Mary Ann Moon

Researchers have identified a new diarrheal syndrome that affects patients who have undergone cord-blood hematopoietic stem-cell transplantation, according to a report in the Sept. 1 issue of the New England Journal of Medicine.

It is important to distinguish the new syndrome, which they call "cord colitis syndrome," from other causes of diarrheal illness that have a similar initial presentation in this patient population – notably graft-versus-host disease (GVHD) – because treatment differs. Cord colitis syndrome responds rapidly to antibiotic therapy but tends to relapse when treatment stops, so a prolonged course is often necessary, said Dr. Alex F. Herrera of the department of medicine, Brigham and Women's Hospital, Boston, and his associates.

Severe diarrhea following hematopoietic stem-cell transplantation (HSCT) can almost always be traced to a variety of sources. Acute GVHD is perhaps the most well-recognized. Classic viral causes include cytomegalovirus and adenovirus, but more common pathogens such as rotavirus and norovirus are being recognized more frequently. Epstein-Barr virus can incite lymphoproliferative disease involving the gut, which produces diarrhea. And protozoal infections from giardia and cryptosporidium have been reported.

In addition, mucositis and neutropenic enterocolitis induced by conditioning regimens frequently cause diarrhea, as do Clostridium difficile infection and long-term medications, the investigators said.

Dr. Herrera and his colleagues noticed several cases of diarrheal illness that could not be attributed to any of these causes among patients who had undergone cord-blood HSCT at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital Hematopoietic Stem Cell Transplantation Service. They reviewed the medical records of all 104 patients who underwent the procedure between March 2003 and April 2010, to characterize the disorder.

The median patient age was 48 years (range, 19-67 years). The patients underwent cord-blood HSCT to treat numerous underlying diseases including acute myeloid leukemia (35%), non-Hodgkin’s lymphoma (22%), myelodysplastic syndrome (10%), Hodgkin’s disease (8%), acute lymphoblastic leukemia (7%), and aplastic anemia (7%).

Eleven of the 104 patients (10.6%) had the cord colitis syndrome, with persistent watery, nonbloody diarrhea associated with weight loss of up to 11 kg (median loss, 2.3 kg). Eight of the 11 required hospitalization.

Stool samples were negative for all bacterial, viral, fungal, protozoal, and parasitic organisms as well as toxins that were tested for. Nevertheless, patients showed a rapid response to empiric antibiotic therapy – usually metronidazole, either alone or in combination with a fluoroquinolone.

The median interval between HSCT and symptom onset was 131 days (range, 88-314 days).

Six patients had abdominal CT during their diagnostic work-up. Five of them showed colonic wall thickening consistent with colitis: two had diffuse colonic involvement, two had significant sigmoid thickening, and one had thickening of the cecum and ascending colon.

All 11 patients underwent diagnostic colonoscopy with biopsy. Grossly, nine showed mucosal erythema, five had edematous mucosa, and four had mucosal ulcerations. Only one patient had hemorrhagic mucosa.

The 37 biopsy specimens showed the full range of inflammatory activity, from none to severe. Histopathologically, specimens showed chronic active colitis associated with granulomas. Neutrophilic infiltration was superimposed on Paneth cell metaplasia, suggesting chronic and ongoing injury. Surface epithelial injury was common, Dr. Herrera and his associates said (N. Engl. J. Med. 2011;365:815-24).

In contrast, GVHD is not associated with granuloma formation, neutrophilic infiltration of the epithelium, or Paneth cell metaplasia. Its hallmark is increased apoptosis, predominately in crypt bases, which was seen only infrequently in cord colitis syndrome.

All the patients with cord colitis syndrome responded to empiric therapy, usually metronidazole, with or without the addition of a fluoroquinolone. Diarrhea either resolved completely or was significantly reduced after a median of 5 days. However, four patients required extended treatment of up to 90 days before symptoms resolved. Another five had relapses at 4-60 days after finishing their antibiotic course, but all five responded to a further maintenance course of antibiotics.

The investigators found no correlation between the cord colitis syndrome and factors such as patient age or race, the underlying hematologic disease, the conditioning regimen, or the regimen to prevent GVHD.

For comparison with these cord-blood stem cell recipients, Dr. Herrera and his colleagues reviewed the records of 1,261 patients who underwent allogeneic peripheral-blood or bone marrow HSCT during the same period at the same center. This included 381 patients who had 609 GI endoscopy and biopsy procedures. None of these patients showed the features of cord colitis syndrome, so it appears to be related strictly to stem cells derived from cord blood, the researchers said.

Dr. Herrera and his associates reported no financial conflicts of interest.

Researchers have identified a new diarrheal syndrome that affects patients who have undergone cord-blood hematopoietic stem-cell transplantation, according to a report in the Sept. 1 issue of the New England Journal of Medicine.

It is important to distinguish the new syndrome, which they call "cord colitis syndrome," from other causes of diarrheal illness that have a similar initial presentation in this patient population – notably graft-versus-host disease (GVHD) – because treatment differs. Cord colitis syndrome responds rapidly to antibiotic therapy but tends to relapse when treatment stops, so a prolonged course is often necessary, said Dr. Alex F. Herrera of the department of medicine, Brigham and Women's Hospital, Boston, and his associates.

Severe diarrhea following hematopoietic stem-cell transplantation (HSCT) can almost always be traced to a variety of sources. Acute GVHD is perhaps the most well-recognized. Classic viral causes include cytomegalovirus and adenovirus, but more common pathogens such as rotavirus and norovirus are being recognized more frequently. Epstein-Barr virus can incite lymphoproliferative disease involving the gut, which produces diarrhea. And protozoal infections from giardia and cryptosporidium have been reported.

In addition, mucositis and neutropenic enterocolitis induced by conditioning regimens frequently cause diarrhea, as do Clostridium difficile infection and long-term medications, the investigators said.

Dr. Herrera and his colleagues noticed several cases of diarrheal illness that could not be attributed to any of these causes among patients who had undergone cord-blood HSCT at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital Hematopoietic Stem Cell Transplantation Service. They reviewed the medical records of all 104 patients who underwent the procedure between March 2003 and April 2010, to characterize the disorder.

The median patient age was 48 years (range, 19-67 years). The patients underwent cord-blood HSCT to treat numerous underlying diseases including acute myeloid leukemia (35%), non-Hodgkin’s lymphoma (22%), myelodysplastic syndrome (10%), Hodgkin’s disease (8%), acute lymphoblastic leukemia (7%), and aplastic anemia (7%).

Eleven of the 104 patients (10.6%) had the cord colitis syndrome, with persistent watery, nonbloody diarrhea associated with weight loss of up to 11 kg (median loss, 2.3 kg). Eight of the 11 required hospitalization.

Stool samples were negative for all bacterial, viral, fungal, protozoal, and parasitic organisms as well as toxins that were tested for. Nevertheless, patients showed a rapid response to empiric antibiotic therapy – usually metronidazole, either alone or in combination with a fluoroquinolone.

The median interval between HSCT and symptom onset was 131 days (range, 88-314 days).

Six patients had abdominal CT during their diagnostic work-up. Five of them showed colonic wall thickening consistent with colitis: two had diffuse colonic involvement, two had significant sigmoid thickening, and one had thickening of the cecum and ascending colon.

All 11 patients underwent diagnostic colonoscopy with biopsy. Grossly, nine showed mucosal erythema, five had edematous mucosa, and four had mucosal ulcerations. Only one patient had hemorrhagic mucosa.

The 37 biopsy specimens showed the full range of inflammatory activity, from none to severe. Histopathologically, specimens showed chronic active colitis associated with granulomas. Neutrophilic infiltration was superimposed on Paneth cell metaplasia, suggesting chronic and ongoing injury. Surface epithelial injury was common, Dr. Herrera and his associates said (N. Engl. J. Med. 2011;365:815-24).

In contrast, GVHD is not associated with granuloma formation, neutrophilic infiltration of the epithelium, or Paneth cell metaplasia. Its hallmark is increased apoptosis, predominately in crypt bases, which was seen only infrequently in cord colitis syndrome.

All the patients with cord colitis syndrome responded to empiric therapy, usually metronidazole, with or without the addition of a fluoroquinolone. Diarrhea either resolved completely or was significantly reduced after a median of 5 days. However, four patients required extended treatment of up to 90 days before symptoms resolved. Another five had relapses at 4-60 days after finishing their antibiotic course, but all five responded to a further maintenance course of antibiotics.

The investigators found no correlation between the cord colitis syndrome and factors such as patient age or race, the underlying hematologic disease, the conditioning regimen, or the regimen to prevent GVHD.

For comparison with these cord-blood stem cell recipients, Dr. Herrera and his colleagues reviewed the records of 1,261 patients who underwent allogeneic peripheral-blood or bone marrow HSCT during the same period at the same center. This included 381 patients who had 609 GI endoscopy and biopsy procedures. None of these patients showed the features of cord colitis syndrome, so it appears to be related strictly to stem cells derived from cord blood, the researchers said.

Dr. Herrera and his associates reported no financial conflicts of interest.

Researchers have identified a new diarrheal syndrome that affects patients who have undergone cord-blood hematopoietic stem-cell transplantation, according to a report in the Sept. 1 issue of the New England Journal of Medicine.

It is important to distinguish the new syndrome, which they call "cord colitis syndrome," from other causes of diarrheal illness that have a similar initial presentation in this patient population – notably graft-versus-host disease (GVHD) – because treatment differs. Cord colitis syndrome responds rapidly to antibiotic therapy but tends to relapse when treatment stops, so a prolonged course is often necessary, said Dr. Alex F. Herrera of the department of medicine, Brigham and Women's Hospital, Boston, and his associates.

Severe diarrhea following hematopoietic stem-cell transplantation (HSCT) can almost always be traced to a variety of sources. Acute GVHD is perhaps the most well-recognized. Classic viral causes include cytomegalovirus and adenovirus, but more common pathogens such as rotavirus and norovirus are being recognized more frequently. Epstein-Barr virus can incite lymphoproliferative disease involving the gut, which produces diarrhea. And protozoal infections from giardia and cryptosporidium have been reported.

In addition, mucositis and neutropenic enterocolitis induced by conditioning regimens frequently cause diarrhea, as do Clostridium difficile infection and long-term medications, the investigators said.

Dr. Herrera and his colleagues noticed several cases of diarrheal illness that could not be attributed to any of these causes among patients who had undergone cord-blood HSCT at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital Hematopoietic Stem Cell Transplantation Service. They reviewed the medical records of all 104 patients who underwent the procedure between March 2003 and April 2010, to characterize the disorder.

The median patient age was 48 years (range, 19-67 years). The patients underwent cord-blood HSCT to treat numerous underlying diseases including acute myeloid leukemia (35%), non-Hodgkin’s lymphoma (22%), myelodysplastic syndrome (10%), Hodgkin’s disease (8%), acute lymphoblastic leukemia (7%), and aplastic anemia (7%).

Eleven of the 104 patients (10.6%) had the cord colitis syndrome, with persistent watery, nonbloody diarrhea associated with weight loss of up to 11 kg (median loss, 2.3 kg). Eight of the 11 required hospitalization.

Stool samples were negative for all bacterial, viral, fungal, protozoal, and parasitic organisms as well as toxins that were tested for. Nevertheless, patients showed a rapid response to empiric antibiotic therapy – usually metronidazole, either alone or in combination with a fluoroquinolone.

The median interval between HSCT and symptom onset was 131 days (range, 88-314 days).

Six patients had abdominal CT during their diagnostic work-up. Five of them showed colonic wall thickening consistent with colitis: two had diffuse colonic involvement, two had significant sigmoid thickening, and one had thickening of the cecum and ascending colon.

All 11 patients underwent diagnostic colonoscopy with biopsy. Grossly, nine showed mucosal erythema, five had edematous mucosa, and four had mucosal ulcerations. Only one patient had hemorrhagic mucosa.

The 37 biopsy specimens showed the full range of inflammatory activity, from none to severe. Histopathologically, specimens showed chronic active colitis associated with granulomas. Neutrophilic infiltration was superimposed on Paneth cell metaplasia, suggesting chronic and ongoing injury. Surface epithelial injury was common, Dr. Herrera and his associates said (N. Engl. J. Med. 2011;365:815-24).

In contrast, GVHD is not associated with granuloma formation, neutrophilic infiltration of the epithelium, or Paneth cell metaplasia. Its hallmark is increased apoptosis, predominately in crypt bases, which was seen only infrequently in cord colitis syndrome.

All the patients with cord colitis syndrome responded to empiric therapy, usually metronidazole, with or without the addition of a fluoroquinolone. Diarrhea either resolved completely or was significantly reduced after a median of 5 days. However, four patients required extended treatment of up to 90 days before symptoms resolved. Another five had relapses at 4-60 days after finishing their antibiotic course, but all five responded to a further maintenance course of antibiotics.

The investigators found no correlation between the cord colitis syndrome and factors such as patient age or race, the underlying hematologic disease, the conditioning regimen, or the regimen to prevent GVHD.

For comparison with these cord-blood stem cell recipients, Dr. Herrera and his colleagues reviewed the records of 1,261 patients who underwent allogeneic peripheral-blood or bone marrow HSCT during the same period at the same center. This included 381 patients who had 609 GI endoscopy and biopsy procedures. None of these patients showed the features of cord colitis syndrome, so it appears to be related strictly to stem cells derived from cord blood, the researchers said.

Dr. Herrera and his associates reported no financial conflicts of interest.

Most of the deaths in patients who sustain severe traumatic brain injury result from withdrawal of life support, usually within the first 3 days of ICU admission, according to a retrospective, multicenter, cohort study published online Aug. 29 in the Canadian Medical Association Journal.

This finding is concerning because the ability to accurately determine prognosis after TBI is so limited. "In some instances, this may be too early for accurate neuroprognostication," Dr. Alexis F. Turgeon of the Centre de Recherche du Centre Hospitalier, Universitaire de Québec-Hôpital de L’Enfant-Jésus, Quebec City, and his associates wrote (Can. Med. Assoc. J. 2011 Aug. 29 [doi: 10.1503/cmaj.101786]).

In addition, their study of TBI mortality in six Canadian trauma centers showed that the rate of withdrawal of life-sustaining therapy varies dramatically from one hospital to another. Such variation "raises the concern that differences in mortality between centers may be partly due to [differences] in physicians’ perceptions of long-term prognosis and physicians’ practice patterns," the researchers wrote.

"Our study highlights the need for high-quality research to better inform decisions to stop life-sustaining treatments for these patients," they noted.

Dr. Turgeon and his colleagues retrospectively assessed outcomes after TBI at six level-one trauma centers in three Canadian provinces over a 2-year period. They randomly selected 60 cases per year at each center to assess for this study, for a total sample size of 720 patients aged 16 years and older.

A total of 77% of the patients were male, and the mean age was 42 years. The most common causes of TBI were motor vehicle crashes (56%), falls (30%), and assaults (8%).

Overall mortality was 32%. More than 70% of the patient deaths stemmed directly from withdrawal of life-sustaining therapy, including 64% of patients who died within 3 days of admission to an ICU.

The rate of withdrawal varied greatly among the centers, ranging from 45% to 87%.

An analysis of numerous factors that might contribute to mortality risk – including patient sex, age, pupillary reactivity at baseline, and Glasgow coma score – showed that they did not account for the variation in the rate of life-support withdrawal. In contrast, the center to which the patient was admitted did account for most of the variation.

Half of the patient deaths occurred within the first 3 days of admission to an ICU. Again, this proportion varied greatly among the medical centers – from a low of 30% to a high of 93%.

This is of particular clinical relevance "when one considers that people who acquire a severe TBI are often young and have few or no comorbidities," Dr. Turgeon and his associates noted.

The most common reasons given for withdrawing life-sustaining therapy were the medical team’s opinion that chance of survival was poor (54% of cases), the next of kin’s opinion that the prognosis was incompatible with the patient’s wishes (34%), and the medical team’s opinion that long-term neurologic prognosis was poor (29%).

The investigators noted that they did not include information on patients’ ethnicity, religious faith, spiritual beliefs, or other factors not written in medical records, "which may have had an impact on decisions surrounding withdrawal of life-sustaining therapy and consequent mortality."

They added that they did not publicly identify the six medical centers "to avoid the potential for drawing spurious inferences about the quality of care."

In a commentary accompanying Dr. Turgeon’s report, Dr. David H. Livingston and Dr. Anne C. Mosenthal wrote, "Although we attribute the variability in withdrawal of life-sustaining therapy to differences in patient preferences, the article by Turgeon and colleagues adds to the growing body of literature that physician practice and the culture of medical centers may play an equally strong role."

The way in which physicians manage the uncertainty in predicting recovery from TBI in their discussions with families "may account for a large proportion of variability in outcomes," they noted (Can. Med. Assoc. J. 2011 Aug. 29 [doi:10.1503/cmaj.110974]).

A lot of the uncertainty arises from the "poor discriminatory power of the tools available to measure the extent of brain injury and the lack of outcome data," they said.

Although the report by Dr. Turgeon and coauthors of variable but often early withdrawal "raises the concern of not only hastening death but increasing mortality for patients who might recover with more time," it should be considered at the same time that "allowing patients to linger when death is inevitable is associated with prolonged suffering for both patients and families," said Dr. Livingston and Dr. Mosenthal, who are with the department of surgery at the University of Medicine and Dentistry of New Jersey, Newark.

This study was supported in part by the Fondation de l’Hôpital de l’Enfant-Jésus, the Fonds de recherche Santé Québec, the Canadian Institutes for Health Research, and Sunnybrook Health Sciences Centre. No financial conflicts of interest were reported. Dr. Livingston and Dr. Mosenthal reported no financial conflicts of interest.

Most of the deaths in patients who sustain severe traumatic brain injury result from withdrawal of life support, usually within the first 3 days of ICU admission, according to a retrospective, multicenter, cohort study published online Aug. 29 in the Canadian Medical Association Journal.

This finding is concerning because the ability to accurately determine prognosis after TBI is so limited. "In some instances, this may be too early for accurate neuroprognostication," Dr. Alexis F. Turgeon of the Centre de Recherche du Centre Hospitalier, Universitaire de Québec-Hôpital de L’Enfant-Jésus, Quebec City, and his associates wrote (Can. Med. Assoc. J. 2011 Aug. 29 [doi: 10.1503/cmaj.101786]).

In addition, their study of TBI mortality in six Canadian trauma centers showed that the rate of withdrawal of life-sustaining therapy varies dramatically from one hospital to another. Such variation "raises the concern that differences in mortality between centers may be partly due to [differences] in physicians’ perceptions of long-term prognosis and physicians’ practice patterns," the researchers wrote.

"Our study highlights the need for high-quality research to better inform decisions to stop life-sustaining treatments for these patients," they noted.

Dr. Turgeon and his colleagues retrospectively assessed outcomes after TBI at six level-one trauma centers in three Canadian provinces over a 2-year period. They randomly selected 60 cases per year at each center to assess for this study, for a total sample size of 720 patients aged 16 years and older.

A total of 77% of the patients were male, and the mean age was 42 years. The most common causes of TBI were motor vehicle crashes (56%), falls (30%), and assaults (8%).

Overall mortality was 32%. More than 70% of the patient deaths stemmed directly from withdrawal of life-sustaining therapy, including 64% of patients who died within 3 days of admission to an ICU.

The rate of withdrawal varied greatly among the centers, ranging from 45% to 87%.

An analysis of numerous factors that might contribute to mortality risk – including patient sex, age, pupillary reactivity at baseline, and Glasgow coma score – showed that they did not account for the variation in the rate of life-support withdrawal. In contrast, the center to which the patient was admitted did account for most of the variation.

Half of the patient deaths occurred within the first 3 days of admission to an ICU. Again, this proportion varied greatly among the medical centers – from a low of 30% to a high of 93%.

This is of particular clinical relevance "when one considers that people who acquire a severe TBI are often young and have few or no comorbidities," Dr. Turgeon and his associates noted.

The most common reasons given for withdrawing life-sustaining therapy were the medical team’s opinion that chance of survival was poor (54% of cases), the next of kin’s opinion that the prognosis was incompatible with the patient’s wishes (34%), and the medical team’s opinion that long-term neurologic prognosis was poor (29%).

The investigators noted that they did not include information on patients’ ethnicity, religious faith, spiritual beliefs, or other factors not written in medical records, "which may have had an impact on decisions surrounding withdrawal of life-sustaining therapy and consequent mortality."

They added that they did not publicly identify the six medical centers "to avoid the potential for drawing spurious inferences about the quality of care."

In a commentary accompanying Dr. Turgeon’s report, Dr. David H. Livingston and Dr. Anne C. Mosenthal wrote, "Although we attribute the variability in withdrawal of life-sustaining therapy to differences in patient preferences, the article by Turgeon and colleagues adds to the growing body of literature that physician practice and the culture of medical centers may play an equally strong role."

The way in which physicians manage the uncertainty in predicting recovery from TBI in their discussions with families "may account for a large proportion of variability in outcomes," they noted (Can. Med. Assoc. J. 2011 Aug. 29 [doi:10.1503/cmaj.110974]).

A lot of the uncertainty arises from the "poor discriminatory power of the tools available to measure the extent of brain injury and the lack of outcome data," they said.

Although the report by Dr. Turgeon and coauthors of variable but often early withdrawal "raises the concern of not only hastening death but increasing mortality for patients who might recover with more time," it should be considered at the same time that "allowing patients to linger when death is inevitable is associated with prolonged suffering for both patients and families," said Dr. Livingston and Dr. Mosenthal, who are with the department of surgery at the University of Medicine and Dentistry of New Jersey, Newark.

This study was supported in part by the Fondation de l’Hôpital de l’Enfant-Jésus, the Fonds de recherche Santé Québec, the Canadian Institutes for Health Research, and Sunnybrook Health Sciences Centre. No financial conflicts of interest were reported. Dr. Livingston and Dr. Mosenthal reported no financial conflicts of interest.

Most of the deaths in patients who sustain severe traumatic brain injury result from withdrawal of life support, usually within the first 3 days of ICU admission, according to a retrospective, multicenter, cohort study published online Aug. 29 in the Canadian Medical Association Journal.

This finding is concerning because the ability to accurately determine prognosis after TBI is so limited. "In some instances, this may be too early for accurate neuroprognostication," Dr. Alexis F. Turgeon of the Centre de Recherche du Centre Hospitalier, Universitaire de Québec-Hôpital de L’Enfant-Jésus, Quebec City, and his associates wrote (Can. Med. Assoc. J. 2011 Aug. 29 [doi: 10.1503/cmaj.101786]).

In addition, their study of TBI mortality in six Canadian trauma centers showed that the rate of withdrawal of life-sustaining therapy varies dramatically from one hospital to another. Such variation "raises the concern that differences in mortality between centers may be partly due to [differences] in physicians’ perceptions of long-term prognosis and physicians’ practice patterns," the researchers wrote.

"Our study highlights the need for high-quality research to better inform decisions to stop life-sustaining treatments for these patients," they noted.

Dr. Turgeon and his colleagues retrospectively assessed outcomes after TBI at six level-one trauma centers in three Canadian provinces over a 2-year period. They randomly selected 60 cases per year at each center to assess for this study, for a total sample size of 720 patients aged 16 years and older.

A total of 77% of the patients were male, and the mean age was 42 years. The most common causes of TBI were motor vehicle crashes (56%), falls (30%), and assaults (8%).

Overall mortality was 32%. More than 70% of the patient deaths stemmed directly from withdrawal of life-sustaining therapy, including 64% of patients who died within 3 days of admission to an ICU.

The rate of withdrawal varied greatly among the centers, ranging from 45% to 87%.

An analysis of numerous factors that might contribute to mortality risk – including patient sex, age, pupillary reactivity at baseline, and Glasgow coma score – showed that they did not account for the variation in the rate of life-support withdrawal. In contrast, the center to which the patient was admitted did account for most of the variation.

Half of the patient deaths occurred within the first 3 days of admission to an ICU. Again, this proportion varied greatly among the medical centers – from a low of 30% to a high of 93%.

This is of particular clinical relevance "when one considers that people who acquire a severe TBI are often young and have few or no comorbidities," Dr. Turgeon and his associates noted.

The most common reasons given for withdrawing life-sustaining therapy were the medical team’s opinion that chance of survival was poor (54% of cases), the next of kin’s opinion that the prognosis was incompatible with the patient’s wishes (34%), and the medical team’s opinion that long-term neurologic prognosis was poor (29%).

The investigators noted that they did not include information on patients’ ethnicity, religious faith, spiritual beliefs, or other factors not written in medical records, "which may have had an impact on decisions surrounding withdrawal of life-sustaining therapy and consequent mortality."

They added that they did not publicly identify the six medical centers "to avoid the potential for drawing spurious inferences about the quality of care."

In a commentary accompanying Dr. Turgeon’s report, Dr. David H. Livingston and Dr. Anne C. Mosenthal wrote, "Although we attribute the variability in withdrawal of life-sustaining therapy to differences in patient preferences, the article by Turgeon and colleagues adds to the growing body of literature that physician practice and the culture of medical centers may play an equally strong role."

The way in which physicians manage the uncertainty in predicting recovery from TBI in their discussions with families "may account for a large proportion of variability in outcomes," they noted (Can. Med. Assoc. J. 2011 Aug. 29 [doi:10.1503/cmaj.110974]).

A lot of the uncertainty arises from the "poor discriminatory power of the tools available to measure the extent of brain injury and the lack of outcome data," they said.

Although the report by Dr. Turgeon and coauthors of variable but often early withdrawal "raises the concern of not only hastening death but increasing mortality for patients who might recover with more time," it should be considered at the same time that "allowing patients to linger when death is inevitable is associated with prolonged suffering for both patients and families," said Dr. Livingston and Dr. Mosenthal, who are with the department of surgery at the University of Medicine and Dentistry of New Jersey, Newark.

This study was supported in part by the Fondation de l’Hôpital de l’Enfant-Jésus, the Fonds de recherche Santé Québec, the Canadian Institutes for Health Research, and Sunnybrook Health Sciences Centre. No financial conflicts of interest were reported. Dr. Livingston and Dr. Mosenthal reported no financial conflicts of interest.

Daily azithromycin prevented acute exacerbations of chronic obstructive pulmonary disease when it was added to usual treatment in a 1-year study, thus improving patients’ quality of life, according to a report in the Aug. 25 issue of the New England Journal of Medicine.

The drug also cut the colonization of certain respiratory pathogens. On the downside, it increased colonization with macrolide-resistant organisms and induced hearing decrements in approximately 5% of patients, said Dr. Richard K. Albert, professor of medicine at the University of Colorado at Denver and chief of medicine at Denver Health, and his associates.

"Given the deleterious effects of acute exacerbations of COPD with respect to the risk of death, quality of life, loss of lung function, and cost of care, adding azithromycin to the treatment regimen [of at-risk patients] is a valuable option," they noted.

However, QTc prolongation is a contraindication to the drug, and patients who are at risk for the cardiac disorder should be monitored if they are given azithromycin. Hearing also should be monitored in all patients. "In addition, it should be recognized that the long-term effects of this treatment on microbial resistance in the community are not known," the investigators said.

Macrolide antibiotics like azithromycin have immunomodulatory and anti-inflammatory properties in addition to their antibacterial action. Several small studies have examined their use in preventing acute exacerbations of COPD, with conflicting results. "Accordingly, we conducted a large, randomized trial to test the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients," said Dr. Albert and his colleagues in the COPD Clinical Research Network.

The prospective study involved 1,142 patients aged 40 years and older who were at risk for acute exacerbations and were randomly assigned to receive either 250 mg of oral azithromycin (570 subjects) or an identical-looking placebo (572 subjects) once daily for 1 year. All were already using inhaled glucocorticoids, long-acting beta-agonists, muscarinic antagonists, and/or continuous supplemental oxygen.

These subjects were followed at 17 sites associated with academic health centers across the United States.

The primary outcome measure – time to the first acute exacerbation of COPD – was significantly increased in the patients taking azithromycin (266 days), compared with those taking placebo (174 days). The hazard ratio of having an acute exacerbation per patient-year was 0.73 in the azithromycin group, compared with the placebo group.

These differences remained significant after the data were adjusted to account for differences between the two groups in sex, forced expiratory volume in 1 second (FEV₁), age, and smoking status, the researchers said (N. Engl. J. Med. 2011;365:689-98).

There were 1,641 acute exacerbations of COPD during the study, and the number was significantly lower in the active-treatment group (741) than in the placebo group (900). "The number needed to treat to prevent one acute exacerbation of COPD was 2.86," they said.

More patients in the azithromycin group than in the placebo group showed significant improvements in quality of life scores.

There were no significant differences between the two groups in the frequency of serious adverse events or of adverse events that prompted discontinuation of treatment. Audiograms showed hearing decrements in 25% of patients taking azithromycin, compared with 20% of those taking placebo.

Among study subjects whose nasopharyngeal swabs showed colonization with respiratory pathogens at baseline, the later prevalence of organisms that were resistant to macrolides was comparable whether they took azithromycin or placebo. In contrast, among subjects who became colonized during the study, the rate of macrolide resistance was twice as high in those taking azithromycin (81%) as in those taking placebo (41%).

"We cannot comment on the safety profile of azithromycin when it is taken for longer than 1 year, and we have no information pertaining to potential effects of long-term macrolide administration on bacterial resistance patterns in the community," Dr. Albert and his associates noted.

They added that they chose the 250-mg dose of azithromycin to minimize the chance of insufficient dosing, and chose daily rather than less-frequent administration to maximize adherence. "It is possible that lower doses or less frequent administration could have produced similar results," Dr. Albert and his colleagues said.

This study was funded by the National Heart, Lung, and Blood Institute and the COPD Clinical Research Network. Dr. Albert reported ties to Gilead Sciences, the Bruce Fagel Law Firm, Elsevier, and Denver Health, and his associates reported ties to numerous industry sources including Pfizer, the marketer of Zithromax in the United States.

Daily azithromycin prevented acute exacerbations of chronic obstructive pulmonary disease when it was added to usual treatment in a 1-year study, thus improving patients’ quality of life, according to a report in the Aug. 25 issue of the New England Journal of Medicine.

The drug also cut the colonization of certain respiratory pathogens. On the downside, it increased colonization with macrolide-resistant organisms and induced hearing decrements in approximately 5% of patients, said Dr. Richard K. Albert, professor of medicine at the University of Colorado at Denver and chief of medicine at Denver Health, and his associates.

"Given the deleterious effects of acute exacerbations of COPD with respect to the risk of death, quality of life, loss of lung function, and cost of care, adding azithromycin to the treatment regimen [of at-risk patients] is a valuable option," they noted.

However, QTc prolongation is a contraindication to the drug, and patients who are at risk for the cardiac disorder should be monitored if they are given azithromycin. Hearing also should be monitored in all patients. "In addition, it should be recognized that the long-term effects of this treatment on microbial resistance in the community are not known," the investigators said.

Macrolide antibiotics like azithromycin have immunomodulatory and anti-inflammatory properties in addition to their antibacterial action. Several small studies have examined their use in preventing acute exacerbations of COPD, with conflicting results. "Accordingly, we conducted a large, randomized trial to test the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients," said Dr. Albert and his colleagues in the COPD Clinical Research Network.

The prospective study involved 1,142 patients aged 40 years and older who were at risk for acute exacerbations and were randomly assigned to receive either 250 mg of oral azithromycin (570 subjects) or an identical-looking placebo (572 subjects) once daily for 1 year. All were already using inhaled glucocorticoids, long-acting beta-agonists, muscarinic antagonists, and/or continuous supplemental oxygen.

These subjects were followed at 17 sites associated with academic health centers across the United States.

The primary outcome measure – time to the first acute exacerbation of COPD – was significantly increased in the patients taking azithromycin (266 days), compared with those taking placebo (174 days). The hazard ratio of having an acute exacerbation per patient-year was 0.73 in the azithromycin group, compared with the placebo group.

These differences remained significant after the data were adjusted to account for differences between the two groups in sex, forced expiratory volume in 1 second (FEV₁), age, and smoking status, the researchers said (N. Engl. J. Med. 2011;365:689-98).

There were 1,641 acute exacerbations of COPD during the study, and the number was significantly lower in the active-treatment group (741) than in the placebo group (900). "The number needed to treat to prevent one acute exacerbation of COPD was 2.86," they said.

More patients in the azithromycin group than in the placebo group showed significant improvements in quality of life scores.

There were no significant differences between the two groups in the frequency of serious adverse events or of adverse events that prompted discontinuation of treatment. Audiograms showed hearing decrements in 25% of patients taking azithromycin, compared with 20% of those taking placebo.

Among study subjects whose nasopharyngeal swabs showed colonization with respiratory pathogens at baseline, the later prevalence of organisms that were resistant to macrolides was comparable whether they took azithromycin or placebo. In contrast, among subjects who became colonized during the study, the rate of macrolide resistance was twice as high in those taking azithromycin (81%) as in those taking placebo (41%).

"We cannot comment on the safety profile of azithromycin when it is taken for longer than 1 year, and we have no information pertaining to potential effects of long-term macrolide administration on bacterial resistance patterns in the community," Dr. Albert and his associates noted.

They added that they chose the 250-mg dose of azithromycin to minimize the chance of insufficient dosing, and chose daily rather than less-frequent administration to maximize adherence. "It is possible that lower doses or less frequent administration could have produced similar results," Dr. Albert and his colleagues said.

This study was funded by the National Heart, Lung, and Blood Institute and the COPD Clinical Research Network. Dr. Albert reported ties to Gilead Sciences, the Bruce Fagel Law Firm, Elsevier, and Denver Health, and his associates reported ties to numerous industry sources including Pfizer, the marketer of Zithromax in the United States.

Daily azithromycin prevented acute exacerbations of chronic obstructive pulmonary disease when it was added to usual treatment in a 1-year study, thus improving patients’ quality of life, according to a report in the Aug. 25 issue of the New England Journal of Medicine.

The drug also cut the colonization of certain respiratory pathogens. On the downside, it increased colonization with macrolide-resistant organisms and induced hearing decrements in approximately 5% of patients, said Dr. Richard K. Albert, professor of medicine at the University of Colorado at Denver and chief of medicine at Denver Health, and his associates.

"Given the deleterious effects of acute exacerbations of COPD with respect to the risk of death, quality of life, loss of lung function, and cost of care, adding azithromycin to the treatment regimen [of at-risk patients] is a valuable option," they noted.

However, QTc prolongation is a contraindication to the drug, and patients who are at risk for the cardiac disorder should be monitored if they are given azithromycin. Hearing also should be monitored in all patients. "In addition, it should be recognized that the long-term effects of this treatment on microbial resistance in the community are not known," the investigators said.

Macrolide antibiotics like azithromycin have immunomodulatory and anti-inflammatory properties in addition to their antibacterial action. Several small studies have examined their use in preventing acute exacerbations of COPD, with conflicting results. "Accordingly, we conducted a large, randomized trial to test the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients," said Dr. Albert and his colleagues in the COPD Clinical Research Network.

The prospective study involved 1,142 patients aged 40 years and older who were at risk for acute exacerbations and were randomly assigned to receive either 250 mg of oral azithromycin (570 subjects) or an identical-looking placebo (572 subjects) once daily for 1 year. All were already using inhaled glucocorticoids, long-acting beta-agonists, muscarinic antagonists, and/or continuous supplemental oxygen.

These subjects were followed at 17 sites associated with academic health centers across the United States.

The primary outcome measure – time to the first acute exacerbation of COPD – was significantly increased in the patients taking azithromycin (266 days), compared with those taking placebo (174 days). The hazard ratio of having an acute exacerbation per patient-year was 0.73 in the azithromycin group, compared with the placebo group.

These differences remained significant after the data were adjusted to account for differences between the two groups in sex, forced expiratory volume in 1 second (FEV₁), age, and smoking status, the researchers said (N. Engl. J. Med. 2011;365:689-98).

There were 1,641 acute exacerbations of COPD during the study, and the number was significantly lower in the active-treatment group (741) than in the placebo group (900). "The number needed to treat to prevent one acute exacerbation of COPD was 2.86," they said.

More patients in the azithromycin group than in the placebo group showed significant improvements in quality of life scores.

There were no significant differences between the two groups in the frequency of serious adverse events or of adverse events that prompted discontinuation of treatment. Audiograms showed hearing decrements in 25% of patients taking azithromycin, compared with 20% of those taking placebo.

Among study subjects whose nasopharyngeal swabs showed colonization with respiratory pathogens at baseline, the later prevalence of organisms that were resistant to macrolides was comparable whether they took azithromycin or placebo. In contrast, among subjects who became colonized during the study, the rate of macrolide resistance was twice as high in those taking azithromycin (81%) as in those taking placebo (41%).

"We cannot comment on the safety profile of azithromycin when it is taken for longer than 1 year, and we have no information pertaining to potential effects of long-term macrolide administration on bacterial resistance patterns in the community," Dr. Albert and his associates noted.

They added that they chose the 250-mg dose of azithromycin to minimize the chance of insufficient dosing, and chose daily rather than less-frequent administration to maximize adherence. "It is possible that lower doses or less frequent administration could have produced similar results," Dr. Albert and his colleagues said.

This study was funded by the National Heart, Lung, and Blood Institute and the COPD Clinical Research Network. Dr. Albert reported ties to Gilead Sciences, the Bruce Fagel Law Firm, Elsevier, and Denver Health, and his associates reported ties to numerous industry sources including Pfizer, the marketer of Zithromax in the United States.

Hospitalization raises the risk that patients’ long-term medications for chronic diseases will be discontinued unintentionally, according to a report in the Aug. 24 issue of JAMA.

That risk is further heightened with ICU care, which suggests that the more patients are transitioned from site to site and from clinician to clinician, the greater the chance that their long-term medications (statins, antiplatelet or anticoagulant agents, levothyroxine, respiratory inhalers, and gastric acid-suppressing drugs) will get lost in the shuffle.

Discontinuing these necessary medications appears to raise patients’ risk of death, further hospitalization, and ED visits for up to 1 year after discharge, said Dr. Chaim M. Bell of St. Michael’s Hospital, Toronto, and his associates. "These findings emphasize the importance of a systematic approach to transitions in health care to ensure medication continuity," they noted.

The investigators conducted a population-based cohort study of all hospitalizations of patients aged 66 years and older in Ontario between 1997 and 2009 to examine medication continuity. They reviewed the records of 396,036 patients who had been taking any of the five types of medications for chronic disease listed above for at least 1 year.

In all, 160,568 of these study subjects were hospitalized during the study period, including 16,474 who were admitted to the ICU; the remaining 208,468 who were not hospitalized served as control subjects. The rate of patients who failed to refill prescriptions of the five categories of medication within 90 days of discharge was calculated.

The investigators excluded cases in which patients developed complications or contraindications to their medications, or otherwise had a clear reason for discontinuing a drug. They also controlled for confounding factors that could influence stopping a medication, such as comorbid disease burden and the number of physician contacts during the year preceding hospitalization.

Drugs in all five medication categories were significantly more likely to be discontinued after hospitalization than in the controls. Rates of unintentional discontinuation were highest for antiplatelet/anticoagulants (19.4%), followed by statins (13.6%), gastric acid suppressors (12.9%), levothyroxine (12.3%), and respiratory inhalers (4.5%). The corresponding rates for control subjects were 11.8%, 10.7%, 9.4%, 11%, and 3%, respectively.

Rates of unintentional discontinuation were even higher among ICU patients in four of the five medication categories (22.8% for antiplatelet/anticoagulants, 15.4% for gastric acid suppressors, 15% for levothyroxine, and 14.6% for statins).

In a secondary analysis, the unintentional discontinuation of antiplatelet/anticoagulants and of statins was associated with higher risk of the combined outcome of death, further hospitalization, or emergency admission for up to 1 year after hospital discharge. "This underscores the widespread prevalence of potential errors of omission and the risk for long-term harm following hospitalization," Dr. Bell and his colleagues said (JAMA 2011;306:840-7).

Although this study was not designed to assess how it is that necessary medications get "dropped" unintentionally, previous studies have suggested that miscommunication during transitions of care is not the only contributor. Many medications for chronic diseases are purposely discontinued during a critical illness, but then restarting them is forgotten or overlooked after the acute event resolves.

Previous research also found that unintentional discontinuation of medications is common, but they were primarily single-site, cross-sectional studies. In contrast, "our study examined potential errors of omission on a system-wide basis for an extended period in a diverse patient population with a focus on long-term medications for chronic diseases," the investigators wrote.

They added that "even though our study cohort only included elderly patients [aged 66 and older], the findings are likely generalizable to the general population."

Hospitalization raises the risk that patients’ long-term medications for chronic diseases will be discontinued unintentionally, according to a report in the Aug. 24 issue of JAMA.

That risk is further heightened with ICU care, which suggests that the more patients are transitioned from site to site and from clinician to clinician, the greater the chance that their long-term medications (statins, antiplatelet or anticoagulant agents, levothyroxine, respiratory inhalers, and gastric acid-suppressing drugs) will get lost in the shuffle.

Discontinuing these necessary medications appears to raise patients’ risk of death, further hospitalization, and ED visits for up to 1 year after discharge, said Dr. Chaim M. Bell of St. Michael’s Hospital, Toronto, and his associates. "These findings emphasize the importance of a systematic approach to transitions in health care to ensure medication continuity," they noted.

The investigators conducted a population-based cohort study of all hospitalizations of patients aged 66 years and older in Ontario between 1997 and 2009 to examine medication continuity. They reviewed the records of 396,036 patients who had been taking any of the five types of medications for chronic disease listed above for at least 1 year.

In all, 160,568 of these study subjects were hospitalized during the study period, including 16,474 who were admitted to the ICU; the remaining 208,468 who were not hospitalized served as control subjects. The rate of patients who failed to refill prescriptions of the five categories of medication within 90 days of discharge was calculated.

The investigators excluded cases in which patients developed complications or contraindications to their medications, or otherwise had a clear reason for discontinuing a drug. They also controlled for confounding factors that could influence stopping a medication, such as comorbid disease burden and the number of physician contacts during the year preceding hospitalization.

Drugs in all five medication categories were significantly more likely to be discontinued after hospitalization than in the controls. Rates of unintentional discontinuation were highest for antiplatelet/anticoagulants (19.4%), followed by statins (13.6%), gastric acid suppressors (12.9%), levothyroxine (12.3%), and respiratory inhalers (4.5%). The corresponding rates for control subjects were 11.8%, 10.7%, 9.4%, 11%, and 3%, respectively.

Rates of unintentional discontinuation were even higher among ICU patients in four of the five medication categories (22.8% for antiplatelet/anticoagulants, 15.4% for gastric acid suppressors, 15% for levothyroxine, and 14.6% for statins).

In a secondary analysis, the unintentional discontinuation of antiplatelet/anticoagulants and of statins was associated with higher risk of the combined outcome of death, further hospitalization, or emergency admission for up to 1 year after hospital discharge. "This underscores the widespread prevalence of potential errors of omission and the risk for long-term harm following hospitalization," Dr. Bell and his colleagues said (JAMA 2011;306:840-7).

Although this study was not designed to assess how it is that necessary medications get "dropped" unintentionally, previous studies have suggested that miscommunication during transitions of care is not the only contributor. Many medications for chronic diseases are purposely discontinued during a critical illness, but then restarting them is forgotten or overlooked after the acute event resolves.

Previous research also found that unintentional discontinuation of medications is common, but they were primarily single-site, cross-sectional studies. In contrast, "our study examined potential errors of omission on a system-wide basis for an extended period in a diverse patient population with a focus on long-term medications for chronic diseases," the investigators wrote.

They added that "even though our study cohort only included elderly patients [aged 66 and older], the findings are likely generalizable to the general population."

Hospitalization raises the risk that patients’ long-term medications for chronic diseases will be discontinued unintentionally, according to a report in the Aug. 24 issue of JAMA.

That risk is further heightened with ICU care, which suggests that the more patients are transitioned from site to site and from clinician to clinician, the greater the chance that their long-term medications (statins, antiplatelet or anticoagulant agents, levothyroxine, respiratory inhalers, and gastric acid-suppressing drugs) will get lost in the shuffle.

Discontinuing these necessary medications appears to raise patients’ risk of death, further hospitalization, and ED visits for up to 1 year after discharge, said Dr. Chaim M. Bell of St. Michael’s Hospital, Toronto, and his associates. "These findings emphasize the importance of a systematic approach to transitions in health care to ensure medication continuity," they noted.

The investigators conducted a population-based cohort study of all hospitalizations of patients aged 66 years and older in Ontario between 1997 and 2009 to examine medication continuity. They reviewed the records of 396,036 patients who had been taking any of the five types of medications for chronic disease listed above for at least 1 year.

In all, 160,568 of these study subjects were hospitalized during the study period, including 16,474 who were admitted to the ICU; the remaining 208,468 who were not hospitalized served as control subjects. The rate of patients who failed to refill prescriptions of the five categories of medication within 90 days of discharge was calculated.

The investigators excluded cases in which patients developed complications or contraindications to their medications, or otherwise had a clear reason for discontinuing a drug. They also controlled for confounding factors that could influence stopping a medication, such as comorbid disease burden and the number of physician contacts during the year preceding hospitalization.

Drugs in all five medication categories were significantly more likely to be discontinued after hospitalization than in the controls. Rates of unintentional discontinuation were highest for antiplatelet/anticoagulants (19.4%), followed by statins (13.6%), gastric acid suppressors (12.9%), levothyroxine (12.3%), and respiratory inhalers (4.5%). The corresponding rates for control subjects were 11.8%, 10.7%, 9.4%, 11%, and 3%, respectively.

Rates of unintentional discontinuation were even higher among ICU patients in four of the five medication categories (22.8% for antiplatelet/anticoagulants, 15.4% for gastric acid suppressors, 15% for levothyroxine, and 14.6% for statins).

In a secondary analysis, the unintentional discontinuation of antiplatelet/anticoagulants and of statins was associated with higher risk of the combined outcome of death, further hospitalization, or emergency admission for up to 1 year after hospital discharge. "This underscores the widespread prevalence of potential errors of omission and the risk for long-term harm following hospitalization," Dr. Bell and his colleagues said (JAMA 2011;306:840-7).

Although this study was not designed to assess how it is that necessary medications get "dropped" unintentionally, previous studies have suggested that miscommunication during transitions of care is not the only contributor. Many medications for chronic diseases are purposely discontinued during a critical illness, but then restarting them is forgotten or overlooked after the acute event resolves.

Previous research also found that unintentional discontinuation of medications is common, but they were primarily single-site, cross-sectional studies. In contrast, "our study examined potential errors of omission on a system-wide basis for an extended period in a diverse patient population with a focus on long-term medications for chronic diseases," the investigators wrote.

They added that "even though our study cohort only included elderly patients [aged 66 and older], the findings are likely generalizable to the general population."

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

Counseling patients to consume specific cholesterol-lowering foods was more successful at reducing low-density lipoprotein cholesterol levels than was standard advice to follow a diet low in saturated fat, according to a study in the Aug. 24 JAMA.

In a study of 351 adults with hyperlipidemia, a dietary intervention that encouraged a high intake of foods rich in viscous fiber, plant sterols, soy protein, and nuts – "foods denoted by the U.S. [Food and Drug Administration] to have a heart health benefit" – decreased LDL cholesterol by 13% after 6 months, compared with a 3% reduction associated with a standard low-fat diet.

It is not yet known whether this cholesterol reduction will translate into decreased coronary heart disease mortality. But the 13% drop in cholesterol is approximately half of that achieved in early statin trials, which corresponded to a 20% decrease in CHD mortality, said Dr. David J.A. Jenkins of the clinical nutrition and risk factor modification center of St. Michael’s Hospital, Toronto, and his associates.

©Tinka/Fotolia.com

In this study, the 137 men and 214 postmenopausal women with hyperlipidemia who were recruited at four medical centers across Canada were randomly assigned to follow one of three diets.

The first was a standard low-fat diet that emphasized high fiber, whole grains, fruits, and vegetables (the control diet). Subjects met with dietitians at baseline, 3 months, and 6 months.

The second was a "routine" intervention diet that specifically promoted plant sterol ester–enriched margarine, oats, barley, psyllium, soy milk, tofu, soy meat analogues, nuts, peas, beans, and lentils, in which subjects similarly met with dietitians at baseline, 3 months, and 6 months.

The third was an "intense" intervention diet in which the food components were identical to those in the routine diet, but subjects also met with dietitians at baseline, 2 weeks, and for monthly visits thereafter for 6 months.

Outcomes were similar between the routine and the intense intervention diets, so the more frequent visits with a dietitian did not confer added benefit. In all three groups, subjects lost a similar amount of weight (1.2-1.7 kg).

The average decrease in LDL cholesterol was 3% with the control diet, compared with 13% with the routine intervention diet and 14% with the intense intervention diet, the investigators said (JAMA 2011;306:831-9).

There were no serious adverse events in any of the three study groups; food allergies were a problem for two participants in the intervention arm.

The dropout rate was deemed "high" at 23%. Such attrition is common in studies in which diets are restricted to this degree, Dr. Jenkins and his colleagues said.

A major limitation of this study was the fact that nearly all the subjects were white, had a low body mass index, and were at low to intermediate risk of CV disease. "The generalizability of this clinical trial to higher-risk, more overweight, or obese patient populations is unknown," the researchers noted.

Moreover, these study subjects "were already consuming an acceptable background diet low in saturated fat and cholesterol," so it is possible that they were better able to adhere to the intervention diets than members of the general population would be.

However, this also means that the effectiveness of the intervention diets would be even more pronounced in the general population, Dr. Jenkins and his associates added.

This study was funded primarily by the Canadian Institutes of Health Research. Loblaw Brands, Solae, and Unilever also provided supplementary funding. Dr. Jenkins and his associates reported ties to Unilever, Santarium, the California Strawberry Commission, Loblaw Supermarket, Herbal Life International, Advanced Foods and Materials Network, Nutritional Fundamental for Health, Pacific Health Laboratories, Metagenics, Bayer Consumer Care, Orafti, Dean Foods, Kellogg’s, Quaker Oats, Procter & Gamble, Coca-Cola, Abbott, Pulse Canada, Saskatchewan Pulse Growers, Canola Council of Canada, Almond Board of California, International Tree Nut Council, Barilla, Solae, Oldways, Haine Celestial, Alpro Foundation, Peanut Institute, Danone, Enzymotec, Viterra Food Processing, and Glycemic Index Laboratories.

Counseling patients to consume specific cholesterol-lowering foods was more successful at reducing low-density lipoprotein cholesterol levels than was standard advice to follow a diet low in saturated fat, according to a study in the Aug. 24 JAMA.

In a study of 351 adults with hyperlipidemia, a dietary intervention that encouraged a high intake of foods rich in viscous fiber, plant sterols, soy protein, and nuts – "foods denoted by the U.S. [Food and Drug Administration] to have a heart health benefit" – decreased LDL cholesterol by 13% after 6 months, compared with a 3% reduction associated with a standard low-fat diet.

It is not yet known whether this cholesterol reduction will translate into decreased coronary heart disease mortality. But the 13% drop in cholesterol is approximately half of that achieved in early statin trials, which corresponded to a 20% decrease in CHD mortality, said Dr. David J.A. Jenkins of the clinical nutrition and risk factor modification center of St. Michael’s Hospital, Toronto, and his associates.

©Tinka/Fotolia.com

In this study, the 137 men and 214 postmenopausal women with hyperlipidemia who were recruited at four medical centers across Canada were randomly assigned to follow one of three diets.

The first was a standard low-fat diet that emphasized high fiber, whole grains, fruits, and vegetables (the control diet). Subjects met with dietitians at baseline, 3 months, and 6 months.

The second was a "routine" intervention diet that specifically promoted plant sterol ester–enriched margarine, oats, barley, psyllium, soy milk, tofu, soy meat analogues, nuts, peas, beans, and lentils, in which subjects similarly met with dietitians at baseline, 3 months, and 6 months.

The third was an "intense" intervention diet in which the food components were identical to those in the routine diet, but subjects also met with dietitians at baseline, 2 weeks, and for monthly visits thereafter for 6 months.

Outcomes were similar between the routine and the intense intervention diets, so the more frequent visits with a dietitian did not confer added benefit. In all three groups, subjects lost a similar amount of weight (1.2-1.7 kg).

The average decrease in LDL cholesterol was 3% with the control diet, compared with 13% with the routine intervention diet and 14% with the intense intervention diet, the investigators said (JAMA 2011;306:831-9).

There were no serious adverse events in any of the three study groups; food allergies were a problem for two participants in the intervention arm.

The dropout rate was deemed "high" at 23%. Such attrition is common in studies in which diets are restricted to this degree, Dr. Jenkins and his colleagues said.

A major limitation of this study was the fact that nearly all the subjects were white, had a low body mass index, and were at low to intermediate risk of CV disease. "The generalizability of this clinical trial to higher-risk, more overweight, or obese patient populations is unknown," the researchers noted.

Moreover, these study subjects "were already consuming an acceptable background diet low in saturated fat and cholesterol," so it is possible that they were better able to adhere to the intervention diets than members of the general population would be.

However, this also means that the effectiveness of the intervention diets would be even more pronounced in the general population, Dr. Jenkins and his associates added.

This study was funded primarily by the Canadian Institutes of Health Research. Loblaw Brands, Solae, and Unilever also provided supplementary funding. Dr. Jenkins and his associates reported ties to Unilever, Santarium, the California Strawberry Commission, Loblaw Supermarket, Herbal Life International, Advanced Foods and Materials Network, Nutritional Fundamental for Health, Pacific Health Laboratories, Metagenics, Bayer Consumer Care, Orafti, Dean Foods, Kellogg’s, Quaker Oats, Procter & Gamble, Coca-Cola, Abbott, Pulse Canada, Saskatchewan Pulse Growers, Canola Council of Canada, Almond Board of California, International Tree Nut Council, Barilla, Solae, Oldways, Haine Celestial, Alpro Foundation, Peanut Institute, Danone, Enzymotec, Viterra Food Processing, and Glycemic Index Laboratories.

Counseling patients to consume specific cholesterol-lowering foods was more successful at reducing low-density lipoprotein cholesterol levels than was standard advice to follow a diet low in saturated fat, according to a study in the Aug. 24 JAMA.

In a study of 351 adults with hyperlipidemia, a dietary intervention that encouraged a high intake of foods rich in viscous fiber, plant sterols, soy protein, and nuts – "foods denoted by the U.S. [Food and Drug Administration] to have a heart health benefit" – decreased LDL cholesterol by 13% after 6 months, compared with a 3% reduction associated with a standard low-fat diet.

It is not yet known whether this cholesterol reduction will translate into decreased coronary heart disease mortality. But the 13% drop in cholesterol is approximately half of that achieved in early statin trials, which corresponded to a 20% decrease in CHD mortality, said Dr. David J.A. Jenkins of the clinical nutrition and risk factor modification center of St. Michael’s Hospital, Toronto, and his associates.

©Tinka/Fotolia.com

In this study, the 137 men and 214 postmenopausal women with hyperlipidemia who were recruited at four medical centers across Canada were randomly assigned to follow one of three diets.

The first was a standard low-fat diet that emphasized high fiber, whole grains, fruits, and vegetables (the control diet). Subjects met with dietitians at baseline, 3 months, and 6 months.

The second was a "routine" intervention diet that specifically promoted plant sterol ester–enriched margarine, oats, barley, psyllium, soy milk, tofu, soy meat analogues, nuts, peas, beans, and lentils, in which subjects similarly met with dietitians at baseline, 3 months, and 6 months.

The third was an "intense" intervention diet in which the food components were identical to those in the routine diet, but subjects also met with dietitians at baseline, 2 weeks, and for monthly visits thereafter for 6 months.

Outcomes were similar between the routine and the intense intervention diets, so the more frequent visits with a dietitian did not confer added benefit. In all three groups, subjects lost a similar amount of weight (1.2-1.7 kg).

The average decrease in LDL cholesterol was 3% with the control diet, compared with 13% with the routine intervention diet and 14% with the intense intervention diet, the investigators said (JAMA 2011;306:831-9).

There were no serious adverse events in any of the three study groups; food allergies were a problem for two participants in the intervention arm.

The dropout rate was deemed "high" at 23%. Such attrition is common in studies in which diets are restricted to this degree, Dr. Jenkins and his colleagues said.

A major limitation of this study was the fact that nearly all the subjects were white, had a low body mass index, and were at low to intermediate risk of CV disease. "The generalizability of this clinical trial to higher-risk, more overweight, or obese patient populations is unknown," the researchers noted.

Moreover, these study subjects "were already consuming an acceptable background diet low in saturated fat and cholesterol," so it is possible that they were better able to adhere to the intervention diets than members of the general population would be.

However, this also means that the effectiveness of the intervention diets would be even more pronounced in the general population, Dr. Jenkins and his associates added.

This study was funded primarily by the Canadian Institutes of Health Research. Loblaw Brands, Solae, and Unilever also provided supplementary funding. Dr. Jenkins and his associates reported ties to Unilever, Santarium, the California Strawberry Commission, Loblaw Supermarket, Herbal Life International, Advanced Foods and Materials Network, Nutritional Fundamental for Health, Pacific Health Laboratories, Metagenics, Bayer Consumer Care, Orafti, Dean Foods, Kellogg’s, Quaker Oats, Procter & Gamble, Coca-Cola, Abbott, Pulse Canada, Saskatchewan Pulse Growers, Canola Council of Canada, Almond Board of California, International Tree Nut Council, Barilla, Solae, Oldways, Haine Celestial, Alpro Foundation, Peanut Institute, Danone, Enzymotec, Viterra Food Processing, and Glycemic Index Laboratories.

The prevalence of diastolic dysfunction increases as people age, even among healthy adults, according to a longitudinal study reported in the Aug. 24 issue of JAMA.

Results of the study add to the findings of previous cross-sectional community studies that diastolic dysfunction is highly prevalent in older adults, demonstrating that during 10 years of follow-up, middle-aged and elderly people were nearly three times more likely to show deteriorating diastolic function than improving diastolic function.

"That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges," said Dr. Garvan C. Kane of Mayo Clinic, Rochester, Minn., and his associates.

Previously, the investigators had performed two cross-sectional analyses of diastolic function in community residents aged 45 and older participating in the Olmsted County Heart Function Study in 1997-2000 and again in 2001-2004. They now report the results of 6 years of further follow-up of a subset of 1,402 of these subjects, which tracked within-patient changes in diastolic function over time.

In all, 90% of the study subjects were white, and 81% lived in urban settings.

Over time, 23% of subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction. The remaining 68% of subjects showed no change in diastolic dysfunction.

"A similar pattern of worsening diastolic function also was observed in a subset of [531] healthy participants" who had been free of hypertension, diabetes, coronary artery disease, and heart failure at baseline. About 20% showed worsening diastolic function, compared with 5% who showed improvement in diastolic dysfunction over time. The remaining 75% showed no change in diastolic dysfunction.

"However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF [left ventricular ejection fraction]," Dr. Kane and his colleagues said (JAMA 2011;306:856-63).

"Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons," they noted.

It follows that preventing such superimposed events by addressing risk factors, particularly hypertension, "might be fundamental to reducing heart failure with preserved LVEF," they added.

The study findings may not be generalizable to nonwhite racial or ethnic populations, since the cohort was predominantly white.

This study was supported by the National Heart, Lung, and Blood Institute, the National Center for Research Resources, the Mayo Foundation, the National Institutes of Health, the Rochester Epidemiology Project, and the National Institute on Aging. No financial conflicts of interest were reported.

The prevalence of diastolic dysfunction increases as people age, even among healthy adults, according to a longitudinal study reported in the Aug. 24 issue of JAMA.

Results of the study add to the findings of previous cross-sectional community studies that diastolic dysfunction is highly prevalent in older adults, demonstrating that during 10 years of follow-up, middle-aged and elderly people were nearly three times more likely to show deteriorating diastolic function than improving diastolic function.

"That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges," said Dr. Garvan C. Kane of Mayo Clinic, Rochester, Minn., and his associates.

Previously, the investigators had performed two cross-sectional analyses of diastolic function in community residents aged 45 and older participating in the Olmsted County Heart Function Study in 1997-2000 and again in 2001-2004. They now report the results of 6 years of further follow-up of a subset of 1,402 of these subjects, which tracked within-patient changes in diastolic function over time.

In all, 90% of the study subjects were white, and 81% lived in urban settings.

Over time, 23% of subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction. The remaining 68% of subjects showed no change in diastolic dysfunction.

"A similar pattern of worsening diastolic function also was observed in a subset of [531] healthy participants" who had been free of hypertension, diabetes, coronary artery disease, and heart failure at baseline. About 20% showed worsening diastolic function, compared with 5% who showed improvement in diastolic dysfunction over time. The remaining 75% showed no change in diastolic dysfunction.

"However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF [left ventricular ejection fraction]," Dr. Kane and his colleagues said (JAMA 2011;306:856-63).

"Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons," they noted.

It follows that preventing such superimposed events by addressing risk factors, particularly hypertension, "might be fundamental to reducing heart failure with preserved LVEF," they added.

The study findings may not be generalizable to nonwhite racial or ethnic populations, since the cohort was predominantly white.

This study was supported by the National Heart, Lung, and Blood Institute, the National Center for Research Resources, the Mayo Foundation, the National Institutes of Health, the Rochester Epidemiology Project, and the National Institute on Aging. No financial conflicts of interest were reported.

The prevalence of diastolic dysfunction increases as people age, even among healthy adults, according to a longitudinal study reported in the Aug. 24 issue of JAMA.

Results of the study add to the findings of previous cross-sectional community studies that diastolic dysfunction is highly prevalent in older adults, demonstrating that during 10 years of follow-up, middle-aged and elderly people were nearly three times more likely to show deteriorating diastolic function than improving diastolic function.

"That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges," said Dr. Garvan C. Kane of Mayo Clinic, Rochester, Minn., and his associates.

Previously, the investigators had performed two cross-sectional analyses of diastolic function in community residents aged 45 and older participating in the Olmsted County Heart Function Study in 1997-2000 and again in 2001-2004. They now report the results of 6 years of further follow-up of a subset of 1,402 of these subjects, which tracked within-patient changes in diastolic function over time.

In all, 90% of the study subjects were white, and 81% lived in urban settings.

Over time, 23% of subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction. The remaining 68% of subjects showed no change in diastolic dysfunction.

"A similar pattern of worsening diastolic function also was observed in a subset of [531] healthy participants" who had been free of hypertension, diabetes, coronary artery disease, and heart failure at baseline. About 20% showed worsening diastolic function, compared with 5% who showed improvement in diastolic dysfunction over time. The remaining 75% showed no change in diastolic dysfunction.

"However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF [left ventricular ejection fraction]," Dr. Kane and his colleagues said (JAMA 2011;306:856-63).

"Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons," they noted.

It follows that preventing such superimposed events by addressing risk factors, particularly hypertension, "might be fundamental to reducing heart failure with preserved LVEF," they added.

The study findings may not be generalizable to nonwhite racial or ethnic populations, since the cohort was predominantly white.

This study was supported by the National Heart, Lung, and Blood Institute, the National Center for Research Resources, the Mayo Foundation, the National Institutes of Health, the Rochester Epidemiology Project, and the National Institute on Aging. No financial conflicts of interest were reported.

A method of administering general anesthesia while monitoring EEG activity to track the patient’s level of consciousness proved to be no better than the standard anesthesia technique at preventing episodes of patient awareness during surgery, according to a study published in the Aug. 18 issue of the New England Journal of Medicine.

"The overall incidence of awareness was lower than anticipated, suggesting that both protocols were likely to have had efficacy, but the finding of fewer cases [with the standard approach than with the EEG method] was contrary to the expected result," said Dr. Michael S. Avidan of the department of anesthesiology at Washington University, St. Louis, and his associates.

"Notwithstanding major advances in our understanding of consciousness and anesthesia, until we clarify fully the mechanisms and measurement of anesthetic-induced unconsciousness and amnesia, some patients are still likely to have this complication," the researchers noted.

Unintended intraoperative awareness (defined as the experience and explicit recall of sensory perceptions during surgery) is estimated to occur in approximately 1% of at-risk patients, and can lead to posttraumatic stress disorder. Approximately 20,000-40,000 U.S. patients each year are estimated to experience such awareness while under general anesthesia.

Some factors that appear to raise the risk of unintended awareness while under general anesthesia are a history of the condition during previous surgery, aortic stenosis, pulmonary hypertension, end-stage lung disease, anticipation of difficult intubation, poor exercise tolerance, impaired cardiac ejection fraction, excess alcohol intake, and the use of benzodiazepines, opiates, or anticonvulsants.

The current standard method for monitoring intraoperative patient awareness doesn’t measure consciousness itself, but instead ensures that "enough" anesthetic is used by tracking the end-tidal anesthetic-agent concentration (ETAC). Maintaining this at 0.7 MAC (minimum alveolar concentration) or higher is thought to decrease the incidence of awareness during surgery.

An alternative method is the bispectral index (BIS), which uses a single EEG signal from a sensor on the patient’s forehead to calculate brain activity and produces a numerical readout on a scale from 0 (indicating the suppression of all brain activity) to 100 (indicating a fully awake state). Maintaining a target range of 40-60 on this scale is thought to both prevent awareness and allow reductions in the dose of anesthetic.

Two previous clinical trials comparing the two techniques have yielded conflicting results.

Dr. Avidan and his colleagues conducted the BAG-RECALL (BIS or Anesthetic Gas to Reduce Explicit Recall) clinical trial to determine whether the BIS method is superior to standard ETAC in at-risk surgical patients.

They randomly assigned 6,041 adults undergoing elective surgery during a 2-year period at three medical centers in the United States and Canada to one or the other technique. In the BIS group, an alarm sounded when the BIS value exceeded 60 or fell below 40. In the ETAC group, an alarm sounded if the ETAC fell below 0.7 or exceeded 1.3 MAC.

In both study groups, a sign was attached to the anesthesia machines reminding clinicians to check these values and consider whether the patient might be aware. In addition, these values were recorded electronically at 1-minute intervals; manual records were kept of anesthesia; and photographs of trends on the monitors were taken and stored digitally.

There were no important differences between the two groups in doses of sedative, hypnotic, opioid, analgesic, or neuromuscular-blocking drugs given, nor in the amount of anesthetic given; the rate of adverse postoperative outcomes including mortality; the median length of stay in intensive care; or the median length of hospital stay.

Patients’ intraoperative awareness was assessed via a questionnaire within 72 hours after surgery and at 30 days after extubation. A total of 49 patients reported some degree of awareness at some time when they were undergoing surgery, Dr. Avidan and his associates said (N. Engl. J. Med. 2011;365:591-600).

All patients who reported that they had memories of the period between "going to sleep" and "waking up" from anesthesia were further evaluated in more detail and were offered referral to a psychologist for counseling.

Contrary to expectations, there were fewer cases of definite intraoperative awareness in the ETAC group (0.07%) than in the BIS group (0.24%). Similarly, there were fewer cases of possible or definite intraoperative awareness in the ETAC group (0.28%) than in the BIS group (0.66%).

Thus, BIS was not superior in preventing intraoperative awareness.

This study was supported by the Foundation for Anesthesia Education and Research, the American Society of Anesthesiologists, the Winnipeg Regional Health Authority, and the departments of anesthesia at the University of Manitoba, Washington University, and the University of Chicago. The researchers reported no financial conflicts of interest.

A method of administering general anesthesia while monitoring EEG activity to track the patient’s level of consciousness proved to be no better than the standard anesthesia technique at preventing episodes of patient awareness during surgery, according to a study published in the Aug. 18 issue of the New England Journal of Medicine.

"The overall incidence of awareness was lower than anticipated, suggesting that both protocols were likely to have had efficacy, but the finding of fewer cases [with the standard approach than with the EEG method] was contrary to the expected result," said Dr. Michael S. Avidan of the department of anesthesiology at Washington University, St. Louis, and his associates.

"Notwithstanding major advances in our understanding of consciousness and anesthesia, until we clarify fully the mechanisms and measurement of anesthetic-induced unconsciousness and amnesia, some patients are still likely to have this complication," the researchers noted.

Unintended intraoperative awareness (defined as the experience and explicit recall of sensory perceptions during surgery) is estimated to occur in approximately 1% of at-risk patients, and can lead to posttraumatic stress disorder. Approximately 20,000-40,000 U.S. patients each year are estimated to experience such awareness while under general anesthesia.

Some factors that appear to raise the risk of unintended awareness while under general anesthesia are a history of the condition during previous surgery, aortic stenosis, pulmonary hypertension, end-stage lung disease, anticipation of difficult intubation, poor exercise tolerance, impaired cardiac ejection fraction, excess alcohol intake, and the use of benzodiazepines, opiates, or anticonvulsants.

The current standard method for monitoring intraoperative patient awareness doesn’t measure consciousness itself, but instead ensures that "enough" anesthetic is used by tracking the end-tidal anesthetic-agent concentration (ETAC). Maintaining this at 0.7 MAC (minimum alveolar concentration) or higher is thought to decrease the incidence of awareness during surgery.

An alternative method is the bispectral index (BIS), which uses a single EEG signal from a sensor on the patient’s forehead to calculate brain activity and produces a numerical readout on a scale from 0 (indicating the suppression of all brain activity) to 100 (indicating a fully awake state). Maintaining a target range of 40-60 on this scale is thought to both prevent awareness and allow reductions in the dose of anesthetic.

Two previous clinical trials comparing the two techniques have yielded conflicting results.

Dr. Avidan and his colleagues conducted the BAG-RECALL (BIS or Anesthetic Gas to Reduce Explicit Recall) clinical trial to determine whether the BIS method is superior to standard ETAC in at-risk surgical patients.

They randomly assigned 6,041 adults undergoing elective surgery during a 2-year period at three medical centers in the United States and Canada to one or the other technique. In the BIS group, an alarm sounded when the BIS value exceeded 60 or fell below 40. In the ETAC group, an alarm sounded if the ETAC fell below 0.7 or exceeded 1.3 MAC.

In both study groups, a sign was attached to the anesthesia machines reminding clinicians to check these values and consider whether the patient might be aware. In addition, these values were recorded electronically at 1-minute intervals; manual records were kept of anesthesia; and photographs of trends on the monitors were taken and stored digitally.

There were no important differences between the two groups in doses of sedative, hypnotic, opioid, analgesic, or neuromuscular-blocking drugs given, nor in the amount of anesthetic given; the rate of adverse postoperative outcomes including mortality; the median length of stay in intensive care; or the median length of hospital stay.

Patients’ intraoperative awareness was assessed via a questionnaire within 72 hours after surgery and at 30 days after extubation. A total of 49 patients reported some degree of awareness at some time when they were undergoing surgery, Dr. Avidan and his associates said (N. Engl. J. Med. 2011;365:591-600).

All patients who reported that they had memories of the period between "going to sleep" and "waking up" from anesthesia were further evaluated in more detail and were offered referral to a psychologist for counseling.

Contrary to expectations, there were fewer cases of definite intraoperative awareness in the ETAC group (0.07%) than in the BIS group (0.24%). Similarly, there were fewer cases of possible or definite intraoperative awareness in the ETAC group (0.28%) than in the BIS group (0.66%).

Thus, BIS was not superior in preventing intraoperative awareness.

This study was supported by the Foundation for Anesthesia Education and Research, the American Society of Anesthesiologists, the Winnipeg Regional Health Authority, and the departments of anesthesia at the University of Manitoba, Washington University, and the University of Chicago. The researchers reported no financial conflicts of interest.

A method of administering general anesthesia while monitoring EEG activity to track the patient’s level of consciousness proved to be no better than the standard anesthesia technique at preventing episodes of patient awareness during surgery, according to a study published in the Aug. 18 issue of the New England Journal of Medicine.

"The overall incidence of awareness was lower than anticipated, suggesting that both protocols were likely to have had efficacy, but the finding of fewer cases [with the standard approach than with the EEG method] was contrary to the expected result," said Dr. Michael S. Avidan of the department of anesthesiology at Washington University, St. Louis, and his associates.

"Notwithstanding major advances in our understanding of consciousness and anesthesia, until we clarify fully the mechanisms and measurement of anesthetic-induced unconsciousness and amnesia, some patients are still likely to have this complication," the researchers noted.

Unintended intraoperative awareness (defined as the experience and explicit recall of sensory perceptions during surgery) is estimated to occur in approximately 1% of at-risk patients, and can lead to posttraumatic stress disorder. Approximately 20,000-40,000 U.S. patients each year are estimated to experience such awareness while under general anesthesia.

Some factors that appear to raise the risk of unintended awareness while under general anesthesia are a history of the condition during previous surgery, aortic stenosis, pulmonary hypertension, end-stage lung disease, anticipation of difficult intubation, poor exercise tolerance, impaired cardiac ejection fraction, excess alcohol intake, and the use of benzodiazepines, opiates, or anticonvulsants.

The current standard method for monitoring intraoperative patient awareness doesn’t measure consciousness itself, but instead ensures that "enough" anesthetic is used by tracking the end-tidal anesthetic-agent concentration (ETAC). Maintaining this at 0.7 MAC (minimum alveolar concentration) or higher is thought to decrease the incidence of awareness during surgery.

An alternative method is the bispectral index (BIS), which uses a single EEG signal from a sensor on the patient’s forehead to calculate brain activity and produces a numerical readout on a scale from 0 (indicating the suppression of all brain activity) to 100 (indicating a fully awake state). Maintaining a target range of 40-60 on this scale is thought to both prevent awareness and allow reductions in the dose of anesthetic.

Two previous clinical trials comparing the two techniques have yielded conflicting results.

Dr. Avidan and his colleagues conducted the BAG-RECALL (BIS or Anesthetic Gas to Reduce Explicit Recall) clinical trial to determine whether the BIS method is superior to standard ETAC in at-risk surgical patients.

They randomly assigned 6,041 adults undergoing elective surgery during a 2-year period at three medical centers in the United States and Canada to one or the other technique. In the BIS group, an alarm sounded when the BIS value exceeded 60 or fell below 40. In the ETAC group, an alarm sounded if the ETAC fell below 0.7 or exceeded 1.3 MAC.

In both study groups, a sign was attached to the anesthesia machines reminding clinicians to check these values and consider whether the patient might be aware. In addition, these values were recorded electronically at 1-minute intervals; manual records were kept of anesthesia; and photographs of trends on the monitors were taken and stored digitally.

There were no important differences between the two groups in doses of sedative, hypnotic, opioid, analgesic, or neuromuscular-blocking drugs given, nor in the amount of anesthetic given; the rate of adverse postoperative outcomes including mortality; the median length of stay in intensive care; or the median length of hospital stay.

Patients’ intraoperative awareness was assessed via a questionnaire within 72 hours after surgery and at 30 days after extubation. A total of 49 patients reported some degree of awareness at some time when they were undergoing surgery, Dr. Avidan and his associates said (N. Engl. J. Med. 2011;365:591-600).

All patients who reported that they had memories of the period between "going to sleep" and "waking up" from anesthesia were further evaluated in more detail and were offered referral to a psychologist for counseling.

Contrary to expectations, there were fewer cases of definite intraoperative awareness in the ETAC group (0.07%) than in the BIS group (0.24%). Similarly, there were fewer cases of possible or definite intraoperative awareness in the ETAC group (0.28%) than in the BIS group (0.66%).

Thus, BIS was not superior in preventing intraoperative awareness.

This study was supported by the Foundation for Anesthesia Education and Research, the American Society of Anesthesiologists, the Winnipeg Regional Health Authority, and the departments of anesthesia at the University of Manitoba, Washington University, and the University of Chicago. The researchers reported no financial conflicts of interest.

The association between smoking and bladder cancer risk appears to be stronger now than it was 30 years ago, particularly among women, according to a report in the Aug. 17 issue of JAMA.

Smoking now accounts for 50% of the population-attributable risk for bladder cancer in men and 52% in women, whereas it accounted for approximately 50% of the risk in men but only 20%-30% of the risk in women in the 1980s, said Neal D. Freedman, Ph.D., of the National Cancer Institute, and his associates.

"This is the first article to our knowledge to demonstrate that ... the population-attributable risks for smoking and bladder cancer are now similar in U.S. men and women," they noted.

© pmphoto/istock.com

An epidemiologic study cannot establish causality, but it appears likely that these findings stem from two trends that occurred during the same time frame: The prevalence of smoking has increased among women, and the composition of cigarette smoke has changed, with higher concentrations of tobacco-specific nitrosamines and of beta-naphthylamine, a known bladder carcinogen.

Dr. Freedman and his colleagues examined the link between smoking and bladder cancer in part because rates of bladder cancer have remained stable over the past 30 years, even though the prevalence of smoking has substantially declined during that period. They used data from the prospective National Institutes of Health-AARP (NIH-AARP) Diet and Health Study, which assessed smoking status and followed men and women residing in eight states from 1995 through 2006.

For this analysis, the investigators focused on 281,394 men and 186,134 women who were aged 50-71 years and were cancer-free at baseline. They linked the study information with data in cancer registries in the eight states, and found that 3,896 of the men and 627 of the women developed incident bladder cancer.

Compared with subjects who had never smoked, those who were current smokers had an adjusted hazard ratio of 3.89 and those who were former smokers had an adjusted HR of 2.14. The adjusted hazard ratio for currently smoking men and women combined was 4.06 (JAMA 2011;306:737-45).

Dr. Freedman and his associates then performed a meta-analysis of seven U.S. prospective cohort studies of smoking and bladder cancer that were conducted in 1963-1987, to compare how risk estimates have changed over time. They found that the summary hazard ratio was 2.94 for men and women combined, "which was significantly lower than that observed in our study."

"These results support the hypothesis that the risk of bladder cancer associated with cigarette smoking has increased with time in the U.S., perhaps a reflection of changing cigarette composition," the researchers said.

The findings further suggest that the stronger association between smoking and bladder cancer may have offset the decreased prevalence of smoking in the population, which might explain why the prevalence of bladder cancer has not declined.

"These observations parallel those previously reported for lung cancer, in which changes in cigarette design have been linked to stronger" associations between smoking and that malignancy, they noted.

This study was limited in that the data did not quantify smoking, so smoking duration or pack-years of exposure could not be accounted for, they added.

This study was supported by the National Institutes of Health, the National Cancer Institute, the AARP, and eight state cancer registries. No other relevant financial disclosures were reported.

The association between smoking and bladder cancer risk appears to be stronger now than it was 30 years ago, particularly among women, according to a report in the Aug. 17 issue of JAMA.

Smoking now accounts for 50% of the population-attributable risk for bladder cancer in men and 52% in women, whereas it accounted for approximately 50% of the risk in men but only 20%-30% of the risk in women in the 1980s, said Neal D. Freedman, Ph.D., of the National Cancer Institute, and his associates.

"This is the first article to our knowledge to demonstrate that ... the population-attributable risks for smoking and bladder cancer are now similar in U.S. men and women," they noted.

© pmphoto/istock.com

An epidemiologic study cannot establish causality, but it appears likely that these findings stem from two trends that occurred during the same time frame: The prevalence of smoking has increased among women, and the composition of cigarette smoke has changed, with higher concentrations of tobacco-specific nitrosamines and of beta-naphthylamine, a known bladder carcinogen.

Dr. Freedman and his colleagues examined the link between smoking and bladder cancer in part because rates of bladder cancer have remained stable over the past 30 years, even though the prevalence of smoking has substantially declined during that period. They used data from the prospective National Institutes of Health-AARP (NIH-AARP) Diet and Health Study, which assessed smoking status and followed men and women residing in eight states from 1995 through 2006.

For this analysis, the investigators focused on 281,394 men and 186,134 women who were aged 50-71 years and were cancer-free at baseline. They linked the study information with data in cancer registries in the eight states, and found that 3,896 of the men and 627 of the women developed incident bladder cancer.

Compared with subjects who had never smoked, those who were current smokers had an adjusted hazard ratio of 3.89 and those who were former smokers had an adjusted HR of 2.14. The adjusted hazard ratio for currently smoking men and women combined was 4.06 (JAMA 2011;306:737-45).

Dr. Freedman and his associates then performed a meta-analysis of seven U.S. prospective cohort studies of smoking and bladder cancer that were conducted in 1963-1987, to compare how risk estimates have changed over time. They found that the summary hazard ratio was 2.94 for men and women combined, "which was significantly lower than that observed in our study."

"These results support the hypothesis that the risk of bladder cancer associated with cigarette smoking has increased with time in the U.S., perhaps a reflection of changing cigarette composition," the researchers said.

The findings further suggest that the stronger association between smoking and bladder cancer may have offset the decreased prevalence of smoking in the population, which might explain why the prevalence of bladder cancer has not declined.

"These observations parallel those previously reported for lung cancer, in which changes in cigarette design have been linked to stronger" associations between smoking and that malignancy, they noted.

This study was limited in that the data did not quantify smoking, so smoking duration or pack-years of exposure could not be accounted for, they added.

This study was supported by the National Institutes of Health, the National Cancer Institute, the AARP, and eight state cancer registries. No other relevant financial disclosures were reported.

The association between smoking and bladder cancer risk appears to be stronger now than it was 30 years ago, particularly among women, according to a report in the Aug. 17 issue of JAMA.

Smoking now accounts for 50% of the population-attributable risk for bladder cancer in men and 52% in women, whereas it accounted for approximately 50% of the risk in men but only 20%-30% of the risk in women in the 1980s, said Neal D. Freedman, Ph.D., of the National Cancer Institute, and his associates.

"This is the first article to our knowledge to demonstrate that ... the population-attributable risks for smoking and bladder cancer are now similar in U.S. men and women," they noted.

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An epidemiologic study cannot establish causality, but it appears likely that these findings stem from two trends that occurred during the same time frame: The prevalence of smoking has increased among women, and the composition of cigarette smoke has changed, with higher concentrations of tobacco-specific nitrosamines and of beta-naphthylamine, a known bladder carcinogen.

Dr. Freedman and his colleagues examined the link between smoking and bladder cancer in part because rates of bladder cancer have remained stable over the past 30 years, even though the prevalence of smoking has substantially declined during that period. They used data from the prospective National Institutes of Health-AARP (NIH-AARP) Diet and Health Study, which assessed smoking status and followed men and women residing in eight states from 1995 through 2006.

For this analysis, the investigators focused on 281,394 men and 186,134 women who were aged 50-71 years and were cancer-free at baseline. They linked the study information with data in cancer registries in the eight states, and found that 3,896 of the men and 627 of the women developed incident bladder cancer.

Compared with subjects who had never smoked, those who were current smokers had an adjusted hazard ratio of 3.89 and those who were former smokers had an adjusted HR of 2.14. The adjusted hazard ratio for currently smoking men and women combined was 4.06 (JAMA 2011;306:737-45).

Dr. Freedman and his associates then performed a meta-analysis of seven U.S. prospective cohort studies of smoking and bladder cancer that were conducted in 1963-1987, to compare how risk estimates have changed over time. They found that the summary hazard ratio was 2.94 for men and women combined, "which was significantly lower than that observed in our study."

"These results support the hypothesis that the risk of bladder cancer associated with cigarette smoking has increased with time in the U.S., perhaps a reflection of changing cigarette composition," the researchers said.

The findings further suggest that the stronger association between smoking and bladder cancer may have offset the decreased prevalence of smoking in the population, which might explain why the prevalence of bladder cancer has not declined.

"These observations parallel those previously reported for lung cancer, in which changes in cigarette design have been linked to stronger" associations between smoking and that malignancy, they noted.

This study was limited in that the data did not quantify smoking, so smoking duration or pack-years of exposure could not be accounted for, they added.

This study was supported by the National Institutes of Health, the National Cancer Institute, the AARP, and eight state cancer registries. No other relevant financial disclosures were reported.

Persistent asymptomatic isolated microscopic hematuria in adolescence and young adulthood appears to be a strong predictor of end-stage renal disease in later adulthood, independent of other risk factors, according to a report in the Aug. 17 JAMA.

Such hematuria is frequently an incidental finding on routine examination in this age group, but its significance has been unclear. Short-term prognosis is favorable, and the condition is generally considered benign. But long-term data are lacking, and uncertainty about the implications has prompted "considerable controversy over appropriate evaluation, management, and prognosis," said Dr. Asaf Vivante of the Israeli Defense Forces Medical Corps and the Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, and his associates.

"The most recent American Academy of Pediatrics guidelines rescinded the recommendation for urine screening during the second decade of life," they noted.

They conducted a nationwide retrospective cohort study to assess the long-term outcomes of persistent asymptomatic isolated microscopic hematuria, which by definition is unaccompanied by proteinuria or kidney abnormalities and unrelated to any systemic condition. By using mandatory military service records, the researchers assessed medical data on over 1.2 million Israelis who were aged 16-25 years at induction in 1975-1997 and who were followed for about 22 years.

Study subjects were initially screened by urinary dipstick test. In those with positive results for hematuria, urinary sediment was examined by microscopy. A total of 3,690 of these young men and women (0.3% of the cohort) were found to have persistent asymptomatic isolated hematuria.

The investigators then used a national end-stage renal disease (ESRD) database to identify all patients receiving any form of renal replacement therapy from 1980 through 2010. During follow-up, 565 members of the study cohort were treated for ESRD.

The incidence of ESRD was 34 per 100,000 person-years for subjects who had had hematuria in adolescence and young adulthood, a strikingly higher rate than the 2.05 cases per 100,000 person-years for subjects who had not had hematuria, Dr. Vivante and his associates said (JAMA 2011;306:729-36).

A total of 0.7% of subjects with hematuria in adolescence developed ESRD, compared with 0.04% of those without hematuria, yielding an unadjusted hazard ratio of 19.5. When the data were adjusted to account for factors that might influence kidney function, such as subject age, sex, BMI, and blood pressure, there was no significant change in the estimated HR (18.5).

In addition, study subjects who had hematuria in adolescence were considerably younger at the onset of ESRD (34 years) than were subjects without hematuria during their youth (38 years).

When the cases of ESRD were categorized by nine possible causes – diabetes, hypertension, glomerulonephritis, hereditary nephritis, interstitial nephritis, cystic kidney disease, secondary glomerulonephritis, drug-induced, and other causes – the clear majority of cases among subjects who had hematuria in adolescence were found to be due to glomerular disease.

"Our findings suggest that persistent asymptomatic isolated microscopic hematuria detected during adolescence and young adulthood is an early marker for primary glomerular injury and may be the first sign of an occult renal disease," the researchers said.

They added that follow-up in this study ended well before subjects reached the age at which ESRD incidence peaks, so their calculations likely underestimate the true significance of hematuria as a predictor for the disease.

Since this study involved only Jewish subjects, the results may not be generalizable to other racial/ethnic groups, and confirmation of these results should be sought in other populations.

"Future studies [also] are warranted to evaluate the utility of population screening in improving clinical outcomes," they noted.

This study was supported by the Israel Defense Forces Medical Corps and the Israeli Ministry of Health. No financial conflicts of interest were reported.

Persistent asymptomatic isolated microscopic hematuria in adolescence and young adulthood appears to be a strong predictor of end-stage renal disease in later adulthood, independent of other risk factors, according to a report in the Aug. 17 JAMA.

Such hematuria is frequently an incidental finding on routine examination in this age group, but its significance has been unclear. Short-term prognosis is favorable, and the condition is generally considered benign. But long-term data are lacking, and uncertainty about the implications has prompted "considerable controversy over appropriate evaluation, management, and prognosis," said Dr. Asaf Vivante of the Israeli Defense Forces Medical Corps and the Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, and his associates.

"The most recent American Academy of Pediatrics guidelines rescinded the recommendation for urine screening during the second decade of life," they noted.

They conducted a nationwide retrospective cohort study to assess the long-term outcomes of persistent asymptomatic isolated microscopic hematuria, which by definition is unaccompanied by proteinuria or kidney abnormalities and unrelated to any systemic condition. By using mandatory military service records, the researchers assessed medical data on over 1.2 million Israelis who were aged 16-25 years at induction in 1975-1997 and who were followed for about 22 years.

Study subjects were initially screened by urinary dipstick test. In those with positive results for hematuria, urinary sediment was examined by microscopy. A total of 3,690 of these young men and women (0.3% of the cohort) were found to have persistent asymptomatic isolated hematuria.

The investigators then used a national end-stage renal disease (ESRD) database to identify all patients receiving any form of renal replacement therapy from 1980 through 2010. During follow-up, 565 members of the study cohort were treated for ESRD.

The incidence of ESRD was 34 per 100,000 person-years for subjects who had had hematuria in adolescence and young adulthood, a strikingly higher rate than the 2.05 cases per 100,000 person-years for subjects who had not had hematuria, Dr. Vivante and his associates said (JAMA 2011;306:729-36).

A total of 0.7% of subjects with hematuria in adolescence developed ESRD, compared with 0.04% of those without hematuria, yielding an unadjusted hazard ratio of 19.5. When the data were adjusted to account for factors that might influence kidney function, such as subject age, sex, BMI, and blood pressure, there was no significant change in the estimated HR (18.5).

In addition, study subjects who had hematuria in adolescence were considerably younger at the onset of ESRD (34 years) than were subjects without hematuria during their youth (38 years).

When the cases of ESRD were categorized by nine possible causes – diabetes, hypertension, glomerulonephritis, hereditary nephritis, interstitial nephritis, cystic kidney disease, secondary glomerulonephritis, drug-induced, and other causes – the clear majority of cases among subjects who had hematuria in adolescence were found to be due to glomerular disease.

"Our findings suggest that persistent asymptomatic isolated microscopic hematuria detected during adolescence and young adulthood is an early marker for primary glomerular injury and may be the first sign of an occult renal disease," the researchers said.

They added that follow-up in this study ended well before subjects reached the age at which ESRD incidence peaks, so their calculations likely underestimate the true significance of hematuria as a predictor for the disease.

Since this study involved only Jewish subjects, the results may not be generalizable to other racial/ethnic groups, and confirmation of these results should be sought in other populations.

"Future studies [also] are warranted to evaluate the utility of population screening in improving clinical outcomes," they noted.

This study was supported by the Israel Defense Forces Medical Corps and the Israeli Ministry of Health. No financial conflicts of interest were reported.

Persistent asymptomatic isolated microscopic hematuria in adolescence and young adulthood appears to be a strong predictor of end-stage renal disease in later adulthood, independent of other risk factors, according to a report in the Aug. 17 JAMA.

Such hematuria is frequently an incidental finding on routine examination in this age group, but its significance has been unclear. Short-term prognosis is favorable, and the condition is generally considered benign. But long-term data are lacking, and uncertainty about the implications has prompted "considerable controversy over appropriate evaluation, management, and prognosis," said Dr. Asaf Vivante of the Israeli Defense Forces Medical Corps and the Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, and his associates.

"The most recent American Academy of Pediatrics guidelines rescinded the recommendation for urine screening during the second decade of life," they noted.

They conducted a nationwide retrospective cohort study to assess the long-term outcomes of persistent asymptomatic isolated microscopic hematuria, which by definition is unaccompanied by proteinuria or kidney abnormalities and unrelated to any systemic condition. By using mandatory military service records, the researchers assessed medical data on over 1.2 million Israelis who were aged 16-25 years at induction in 1975-1997 and who were followed for about 22 years.

Study subjects were initially screened by urinary dipstick test. In those with positive results for hematuria, urinary sediment was examined by microscopy. A total of 3,690 of these young men and women (0.3% of the cohort) were found to have persistent asymptomatic isolated hematuria.

The investigators then used a national end-stage renal disease (ESRD) database to identify all patients receiving any form of renal replacement therapy from 1980 through 2010. During follow-up, 565 members of the study cohort were treated for ESRD.

The incidence of ESRD was 34 per 100,000 person-years for subjects who had had hematuria in adolescence and young adulthood, a strikingly higher rate than the 2.05 cases per 100,000 person-years for subjects who had not had hematuria, Dr. Vivante and his associates said (JAMA 2011;306:729-36).

A total of 0.7% of subjects with hematuria in adolescence developed ESRD, compared with 0.04% of those without hematuria, yielding an unadjusted hazard ratio of 19.5. When the data were adjusted to account for factors that might influence kidney function, such as subject age, sex, BMI, and blood pressure, there was no significant change in the estimated HR (18.5).

In addition, study subjects who had hematuria in adolescence were considerably younger at the onset of ESRD (34 years) than were subjects without hematuria during their youth (38 years).

When the cases of ESRD were categorized by nine possible causes – diabetes, hypertension, glomerulonephritis, hereditary nephritis, interstitial nephritis, cystic kidney disease, secondary glomerulonephritis, drug-induced, and other causes – the clear majority of cases among subjects who had hematuria in adolescence were found to be due to glomerular disease.

"Our findings suggest that persistent asymptomatic isolated microscopic hematuria detected during adolescence and young adulthood is an early marker for primary glomerular injury and may be the first sign of an occult renal disease," the researchers said.

They added that follow-up in this study ended well before subjects reached the age at which ESRD incidence peaks, so their calculations likely underestimate the true significance of hematuria as a predictor for the disease.

Since this study involved only Jewish subjects, the results may not be generalizable to other racial/ethnic groups, and confirmation of these results should be sought in other populations.

"Future studies [also] are warranted to evaluate the utility of population screening in improving clinical outcomes," they noted.

This study was supported by the Israel Defense Forces Medical Corps and the Israeli Ministry of Health. No financial conflicts of interest were reported.