetapir and is owned by Eli Lilly. Dr. Fleisher and his associates reported numerous ties to industry sources. Dr. Wolk’s study was sponsored by GE Healthcare, which manufactures flutemetamol.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Three new regimens for preventing tuberculosis in HIV-infected adults appear effective, though no more effective than the standard 6-month course of isoniazid, according to a report in the July 7 New England Journal of Medicine.

All three new regimens facilitated adherence, however, which "could substantially increase the number of patients who receive and complete preventive therapy,"according to Dr. Neil A. Martinson of the division of infectious diseases, Johns Hopkins University, Baltimore, and his associates.

Photo credit: Janice Carr/CDC

Results were more disappointing in a separate study of TB prophylaxis among HIV-exposed and HIV-infected children, which showed that preventive isoniazid was no better than placebo at improving TB-free survival in that age group.

Tuberculosis is the most common opportunistic infection and the leading cause of death in adults and children infected with HIV, especially in Africa.

For adults, the World Health Organization endorses routine prophylaxis with 6 months of isoniazid, but the number of public health programs that provide such treatment is "exceedingly low," according to Dr. Martinson. The chief obstacle is concern about low therapy completion rates, which lead to both reinfection and the selection of drug-resistant mycobacterial strains.

To address these concerns, the investigators studied the use of a 12-week course of rifapentine (900 mg) given weekly or rifampin (600 mg) given twice weekly, both with isoniazid (900 mg), as well as long-term continuous administration of isoniazid (300 mg daily) for up to 6 years, which may be more potent than shorter courses of the drug and thus may prevent reinfection in areas in which TB is endemic, the investigators wrote.

These three regimens were compared against the standard prophylaxis, a 6-month course of isoniazid (300 mg daily), in 1,148 tuberculin-positive HIV-infected adults in South Africa. The median patient age was 30 years, and 83% were women.

The primary end point was tuberculosis-free survival. After a median follow-up of 4 years, there were no significant differences in this end point between any of the new regimens and the standard regimen, the investigators said. Incidences of active TB or death were 3.1/100 person-years in the rifapentine-isoniazid group, 2.9 in the rifampin-isoniazid group, and 2.7 in the long-term continuous isoniazid group, as compared with 3.6/100 person-years in the control group (N. Engl. J. Med. 2011;365:11-20).

However, the shorter regimens had higher adherence rates, in part because treatment was supervised and adverse reactions were minimized.

The proportions of patients who reported taking more than 90% of their medication were 95.7% in the rifapentine-isoniazid group, 94.8% in the rifampin-isoniazid group, and 83.8% in the control group. Among patients in the long-term isoniazid group, 89.1% took their medication from the total follow-up time.

The shorter regimens did not appear to select for drug-resistant TB, but the number of cases that were cultured was relatively small, they noted.

In the second study, 548 HIV-infected infants and 804 uninfected but HIV-exposed infants aged 3-4 months were enrolled at three medical centers in South Africa and one in Botswana. All the infants had received bacille Calmette-Guérin (BCG) vaccination within 30 days of birth, before their HIV status had been determined, said Dr. Shabir A. Madhi of the University of the Witwatersrand, Johannesburg, and associates.

These study subjects were randomly assigned to receive daily isoniazid to prevent TB acquisition or placebo. The primary end point was TB-free survival at 96 weeks after randomization.

In the HIV-infected cohort, either tuberculosis or death occurred in 52 children (19%) in the isoniazid group, compared with 53 (also 19%) in the placebo group, indicating no beneficial effect for prophylaxis. A post hoc analysis also showed no benefit in subgroups of patients categorized by whether they had definite or probable TB infection.

The findings were similar for the HIV-exposed cohort, in which tuberculosis or death occurred in 39 children (10%) who received isoniazid and 45 (11%) who received placebo, a nonsignificant difference, Dr. Madhi and colleagues said (N. Engl. J. Med. 2011;365:21-31).

The findings indicate that, unlike adults, children do not benefit from isoniazid prophylaxis, they said.

Dr. Martinson’s study was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health Fogarty International Center, and the U.S. Agency for International Development. Dr. Martinson reported receiving lecture fees from Alere. Dr. Madhi’s study was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, Harvard School of Public Health, Boston, and the Secure the Future Fund of Bristol-Myers Squibb. Dr. Madhi and associates reported ties to numerous industry sources.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Nesiritide has no effect on 30-day mortality or rehospitalization rates in patients with acute decompensated heart failure, according to results of the ASCEND-HF trial reported in the July 7 issue of the New England Journal of Medicine.

In a large 3-year international clinical trial called by an independent panel "to answer the question of whether nesiritide is effective and safe," the drug also failed to improve self-reported dyspnea at 6 hours or 24 hours. It did not worsen renal function, but it nearly doubled the rates of both symptomatic and asymptomatic hypotension.

"Nesiritide thus cannot be recommended in the broad population of patients with acute decompensated heart failure represented by the study population in this trial," wrote Dr. Christopher M. O’Connor of Duke Clinical Research Institute, Durham, N.C., and his associates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilatory action, was approved in 2001 for use in patients with acute heart failure, based on separate small studies showing that it reduced pulmonary-capillary wedge pressure and eased dyspnea within 3 hours of administration. Later meta-analyses of these and other small trials, however, indicated that the drug worsened renal function and nearly doubled early mortality.

"In hindsight, nesiritide was approved and swiftly adopted in the United States because of its perceived large benefit in relieving dyspnea and congestion, and then its used markedly decreased because of published meta-analyses reporting a detrimental effect on survival and renal function. Our study showed that neither belief was accurate," Dr. O’Connor and his colleagues noted.

ASCEND-HF involved 7,141 patients treated at 398 medical centers around the world. All the participants received standard therapies including diuretics, morphine, and vasoactive medications. Half also received intravenous nesiritide and half received a placebo for up to 7 days.

The two coprimary end points were change in self-reported dyspnea at 6 and 24 hours and rehospitalization for heart failure or death from any cause within 30 days. There was a slight numerical advantage with nesiritide over placebo for dyspnea (44.5% vs. 42.1%, P = .03), but it did not reach the prespecified level for statistical significance. The rates of the second end point were 9.4% with nesiritide and 10.1% with placebo, another nonsignificant difference.

The two study groups also showed no significant differences in self-reported patient well-being, rehospitalization for cardiovascular causes, death from cardiovascular causes, total days alive and out of the hospital at 1 month, rates of persistent or worsening HF, or death from any cause at 1 month. Rates of renal impairment also were comparable between the two groups, regardless of baseline renal insufficiency, the investigators noted (N. Engl. J. Med. 2011;365:32-43).

Significantly more patients who received nesiritide had an episode of asymptomatic (21.4%) or symptomatic (7.2%) hypotension, compared with patients who received placebo (12.4% and 4.0%, respectively).

"The development of nesiritide poses fundamental questions about the manner in which therapies are developed and assessed. Because nesiritide was not studied in a major outcome trial early in its life cycle, both patients and physicians lacked an appropriate understanding of the proper role of the drug in practice.

"Our findings underscore the fact that systematic overviews with small numbers of events can yield unreliable estimates of the balance of benefits and risks, and interpretation of the data is confounded by these imprecise estimates," Dr. O’Connor and his colleagues wrote.

The results also "highlight the urgent need for rigorously designed trials with adequate power to provide reliable estimates that can replace incomplete or inadequate evidence as a basis for therapeutic decisions," they added. The ASCEND-HF results were presented at the annual scientific sessions of the American Heart Association in November 2010.

ASCEND-HF was sponsored by Scios, a Johnson & Johnson company, which markets nesiritide (Natrecor). The investigators reported ties to numerous industry sources. Dr. O’Connor has received consulting fees from Medtronic, Forest, Amgen, Medpace, Roche, and Actelion. Two of the authors are employees of Johnson & Johnson.

Middle-age and older women who avoid smoking, exercise regularly, follow a healthy diet, and maintain a healthy weight cut their risk of sudden cardiac death by 92%, compared with those who do not, according to a report in the July 6 JAMA.

If it is assumed that these four factors – smoking, lack of exercise, a poor diet, and obesity – play a causal role in sudden cardiac death (SCD), then approximately 80% of these deaths are preventable among women without diagnosed coronary heart disease, said Stephanie E. Chiuve, Sc.D., of the division of preventive medicine, Brigham and Women’s Hospital, Boston, and her associates.

Photo credit: © pressmaster/Fotolia.com

In what they described as the first study to examine the combination of four lifestyle factors and risk of SCD, the investigators used data collected in the Nurses’ Health Study on 81,722 women who were aged 30-55 years at baseline in 1976. The study subjects were assessed biennially for smoking status, weight, menopausal status, use of medications, and physician-diagnosed disease, and were evaluated at longer intervals for diet and physical activity, over a total follow-up of 26 years (1984-2010).

The mean age at final follow-up was 72 years. There were 321 cases of SCD during follow-up.

A low-risk lifestyle was inversely related with SCD risk. The absolute risks of SCD were 22 cases/100,000 person-years with no low-risk lifestyle factors, 17 cases with one low-risk factor, 18 cases with two low-risk factors, 13 cases with three factors, and 16 cases with four.

Compared with women who had no low-risk lifestyle factors, who constituted 3% of the cohort, those with all four low-risk factors (who comprised 8% of the cohort) had a relative risk of 0.08 for SCD.

Women who followed all four low-risk lifestyle factors "had a 92% lower risk of SCD" compared with women with none of the low-risk lifestyle factors. "If these associations are causal, 81% of SCD within this cohort may have been prevented if all women adhered to a low-risk lifestyle," Dr. Chiuve and her colleagues said.

Extrapolating these results to the general U.S. female population, "Among women without diagnosed coronary heart disease, in whom the majority of SCD events occur, it is possible that 79% of SCD may be attributed to unhealthy lifestyle practices," they said (JAMA 2011;306:62-9).

Conversely, widespread adoption of a healthy lifestyle would "make a substantial impact" on reducing sudden cardiac death.

Primary prevention of SCD is a particular concern for women, who are half as likely as men to show left ventricular dysfunction and two-thirds less likely to be diagnosed as having coronary heart disease before SCD occurs. Women are therefore less likely to receive beta-blocker therapy or an implantable cardioverter-defibrillator to prevent the SCD.

This study was limited in that the NHS involved mostly white, well-educated, female health professionals, so the findings may not be generalizable to men or to people of other ethnicities.

The study was supported by the National Institutes of Health and the American Heart Association. An associate of Dr. Chiuve reported ties to the nutrition advisory board for UNO’s restaurant.

Middle-age and older women who avoid smoking, exercise regularly, follow a healthy diet, and maintain a healthy weight cut their risk of sudden cardiac death by 92%, compared with those who do not, according to a report in the July 6 JAMA.

If it is assumed that these four factors – smoking, lack of exercise, a poor diet, and obesity – play a causal role in sudden cardiac death (SCD), then approximately 80% of these deaths are preventable among women without diagnosed coronary heart disease, said Stephanie E. Chiuve, Sc.D., of the division of preventive medicine, Brigham and Women’s Hospital, Boston, and her associates.

Photo credit: © pressmaster/Fotolia.com

In what they described as the first study to examine the combination of four lifestyle factors and risk of SCD, the investigators used data collected in the Nurses’ Health Study on 81,722 women who were aged 30-55 years at baseline in 1976. The study subjects were assessed biennially for smoking status, weight, menopausal status, use of medications, and physician-diagnosed disease, and were evaluated at longer intervals for diet and physical activity, over a total follow-up of 26 years (1984-2010).

The mean age at final follow-up was 72 years. There were 321 cases of SCD during follow-up.

A low-risk lifestyle was inversely related with SCD risk. The absolute risks of SCD were 22 cases/100,000 person-years with no low-risk lifestyle factors, 17 cases with one low-risk factor, 18 cases with two low-risk factors, 13 cases with three factors, and 16 cases with four.

Compared with women who had no low-risk lifestyle factors, who constituted 3% of the cohort, those with all four low-risk factors (who comprised 8% of the cohort) had a relative risk of 0.08 for SCD.

Women who followed all four low-risk lifestyle factors "had a 92% lower risk of SCD" compared with women with none of the low-risk lifestyle factors. "If these associations are causal, 81% of SCD within this cohort may have been prevented if all women adhered to a low-risk lifestyle," Dr. Chiuve and her colleagues said.

Extrapolating these results to the general U.S. female population, "Among women without diagnosed coronary heart disease, in whom the majority of SCD events occur, it is possible that 79% of SCD may be attributed to unhealthy lifestyle practices," they said (JAMA 2011;306:62-9).

Conversely, widespread adoption of a healthy lifestyle would "make a substantial impact" on reducing sudden cardiac death.

Primary prevention of SCD is a particular concern for women, who are half as likely as men to show left ventricular dysfunction and two-thirds less likely to be diagnosed as having coronary heart disease before SCD occurs. Women are therefore less likely to receive beta-blocker therapy or an implantable cardioverter-defibrillator to prevent the SCD.

This study was limited in that the NHS involved mostly white, well-educated, female health professionals, so the findings may not be generalizable to men or to people of other ethnicities.

The study was supported by the National Institutes of Health and the American Heart Association. An associate of Dr. Chiuve reported ties to the nutrition advisory board for UNO’s restaurant.

Middle-age and older women who avoid smoking, exercise regularly, follow a healthy diet, and maintain a healthy weight cut their risk of sudden cardiac death by 92%, compared with those who do not, according to a report in the July 6 JAMA.

If it is assumed that these four factors – smoking, lack of exercise, a poor diet, and obesity – play a causal role in sudden cardiac death (SCD), then approximately 80% of these deaths are preventable among women without diagnosed coronary heart disease, said Stephanie E. Chiuve, Sc.D., of the division of preventive medicine, Brigham and Women’s Hospital, Boston, and her associates.

Photo credit: © pressmaster/Fotolia.com

In what they described as the first study to examine the combination of four lifestyle factors and risk of SCD, the investigators used data collected in the Nurses’ Health Study on 81,722 women who were aged 30-55 years at baseline in 1976. The study subjects were assessed biennially for smoking status, weight, menopausal status, use of medications, and physician-diagnosed disease, and were evaluated at longer intervals for diet and physical activity, over a total follow-up of 26 years (1984-2010).

The mean age at final follow-up was 72 years. There were 321 cases of SCD during follow-up.

A low-risk lifestyle was inversely related with SCD risk. The absolute risks of SCD were 22 cases/100,000 person-years with no low-risk lifestyle factors, 17 cases with one low-risk factor, 18 cases with two low-risk factors, 13 cases with three factors, and 16 cases with four.

Compared with women who had no low-risk lifestyle factors, who constituted 3% of the cohort, those with all four low-risk factors (who comprised 8% of the cohort) had a relative risk of 0.08 for SCD.

Women who followed all four low-risk lifestyle factors "had a 92% lower risk of SCD" compared with women with none of the low-risk lifestyle factors. "If these associations are causal, 81% of SCD within this cohort may have been prevented if all women adhered to a low-risk lifestyle," Dr. Chiuve and her colleagues said.

Extrapolating these results to the general U.S. female population, "Among women without diagnosed coronary heart disease, in whom the majority of SCD events occur, it is possible that 79% of SCD may be attributed to unhealthy lifestyle practices," they said (JAMA 2011;306:62-9).

Conversely, widespread adoption of a healthy lifestyle would "make a substantial impact" on reducing sudden cardiac death.

Primary prevention of SCD is a particular concern for women, who are half as likely as men to show left ventricular dysfunction and two-thirds less likely to be diagnosed as having coronary heart disease before SCD occurs. Women are therefore less likely to receive beta-blocker therapy or an implantable cardioverter-defibrillator to prevent the SCD.

This study was limited in that the NHS involved mostly white, well-educated, female health professionals, so the findings may not be generalizable to men or to people of other ethnicities.

The study was supported by the National Institutes of Health and the American Heart Association. An associate of Dr. Chiuve reported ties to the nutrition advisory board for UNO’s restaurant.

Middle-age and older women who avoid smoking, exercise regularly, follow a healthy diet, and maintain a healthy weight cut their risk of sudden cardiac death by 92%, compared with those who do not, according to a report in the July 6 JAMA.

If it is assumed that these four factors – smoking, lack of exercise, a poor diet, and obesity – play a causal role in sudden cardiac death (SCD), then approximately 80% of these deaths are preventable among women without diagnosed coronary heart disease, said Stephanie E. Chiuve, Sc.D., of the division of preventive medicine, Brigham and Women’s Hospital, Boston, and her associates.

Photo credit: © pressmaster/Fotolia.com

In what they described as the first study to examine the combination of four lifestyle factors and risk of SCD, the investigators used data collected in the Nurses’ Health Study on 81,722 women who were aged 30-55 years at baseline in 1976. The study subjects were assessed biennially for smoking status, weight, menopausal status, use of medications, and physician-diagnosed disease, and were evaluated at longer intervals for diet and physical activity, over a total follow-up of 26 years (1984-2010).

The mean age at final follow-up was 72 years. There were 321 cases of SCD during follow-up.

A low-risk lifestyle was inversely related with SCD risk. The absolute risks of SCD were 22 cases/100,000 person-years with no low-risk lifestyle factors, 17 cases with one low-risk factor, 18 cases with two low-risk factors, 13 cases with three factors, and 16 cases with four.

Compared with women who had no low-risk lifestyle factors, who constituted 3% of the cohort, those with all four low-risk factors (who comprised 8% of the cohort) had a relative risk of 0.08 for SCD.

Women who followed all four low-risk lifestyle factors "had a 92% lower risk of SCD" compared with women with none of the low-risk lifestyle factors. "If these associations are causal, 81% of SCD within this cohort may have been prevented if all women adhered to a low-risk lifestyle," Dr. Chiuve and her colleagues said.

Extrapolating these results to the general U.S. female population, "Among women without diagnosed coronary heart disease, in whom the majority of SCD events occur, it is possible that 79% of SCD may be attributed to unhealthy lifestyle practices," they said (JAMA 2011;306:62-9).

Conversely, widespread adoption of a healthy lifestyle would "make a substantial impact" on reducing sudden cardiac death.

Primary prevention of SCD is a particular concern for women, who are half as likely as men to show left ventricular dysfunction and two-thirds less likely to be diagnosed as having coronary heart disease before SCD occurs. Women are therefore less likely to receive beta-blocker therapy or an implantable cardioverter-defibrillator to prevent the SCD.

This study was limited in that the NHS involved mostly white, well-educated, female health professionals, so the findings may not be generalizable to men or to people of other ethnicities.

The study was supported by the National Institutes of Health and the American Heart Association. An associate of Dr. Chiuve reported ties to the nutrition advisory board for UNO’s restaurant.

Middle-age and older women who avoid smoking, exercise regularly, follow a healthy diet, and maintain a healthy weight cut their risk of sudden cardiac death by 92%, compared with those who do not, according to a report in the July 6 JAMA.

If it is assumed that these four factors – smoking, lack of exercise, a poor diet, and obesity – play a causal role in sudden cardiac death (SCD), then approximately 80% of these deaths are preventable among women without diagnosed coronary heart disease, said Stephanie E. Chiuve, Sc.D., of the division of preventive medicine, Brigham and Women’s Hospital, Boston, and her associates.

Photo credit: © pressmaster/Fotolia.com

In what they described as the first study to examine the combination of four lifestyle factors and risk of SCD, the investigators used data collected in the Nurses’ Health Study on 81,722 women who were aged 30-55 years at baseline in 1976. The study subjects were assessed biennially for smoking status, weight, menopausal status, use of medications, and physician-diagnosed disease, and were evaluated at longer intervals for diet and physical activity, over a total follow-up of 26 years (1984-2010).

The mean age at final follow-up was 72 years. There were 321 cases of SCD during follow-up.

A low-risk lifestyle was inversely related with SCD risk. The absolute risks of SCD were 22 cases/100,000 person-years with no low-risk lifestyle factors, 17 cases with one low-risk factor, 18 cases with two low-risk factors, 13 cases with three factors, and 16 cases with four.

Compared with women who had no low-risk lifestyle factors, who constituted 3% of the cohort, those with all four low-risk factors (who comprised 8% of the cohort) had a relative risk of 0.08 for SCD.

Women who followed all four low-risk lifestyle factors "had a 92% lower risk of SCD" compared with women with none of the low-risk lifestyle factors. "If these associations are causal, 81% of SCD within this cohort may have been prevented if all women adhered to a low-risk lifestyle," Dr. Chiuve and her colleagues said.

Extrapolating these results to the general U.S. female population, "Among women without diagnosed coronary heart disease, in whom the majority of SCD events occur, it is possible that 79% of SCD may be attributed to unhealthy lifestyle practices," they said (JAMA 2011;306:62-9).

Conversely, widespread adoption of a healthy lifestyle would "make a substantial impact" on reducing sudden cardiac death.

Primary prevention of SCD is a particular concern for women, who are half as likely as men to show left ventricular dysfunction and two-thirds less likely to be diagnosed as having coronary heart disease before SCD occurs. Women are therefore less likely to receive beta-blocker therapy or an implantable cardioverter-defibrillator to prevent the SCD.

This study was limited in that the NHS involved mostly white, well-educated, female health professionals, so the findings may not be generalizable to men or to people of other ethnicities.

The study was supported by the National Institutes of Health and the American Heart Association. An associate of Dr. Chiuve reported ties to the nutrition advisory board for UNO’s restaurant.

Middle-age and older women who avoid smoking, exercise regularly, follow a healthy diet, and maintain a healthy weight cut their risk of sudden cardiac death by 92%, compared with those who do not, according to a report in the July 6 JAMA.

If it is assumed that these four factors – smoking, lack of exercise, a poor diet, and obesity – play a causal role in sudden cardiac death (SCD), then approximately 80% of these deaths are preventable among women without diagnosed coronary heart disease, said Stephanie E. Chiuve, Sc.D., of the division of preventive medicine, Brigham and Women’s Hospital, Boston, and her associates.

Photo credit: © pressmaster/Fotolia.com

In what they described as the first study to examine the combination of four lifestyle factors and risk of SCD, the investigators used data collected in the Nurses’ Health Study on 81,722 women who were aged 30-55 years at baseline in 1976. The study subjects were assessed biennially for smoking status, weight, menopausal status, use of medications, and physician-diagnosed disease, and were evaluated at longer intervals for diet and physical activity, over a total follow-up of 26 years (1984-2010).

The mean age at final follow-up was 72 years. There were 321 cases of SCD during follow-up.

A low-risk lifestyle was inversely related with SCD risk. The absolute risks of SCD were 22 cases/100,000 person-years with no low-risk lifestyle factors, 17 cases with one low-risk factor, 18 cases with two low-risk factors, 13 cases with three factors, and 16 cases with four.

Compared with women who had no low-risk lifestyle factors, who constituted 3% of the cohort, those with all four low-risk factors (who comprised 8% of the cohort) had a relative risk of 0.08 for SCD.

Women who followed all four low-risk lifestyle factors "had a 92% lower risk of SCD" compared with women with none of the low-risk lifestyle factors. "If these associations are causal, 81% of SCD within this cohort may have been prevented if all women adhered to a low-risk lifestyle," Dr. Chiuve and her colleagues said.

Extrapolating these results to the general U.S. female population, "Among women without diagnosed coronary heart disease, in whom the majority of SCD events occur, it is possible that 79% of SCD may be attributed to unhealthy lifestyle practices," they said (JAMA 2011;306:62-9).

Conversely, widespread adoption of a healthy lifestyle would "make a substantial impact" on reducing sudden cardiac death.

Primary prevention of SCD is a particular concern for women, who are half as likely as men to show left ventricular dysfunction and two-thirds less likely to be diagnosed as having coronary heart disease before SCD occurs. Women are therefore less likely to receive beta-blocker therapy or an implantable cardioverter-defibrillator to prevent the SCD.

This study was limited in that the NHS involved mostly white, well-educated, female health professionals, so the findings may not be generalizable to men or to people of other ethnicities.

The study was supported by the National Institutes of Health and the American Heart Association. An associate of Dr. Chiuve reported ties to the nutrition advisory board for UNO’s restaurant.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.