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High BMI appears to cause gallstones
An elevated body mass index is not just associated with symptomatic gallstone disease, it appears to cause the disease, according to a report published in Hepatology (doi:10.1002/hep.26563).
Many epidemiologic and observational studies have noted a clear association between a high BMI and an increased risk for gallstones, but have not been able to pin down a causal effect. It was impossible to rule out confounding by some other factor, such as a high-fat diet, that simultaneously caused both the elevation in BMI and the elevation in risk for gallstones. Similarly, it was impossible to rule out reverse causation, such as the colicky pain of gallstone disease caused the physical inactivity that then led to a high BMI.
A new epidemiologic statistical approach known as Mendelian randomization is thought to avert both confounding and reverse causation by pinpointing the genetic variants that are linked to a high BMI (which are a constant throughout the lifespan) but that are not related to confounding factors, then determining whether they are also linked to gallstone disease. "If raised BMI truly is a causal factor in the development of gallstone disease, genetic variants that increase BMI would be expected to also increase risk of gallstone disease," said Dr. Stefan Stender of the department of clinical biochemistry, Rigshospitalet, University of Copenhagen, and his associates.
They studied 77,679 Danish adults from the general population who participated in two large prospective studies: the Copenhagen General Population Study (67,314 subjects) and the Copenhagen City Heart Study (10,365 subjects). All the participants had donated blood samples that could be used for DNA extraction and genotyping.
A total of 4,106 of these subjects developed symptomatic gallstone disease during follow-up of up to 34 years.
The researchers used genotyping to identify study subjects who carried any of the three polymorphisms that have the largest known effect sizes for association with BMI in European populations: FTO (rs9939609), MC4R (rs17782313), or TMEM18 (rs6548238). Each of these can be carried on two possible alleles, so any given subject could carry one to six affected alleles. The number of BMI-increasing alleles, from one to six, was determined for each study subject.
In an initial analysis of the data, the mean baseline BMI was 55% higher (11 kg/m2) in subjects carrying the most alleles compared with those carrying the fewest.
Increasing BMI was associated with a stepwise increase in the risk of developing symptomatic gallstone disease.
In the overall cohort, the risk of symptomatic gallstone disease was increased 7% for every 1-kg/m2 increase in BMI. In the Mendelian randomization cohort, the risk of gallstone disease increased 17% with every 1-kg/m2 increase in BMI. The concordance between these two estimates indicates that BMI itself is a causal risk factor for symptomatic gallstone disease, Dr. Stender and his associates said.
This study did not include data on gallstone composition and was not designed to examine the pathophysiologic mechanisms by which a high BMI causes gallstone formation. However, numerous other studies have proposed several possible mechanisms, they noted.
Obesity may raise cholesterol synthesis and hepatobiliary cholesterol efflux, "a key event in the development of cholesterol gallstones." High abdominal fat mass may induce gallbladder hypomotility and bile stasis, "another risk factor for gallstone formation."
In addition, substances secreted by or metabolized by adipocytes could influence gallstone formation. For example, estrogen is produced by adipocytes and may promote gallstone formation by raising the rate of hepatobiliary cholesterol efflux. And leptin, which is also secreted by adipocytes, may have lithogenic effects.
Adinopectin, another hormone secreted by adipocytes, has been linked to gallstones in both animal and human studies. And obesity-associated hyperinsulinemia may induce gallstone formation by causing the secretion of more lithogenic bile.
This study was limited in that it included only white people of Danish descent. "Because ethnic differences in gallstone prevalence are well known, the results reported here may not necessarily translate to other ethnicities," Dr. Stender and his colleagues said.
This study was supported by the Danish Medical Research Council, the Rigshospitalet at Copenhagen University, and the Odd Fellow Order. No financial conflicts of interest were reported.
An elevated body mass index is not just associated with symptomatic gallstone disease, it appears to cause the disease, according to a report published in Hepatology (doi:10.1002/hep.26563).
Many epidemiologic and observational studies have noted a clear association between a high BMI and an increased risk for gallstones, but have not been able to pin down a causal effect. It was impossible to rule out confounding by some other factor, such as a high-fat diet, that simultaneously caused both the elevation in BMI and the elevation in risk for gallstones. Similarly, it was impossible to rule out reverse causation, such as the colicky pain of gallstone disease caused the physical inactivity that then led to a high BMI.
A new epidemiologic statistical approach known as Mendelian randomization is thought to avert both confounding and reverse causation by pinpointing the genetic variants that are linked to a high BMI (which are a constant throughout the lifespan) but that are not related to confounding factors, then determining whether they are also linked to gallstone disease. "If raised BMI truly is a causal factor in the development of gallstone disease, genetic variants that increase BMI would be expected to also increase risk of gallstone disease," said Dr. Stefan Stender of the department of clinical biochemistry, Rigshospitalet, University of Copenhagen, and his associates.
They studied 77,679 Danish adults from the general population who participated in two large prospective studies: the Copenhagen General Population Study (67,314 subjects) and the Copenhagen City Heart Study (10,365 subjects). All the participants had donated blood samples that could be used for DNA extraction and genotyping.
A total of 4,106 of these subjects developed symptomatic gallstone disease during follow-up of up to 34 years.
The researchers used genotyping to identify study subjects who carried any of the three polymorphisms that have the largest known effect sizes for association with BMI in European populations: FTO (rs9939609), MC4R (rs17782313), or TMEM18 (rs6548238). Each of these can be carried on two possible alleles, so any given subject could carry one to six affected alleles. The number of BMI-increasing alleles, from one to six, was determined for each study subject.
In an initial analysis of the data, the mean baseline BMI was 55% higher (11 kg/m2) in subjects carrying the most alleles compared with those carrying the fewest.
Increasing BMI was associated with a stepwise increase in the risk of developing symptomatic gallstone disease.
In the overall cohort, the risk of symptomatic gallstone disease was increased 7% for every 1-kg/m2 increase in BMI. In the Mendelian randomization cohort, the risk of gallstone disease increased 17% with every 1-kg/m2 increase in BMI. The concordance between these two estimates indicates that BMI itself is a causal risk factor for symptomatic gallstone disease, Dr. Stender and his associates said.
This study did not include data on gallstone composition and was not designed to examine the pathophysiologic mechanisms by which a high BMI causes gallstone formation. However, numerous other studies have proposed several possible mechanisms, they noted.
Obesity may raise cholesterol synthesis and hepatobiliary cholesterol efflux, "a key event in the development of cholesterol gallstones." High abdominal fat mass may induce gallbladder hypomotility and bile stasis, "another risk factor for gallstone formation."
In addition, substances secreted by or metabolized by adipocytes could influence gallstone formation. For example, estrogen is produced by adipocytes and may promote gallstone formation by raising the rate of hepatobiliary cholesterol efflux. And leptin, which is also secreted by adipocytes, may have lithogenic effects.
Adinopectin, another hormone secreted by adipocytes, has been linked to gallstones in both animal and human studies. And obesity-associated hyperinsulinemia may induce gallstone formation by causing the secretion of more lithogenic bile.
This study was limited in that it included only white people of Danish descent. "Because ethnic differences in gallstone prevalence are well known, the results reported here may not necessarily translate to other ethnicities," Dr. Stender and his colleagues said.
This study was supported by the Danish Medical Research Council, the Rigshospitalet at Copenhagen University, and the Odd Fellow Order. No financial conflicts of interest were reported.
An elevated body mass index is not just associated with symptomatic gallstone disease, it appears to cause the disease, according to a report published in Hepatology (doi:10.1002/hep.26563).
Many epidemiologic and observational studies have noted a clear association between a high BMI and an increased risk for gallstones, but have not been able to pin down a causal effect. It was impossible to rule out confounding by some other factor, such as a high-fat diet, that simultaneously caused both the elevation in BMI and the elevation in risk for gallstones. Similarly, it was impossible to rule out reverse causation, such as the colicky pain of gallstone disease caused the physical inactivity that then led to a high BMI.
A new epidemiologic statistical approach known as Mendelian randomization is thought to avert both confounding and reverse causation by pinpointing the genetic variants that are linked to a high BMI (which are a constant throughout the lifespan) but that are not related to confounding factors, then determining whether they are also linked to gallstone disease. "If raised BMI truly is a causal factor in the development of gallstone disease, genetic variants that increase BMI would be expected to also increase risk of gallstone disease," said Dr. Stefan Stender of the department of clinical biochemistry, Rigshospitalet, University of Copenhagen, and his associates.
They studied 77,679 Danish adults from the general population who participated in two large prospective studies: the Copenhagen General Population Study (67,314 subjects) and the Copenhagen City Heart Study (10,365 subjects). All the participants had donated blood samples that could be used for DNA extraction and genotyping.
A total of 4,106 of these subjects developed symptomatic gallstone disease during follow-up of up to 34 years.
The researchers used genotyping to identify study subjects who carried any of the three polymorphisms that have the largest known effect sizes for association with BMI in European populations: FTO (rs9939609), MC4R (rs17782313), or TMEM18 (rs6548238). Each of these can be carried on two possible alleles, so any given subject could carry one to six affected alleles. The number of BMI-increasing alleles, from one to six, was determined for each study subject.
In an initial analysis of the data, the mean baseline BMI was 55% higher (11 kg/m2) in subjects carrying the most alleles compared with those carrying the fewest.
Increasing BMI was associated with a stepwise increase in the risk of developing symptomatic gallstone disease.
In the overall cohort, the risk of symptomatic gallstone disease was increased 7% for every 1-kg/m2 increase in BMI. In the Mendelian randomization cohort, the risk of gallstone disease increased 17% with every 1-kg/m2 increase in BMI. The concordance between these two estimates indicates that BMI itself is a causal risk factor for symptomatic gallstone disease, Dr. Stender and his associates said.
This study did not include data on gallstone composition and was not designed to examine the pathophysiologic mechanisms by which a high BMI causes gallstone formation. However, numerous other studies have proposed several possible mechanisms, they noted.
Obesity may raise cholesterol synthesis and hepatobiliary cholesterol efflux, "a key event in the development of cholesterol gallstones." High abdominal fat mass may induce gallbladder hypomotility and bile stasis, "another risk factor for gallstone formation."
In addition, substances secreted by or metabolized by adipocytes could influence gallstone formation. For example, estrogen is produced by adipocytes and may promote gallstone formation by raising the rate of hepatobiliary cholesterol efflux. And leptin, which is also secreted by adipocytes, may have lithogenic effects.
Adinopectin, another hormone secreted by adipocytes, has been linked to gallstones in both animal and human studies. And obesity-associated hyperinsulinemia may induce gallstone formation by causing the secretion of more lithogenic bile.
This study was limited in that it included only white people of Danish descent. "Because ethnic differences in gallstone prevalence are well known, the results reported here may not necessarily translate to other ethnicities," Dr. Stender and his colleagues said.
This study was supported by the Danish Medical Research Council, the Rigshospitalet at Copenhagen University, and the Odd Fellow Order. No financial conflicts of interest were reported.
FROM HEPATOLOGY
Major finding: In the overall cohort, the risk of symptomatic gallstone disease was increased 7% for every 1-kg/m2 increase in BMI, and in the Mendelian randomization cohort, the risk of gallstone disease increased 17% with every 1-kg/m2 increase in BMI.
Data source: A Mendelian randomization study involving 77,679 adults from the Danish general population who were genotyped to identify carriers of three BMI-increasing polymorphisms and who were followed for up to 34 years for the development of symptomatic gallstone disease.
Disclosures: This study was supported by the Danish Medical Research Council, the Rigshospitalet at Copenhagen University, and the Odd Fellow Order. No financial conflicts of interest were reported.
'Decision aids' inform men but don’t alter prostate screening rate
Both a printed and a web-based interactive "decision aid" for prostate cancer screening improved men’s understanding of the risks and benefits of screening, compared with usual care, according to a report published online July 29 in JAMA Internal Medicine.
However, neither form of decision aid altered the rate of prostate cancer screening 1 year later, said Kathryn L. Taylor, Ph.D., of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, and her associates.
Decision aids are tools for informing patients about a medical condition – in this case, prostate cancer – and reviewing the possible benefits, harms, and scientific uncertainties regarding screening options. These aids are particularly useful when there are trade-offs between risks and benefits; the efficacy and outcomes of screening are unclear; and/or overdiagnosis and overtreatment are genuine concerns – all of which apply to prostate cancer screening.
"Most men overestimate the benefits of prostate cancer screening and are unaware of its limitations," the investigators said.
Decision aids are not intended to either encourage or discourage screening. Instead, they "present the benefits and limitations of screening to help men make choices consistent with their preferences."
Dr. Taylor and her colleagues performed a randomized clinical trial to compare the usefulness of two decision aids against usual care in the long-term (1-year) choice to participate in or refrain from prostate cancer screening. The study subjects were 1,879 outpatients aged 45-70 years, who were recruited from any one of three Washington, D.C., health systems.
This study population was one of the largest and most representative to date to participate in a randomized trial of this issue. African Americans accounted for 40% of the subjects, and about 24% were from lower socioeconomic backgrounds, the investigators noted.
The two decision aids had identical content and were presented at an eighth-grade reading level. Both included general information about the prostate gland, as well as descriptions of screening tests and possible results. They covered treatment options and possible adverse effects, and they reviewed the risk factors for prostate cancer.
Both decision aids encouraged the men to discuss screening with a physician. They also included a values clarification tool and references for further information.
The web-based interactive decision aid had, in addition to these, a narrator who read most of the text aloud, pop-up definitions of medical terms, video testimonials, and animation.
The study subjects were randomly assigned to receive the print decision aid (628 men), the web-based decision aid (625 men), or usual care (626 men). They were assessed at baseline, 1 month after study assignment, and 13 months after study assignment for their knowledge of prostate cancer and prostate cancer testing; the controversy over screening; risk factors; and the benefits and limitations of treatment.
Subjects also reported the conflict they experienced over the decision to participate in or abstain from prostate cancer screening, as well as their satisfaction regarding their most recent decision to either participate in or abstain from screening.
At the 13-month assessment, the subjects also reported whether they had undergone a PSA test, a digital rectal exam, or both during the 1-year follow-up period.
Both decision aids were more effective than usual care in increasing the subjects’ knowledge and reducing their decisional conflict, with effect sizes indicating clinically significant differences, Dr. Taylor and her associates reported (JAMA Intern. Med. 2013 July 29 [doi: 10.1001/jamainternmed.2013.9523]).
This is the first study to find reduced decisional conflict for a year following a decision-aid intervention, and suggests that these tools help men to remain certain about their screening choice.
Even though 90% of the men said that they had access to the Internet and 67% said they used it daily, the web-based decision aid was not significantly more effective than the print decision aid at imparting knowledge or reducing decisional conflict. "In fact, participants in the print arm [of the study] reported significantly greater satisfaction than those in the web arm at the 1-month assessment," the researchers said.
"These results call into question the widespread assumption that interactive, web-based delivery necessarily leads to better outcomes," they added.
At the end of follow-up, 58.3% of the study subjects reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced.
There also were no significant differences in rates of screening among men given the print decision aid, those given the web-based decision aid, and those given usual care.
These findings suggest that the decision aids offer neutrality and don’t influence the choice of whether or not to undergo screening, "which allows patients and providers to individualize the decision," Dr. Taylor and her associates said.
It remains critical to assist men in making informed decisions regarding screening for prostate cancer, because of the conflicting recommendations for screening and the mixed messages about its effectiveness, they added.
This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.
Both a printed and a web-based interactive "decision aid" for prostate cancer screening improved men’s understanding of the risks and benefits of screening, compared with usual care, according to a report published online July 29 in JAMA Internal Medicine.
However, neither form of decision aid altered the rate of prostate cancer screening 1 year later, said Kathryn L. Taylor, Ph.D., of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, and her associates.
Decision aids are tools for informing patients about a medical condition – in this case, prostate cancer – and reviewing the possible benefits, harms, and scientific uncertainties regarding screening options. These aids are particularly useful when there are trade-offs between risks and benefits; the efficacy and outcomes of screening are unclear; and/or overdiagnosis and overtreatment are genuine concerns – all of which apply to prostate cancer screening.
"Most men overestimate the benefits of prostate cancer screening and are unaware of its limitations," the investigators said.
Decision aids are not intended to either encourage or discourage screening. Instead, they "present the benefits and limitations of screening to help men make choices consistent with their preferences."
Dr. Taylor and her colleagues performed a randomized clinical trial to compare the usefulness of two decision aids against usual care in the long-term (1-year) choice to participate in or refrain from prostate cancer screening. The study subjects were 1,879 outpatients aged 45-70 years, who were recruited from any one of three Washington, D.C., health systems.
This study population was one of the largest and most representative to date to participate in a randomized trial of this issue. African Americans accounted for 40% of the subjects, and about 24% were from lower socioeconomic backgrounds, the investigators noted.
The two decision aids had identical content and were presented at an eighth-grade reading level. Both included general information about the prostate gland, as well as descriptions of screening tests and possible results. They covered treatment options and possible adverse effects, and they reviewed the risk factors for prostate cancer.
Both decision aids encouraged the men to discuss screening with a physician. They also included a values clarification tool and references for further information.
The web-based interactive decision aid had, in addition to these, a narrator who read most of the text aloud, pop-up definitions of medical terms, video testimonials, and animation.
The study subjects were randomly assigned to receive the print decision aid (628 men), the web-based decision aid (625 men), or usual care (626 men). They were assessed at baseline, 1 month after study assignment, and 13 months after study assignment for their knowledge of prostate cancer and prostate cancer testing; the controversy over screening; risk factors; and the benefits and limitations of treatment.
Subjects also reported the conflict they experienced over the decision to participate in or abstain from prostate cancer screening, as well as their satisfaction regarding their most recent decision to either participate in or abstain from screening.
At the 13-month assessment, the subjects also reported whether they had undergone a PSA test, a digital rectal exam, or both during the 1-year follow-up period.
Both decision aids were more effective than usual care in increasing the subjects’ knowledge and reducing their decisional conflict, with effect sizes indicating clinically significant differences, Dr. Taylor and her associates reported (JAMA Intern. Med. 2013 July 29 [doi: 10.1001/jamainternmed.2013.9523]).
This is the first study to find reduced decisional conflict for a year following a decision-aid intervention, and suggests that these tools help men to remain certain about their screening choice.
Even though 90% of the men said that they had access to the Internet and 67% said they used it daily, the web-based decision aid was not significantly more effective than the print decision aid at imparting knowledge or reducing decisional conflict. "In fact, participants in the print arm [of the study] reported significantly greater satisfaction than those in the web arm at the 1-month assessment," the researchers said.
"These results call into question the widespread assumption that interactive, web-based delivery necessarily leads to better outcomes," they added.
At the end of follow-up, 58.3% of the study subjects reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced.
There also were no significant differences in rates of screening among men given the print decision aid, those given the web-based decision aid, and those given usual care.
These findings suggest that the decision aids offer neutrality and don’t influence the choice of whether or not to undergo screening, "which allows patients and providers to individualize the decision," Dr. Taylor and her associates said.
It remains critical to assist men in making informed decisions regarding screening for prostate cancer, because of the conflicting recommendations for screening and the mixed messages about its effectiveness, they added.
This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.
Both a printed and a web-based interactive "decision aid" for prostate cancer screening improved men’s understanding of the risks and benefits of screening, compared with usual care, according to a report published online July 29 in JAMA Internal Medicine.
However, neither form of decision aid altered the rate of prostate cancer screening 1 year later, said Kathryn L. Taylor, Ph.D., of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, and her associates.
Decision aids are tools for informing patients about a medical condition – in this case, prostate cancer – and reviewing the possible benefits, harms, and scientific uncertainties regarding screening options. These aids are particularly useful when there are trade-offs between risks and benefits; the efficacy and outcomes of screening are unclear; and/or overdiagnosis and overtreatment are genuine concerns – all of which apply to prostate cancer screening.
"Most men overestimate the benefits of prostate cancer screening and are unaware of its limitations," the investigators said.
Decision aids are not intended to either encourage or discourage screening. Instead, they "present the benefits and limitations of screening to help men make choices consistent with their preferences."
Dr. Taylor and her colleagues performed a randomized clinical trial to compare the usefulness of two decision aids against usual care in the long-term (1-year) choice to participate in or refrain from prostate cancer screening. The study subjects were 1,879 outpatients aged 45-70 years, who were recruited from any one of three Washington, D.C., health systems.
This study population was one of the largest and most representative to date to participate in a randomized trial of this issue. African Americans accounted for 40% of the subjects, and about 24% were from lower socioeconomic backgrounds, the investigators noted.
The two decision aids had identical content and were presented at an eighth-grade reading level. Both included general information about the prostate gland, as well as descriptions of screening tests and possible results. They covered treatment options and possible adverse effects, and they reviewed the risk factors for prostate cancer.
Both decision aids encouraged the men to discuss screening with a physician. They also included a values clarification tool and references for further information.
The web-based interactive decision aid had, in addition to these, a narrator who read most of the text aloud, pop-up definitions of medical terms, video testimonials, and animation.
The study subjects were randomly assigned to receive the print decision aid (628 men), the web-based decision aid (625 men), or usual care (626 men). They were assessed at baseline, 1 month after study assignment, and 13 months after study assignment for their knowledge of prostate cancer and prostate cancer testing; the controversy over screening; risk factors; and the benefits and limitations of treatment.
Subjects also reported the conflict they experienced over the decision to participate in or abstain from prostate cancer screening, as well as their satisfaction regarding their most recent decision to either participate in or abstain from screening.
At the 13-month assessment, the subjects also reported whether they had undergone a PSA test, a digital rectal exam, or both during the 1-year follow-up period.
Both decision aids were more effective than usual care in increasing the subjects’ knowledge and reducing their decisional conflict, with effect sizes indicating clinically significant differences, Dr. Taylor and her associates reported (JAMA Intern. Med. 2013 July 29 [doi: 10.1001/jamainternmed.2013.9523]).
This is the first study to find reduced decisional conflict for a year following a decision-aid intervention, and suggests that these tools help men to remain certain about their screening choice.
Even though 90% of the men said that they had access to the Internet and 67% said they used it daily, the web-based decision aid was not significantly more effective than the print decision aid at imparting knowledge or reducing decisional conflict. "In fact, participants in the print arm [of the study] reported significantly greater satisfaction than those in the web arm at the 1-month assessment," the researchers said.
"These results call into question the widespread assumption that interactive, web-based delivery necessarily leads to better outcomes," they added.
At the end of follow-up, 58.3% of the study subjects reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced.
There also were no significant differences in rates of screening among men given the print decision aid, those given the web-based decision aid, and those given usual care.
These findings suggest that the decision aids offer neutrality and don’t influence the choice of whether or not to undergo screening, "which allows patients and providers to individualize the decision," Dr. Taylor and her associates said.
It remains critical to assist men in making informed decisions regarding screening for prostate cancer, because of the conflicting recommendations for screening and the mixed messages about its effectiveness, they added.
This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.
FROM JAMA INTERNAL MEDICINE
Major finding: Regardless of whether study subjects reviewed a printed or a web-based decision aid, 58.3% reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced
Data source: A randomized controlled trial that involved 1,879 men and compared their knowledge about prostate cancer and the screening controversy after being given usual care, a printed decision aid, or a web-based interactive decision aid.
Disclosures: This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.
Glucose, insulin measures unrelated to AD pathology
Serial measures of glucose and insulin homeostasis taken over 20 years’ time show no association with the development of Alzheimer’s disease symptoms or pathology, according to a report published July 29 in JAMA Neurology.
These findings, from a large, prospective, cohort study that included multiple physical and cognitive assessments during middle and old age as well as autopsy results, indicate that glucose intolerance and insulin resistance likely do not play a role in Alzheimer’s disease (AD) pathogenesis, said Dr. Madhav Thambisetty of the National Institute on Aging, Baltimore, and his associates.
"Our results concur with other studies that found no association between diabetes mellitus and AD pathology, and we extend these observations more broadly to include hyperglycemia and insulin resistance," they noted.
Dr. Thambisetty and his colleagues used data from the Baltimore Longitudinal Study of Aging (BLSA) to examine the assertion that diabetes and glucose intolerance may be risk factors for AD. Some studies have reported excess cognitive impairment and lower cognitive performance in patients with metabolic derangements, as well as a doubling of the risk for AD in those with full-blown diabetes. Other studies have not confirmed any such links.
The BLSA is a longitudinal study involving older men and women who undergo periodic oral glucose tolerance testing (OGTT) as part of serial comprehensive physical examinations, as well as periodic neurologic examination and neuropsychological testing. The BLSA includes an autopsy substudy of subjects who agreed to postmortem brain examinations and a neuroimaging substudy of subjects who had periodic in-vivo assessment of fibrillar amyloid-beta levels using carbon-11-labeled Pittsburgh Compound B (C-PiB).
For their analysis, Dr. Thambisetty and his associates focused on 197 subjects who were cognitively and neurologically normal at study entry and were aged at least 69 years at the time of death (mean age at death was 88 years). During a mean follow-up period of 22 years, the participants underwent at least two OGTTs during follow-up, and 53 also underwent C-PiB brain imaging. All participants underwent brain autopsy that included quantification of beta-amyloid plaques. Overall, 95% of subjects in the study were white.
The study design, with its serial assessments over a long period of time, allowed the investigators "to determine the effect of prolonged burdens of hyperglycemia and insulin resistance on pathological findings in the brain." The study results indicate that these metabolic measures show no association with AD pathology even at its earliest stages, they said.
In the first analysis of the data, the 197 study subjects were divided into tertiles according to mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values. The investigators found no significant difference among these groups in any measure of AD pathology.
A further analysis of individual, rather than grouped glucose and insulin measures also found no significant association between any measure of AD pathology and any measure of glucose or insulin homeostasis after controlling for the effects of age and sex at death.
A third analysis that examined the rates of change in glucose and insulin values over the lifetime of each participant also showed no significant differences among subjects with low, medium, or high AD pathology scores, the investigators said (JAMA Neurol. 2013 July 29 [doi:10.1001/jamaneurol.2013.284]).
When the participants were categorized by the absence (96 subjects) or presence (101 subjects) of dementia, there were no significant differences in mean nondementia/dementia values for fasting glucose (100/98 mg per dL), fasting insulin (9.6/9.0 micro IU/mL), fasting homeostasis modeling assessment (HOMA, 2.4/2.2), 120-minute glucose (156/149 mg per dL), 120-minute insulin (63/57 micro IU/mL), and 120-minute HOMA (25/22).
In the subgroup of subjects who underwent periodic C-PiB brain scanning, no significant differences were found in beta-amyloid deposition between those with the highest and those with the lowest mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values.
In addition, there was no significant difference between subjects with the highest and those with the lowest levels of beta-amyloid deposition in glucose metabolism or insulin resistance. And there were no differences in metabolic measures when the analysis was restricted to beta-amyloid deposition in the posterior cingulate/precuneus and the medial temporal lobe, "two areas where fibrillar beta-amyloid is deposited early in the course of AD," Dr. Thambisetty and his colleagues wrote.
When the investigators limited their analyses to metabolic measures obtained at relatively younger ages (mean age of 53 years), they found no significant relationship between AD pathology and glucose, insulin, and insulin resistance.
In a final analysis, the researchers focused on the 30 subjects who had been taking diabetes medications at the time of death and who had undergone autopsy. "We found no significant difference in any measure of AD pathology, whether or not the participant was taking the medication," they wrote.
It is possible that insulin resistance within the brain doesn’t correlate with peripheral measures of insulin resistance, so further study of this question is warranted. Moreover, AD is a complex process that involves more than just beta-amyloid accumulation, so "long-term therapeutic trials [also] are important to elucidate this issue," the investigators added.
This study was supported by the National Institute on Aging and the Burroughs Wellcome Fund for Translational Research. No financial conflicts of interest were reported.
Serial measures of glucose and insulin homeostasis taken over 20 years’ time show no association with the development of Alzheimer’s disease symptoms or pathology, according to a report published July 29 in JAMA Neurology.
These findings, from a large, prospective, cohort study that included multiple physical and cognitive assessments during middle and old age as well as autopsy results, indicate that glucose intolerance and insulin resistance likely do not play a role in Alzheimer’s disease (AD) pathogenesis, said Dr. Madhav Thambisetty of the National Institute on Aging, Baltimore, and his associates.
"Our results concur with other studies that found no association between diabetes mellitus and AD pathology, and we extend these observations more broadly to include hyperglycemia and insulin resistance," they noted.
Dr. Thambisetty and his colleagues used data from the Baltimore Longitudinal Study of Aging (BLSA) to examine the assertion that diabetes and glucose intolerance may be risk factors for AD. Some studies have reported excess cognitive impairment and lower cognitive performance in patients with metabolic derangements, as well as a doubling of the risk for AD in those with full-blown diabetes. Other studies have not confirmed any such links.
The BLSA is a longitudinal study involving older men and women who undergo periodic oral glucose tolerance testing (OGTT) as part of serial comprehensive physical examinations, as well as periodic neurologic examination and neuropsychological testing. The BLSA includes an autopsy substudy of subjects who agreed to postmortem brain examinations and a neuroimaging substudy of subjects who had periodic in-vivo assessment of fibrillar amyloid-beta levels using carbon-11-labeled Pittsburgh Compound B (C-PiB).
For their analysis, Dr. Thambisetty and his associates focused on 197 subjects who were cognitively and neurologically normal at study entry and were aged at least 69 years at the time of death (mean age at death was 88 years). During a mean follow-up period of 22 years, the participants underwent at least two OGTTs during follow-up, and 53 also underwent C-PiB brain imaging. All participants underwent brain autopsy that included quantification of beta-amyloid plaques. Overall, 95% of subjects in the study were white.
The study design, with its serial assessments over a long period of time, allowed the investigators "to determine the effect of prolonged burdens of hyperglycemia and insulin resistance on pathological findings in the brain." The study results indicate that these metabolic measures show no association with AD pathology even at its earliest stages, they said.
In the first analysis of the data, the 197 study subjects were divided into tertiles according to mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values. The investigators found no significant difference among these groups in any measure of AD pathology.
A further analysis of individual, rather than grouped glucose and insulin measures also found no significant association between any measure of AD pathology and any measure of glucose or insulin homeostasis after controlling for the effects of age and sex at death.
A third analysis that examined the rates of change in glucose and insulin values over the lifetime of each participant also showed no significant differences among subjects with low, medium, or high AD pathology scores, the investigators said (JAMA Neurol. 2013 July 29 [doi:10.1001/jamaneurol.2013.284]).
When the participants were categorized by the absence (96 subjects) or presence (101 subjects) of dementia, there were no significant differences in mean nondementia/dementia values for fasting glucose (100/98 mg per dL), fasting insulin (9.6/9.0 micro IU/mL), fasting homeostasis modeling assessment (HOMA, 2.4/2.2), 120-minute glucose (156/149 mg per dL), 120-minute insulin (63/57 micro IU/mL), and 120-minute HOMA (25/22).
In the subgroup of subjects who underwent periodic C-PiB brain scanning, no significant differences were found in beta-amyloid deposition between those with the highest and those with the lowest mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values.
In addition, there was no significant difference between subjects with the highest and those with the lowest levels of beta-amyloid deposition in glucose metabolism or insulin resistance. And there were no differences in metabolic measures when the analysis was restricted to beta-amyloid deposition in the posterior cingulate/precuneus and the medial temporal lobe, "two areas where fibrillar beta-amyloid is deposited early in the course of AD," Dr. Thambisetty and his colleagues wrote.
When the investigators limited their analyses to metabolic measures obtained at relatively younger ages (mean age of 53 years), they found no significant relationship between AD pathology and glucose, insulin, and insulin resistance.
In a final analysis, the researchers focused on the 30 subjects who had been taking diabetes medications at the time of death and who had undergone autopsy. "We found no significant difference in any measure of AD pathology, whether or not the participant was taking the medication," they wrote.
It is possible that insulin resistance within the brain doesn’t correlate with peripheral measures of insulin resistance, so further study of this question is warranted. Moreover, AD is a complex process that involves more than just beta-amyloid accumulation, so "long-term therapeutic trials [also] are important to elucidate this issue," the investigators added.
This study was supported by the National Institute on Aging and the Burroughs Wellcome Fund for Translational Research. No financial conflicts of interest were reported.
Serial measures of glucose and insulin homeostasis taken over 20 years’ time show no association with the development of Alzheimer’s disease symptoms or pathology, according to a report published July 29 in JAMA Neurology.
These findings, from a large, prospective, cohort study that included multiple physical and cognitive assessments during middle and old age as well as autopsy results, indicate that glucose intolerance and insulin resistance likely do not play a role in Alzheimer’s disease (AD) pathogenesis, said Dr. Madhav Thambisetty of the National Institute on Aging, Baltimore, and his associates.
"Our results concur with other studies that found no association between diabetes mellitus and AD pathology, and we extend these observations more broadly to include hyperglycemia and insulin resistance," they noted.
Dr. Thambisetty and his colleagues used data from the Baltimore Longitudinal Study of Aging (BLSA) to examine the assertion that diabetes and glucose intolerance may be risk factors for AD. Some studies have reported excess cognitive impairment and lower cognitive performance in patients with metabolic derangements, as well as a doubling of the risk for AD in those with full-blown diabetes. Other studies have not confirmed any such links.
The BLSA is a longitudinal study involving older men and women who undergo periodic oral glucose tolerance testing (OGTT) as part of serial comprehensive physical examinations, as well as periodic neurologic examination and neuropsychological testing. The BLSA includes an autopsy substudy of subjects who agreed to postmortem brain examinations and a neuroimaging substudy of subjects who had periodic in-vivo assessment of fibrillar amyloid-beta levels using carbon-11-labeled Pittsburgh Compound B (C-PiB).
For their analysis, Dr. Thambisetty and his associates focused on 197 subjects who were cognitively and neurologically normal at study entry and were aged at least 69 years at the time of death (mean age at death was 88 years). During a mean follow-up period of 22 years, the participants underwent at least two OGTTs during follow-up, and 53 also underwent C-PiB brain imaging. All participants underwent brain autopsy that included quantification of beta-amyloid plaques. Overall, 95% of subjects in the study were white.
The study design, with its serial assessments over a long period of time, allowed the investigators "to determine the effect of prolonged burdens of hyperglycemia and insulin resistance on pathological findings in the brain." The study results indicate that these metabolic measures show no association with AD pathology even at its earliest stages, they said.
In the first analysis of the data, the 197 study subjects were divided into tertiles according to mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values. The investigators found no significant difference among these groups in any measure of AD pathology.
A further analysis of individual, rather than grouped glucose and insulin measures also found no significant association between any measure of AD pathology and any measure of glucose or insulin homeostasis after controlling for the effects of age and sex at death.
A third analysis that examined the rates of change in glucose and insulin values over the lifetime of each participant also showed no significant differences among subjects with low, medium, or high AD pathology scores, the investigators said (JAMA Neurol. 2013 July 29 [doi:10.1001/jamaneurol.2013.284]).
When the participants were categorized by the absence (96 subjects) or presence (101 subjects) of dementia, there were no significant differences in mean nondementia/dementia values for fasting glucose (100/98 mg per dL), fasting insulin (9.6/9.0 micro IU/mL), fasting homeostasis modeling assessment (HOMA, 2.4/2.2), 120-minute glucose (156/149 mg per dL), 120-minute insulin (63/57 micro IU/mL), and 120-minute HOMA (25/22).
In the subgroup of subjects who underwent periodic C-PiB brain scanning, no significant differences were found in beta-amyloid deposition between those with the highest and those with the lowest mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values.
In addition, there was no significant difference between subjects with the highest and those with the lowest levels of beta-amyloid deposition in glucose metabolism or insulin resistance. And there were no differences in metabolic measures when the analysis was restricted to beta-amyloid deposition in the posterior cingulate/precuneus and the medial temporal lobe, "two areas where fibrillar beta-amyloid is deposited early in the course of AD," Dr. Thambisetty and his colleagues wrote.
When the investigators limited their analyses to metabolic measures obtained at relatively younger ages (mean age of 53 years), they found no significant relationship between AD pathology and glucose, insulin, and insulin resistance.
In a final analysis, the researchers focused on the 30 subjects who had been taking diabetes medications at the time of death and who had undergone autopsy. "We found no significant difference in any measure of AD pathology, whether or not the participant was taking the medication," they wrote.
It is possible that insulin resistance within the brain doesn’t correlate with peripheral measures of insulin resistance, so further study of this question is warranted. Moreover, AD is a complex process that involves more than just beta-amyloid accumulation, so "long-term therapeutic trials [also] are important to elucidate this issue," the investigators added.
This study was supported by the National Institute on Aging and the Burroughs Wellcome Fund for Translational Research. No financial conflicts of interest were reported.
FROM JAMA NEUROLOGY
Major finding: There were no significant differences in mean nondementia/dementia values for fasting glucose (100/98 mg/dL), fasting insulin (9.6/9.0 micro IU/mL), fasting homeostasis modeling assessment (HOMA, 2.4/2.2), 120-minute glucose (156/149 mg/dL), 120-minute insulin (63/57 micro IU/mL), and 120-minute HOMA (25/22).
Data source: A secondary analysis of data on 197 participants in the prospective Baltimore Longitudinal Study of Aging who underwent serial physical, neurological, and neuropsychological assessments during a mean follow-up period of 22 years.
Disclosures: This study was supported by the National Institute on Aging and the Burroughs Wellcome Fund for Translational Research. No financial conflicts of interest were reported.
New risk scheme to predict stroke in AF
A new scheme for assessing stroke risk, based on data amassed in the Anticoagulation and Risk Factors in AF, or ATRIA, cohort, performed better than the schemes currently recommended in leading clinical guidelines, according to a report published online in the Journal of the American Heart Association.
In a derivation study in which the ATRIA scheme was developed and a separate validation study in which its accuracy was confirmed, the ATRIA scores identified a substantially larger proportion of atrial fibrillation patients – 46% – as being at low risk for stroke, compared with other risk schemes currently in widespread use. This would allow clinicians to consider forgoing anticoagulant therapy in nearly half of AF patients.
The new scheme was particularly useful in calculating stroke risk in primary prevention patients, "the large group whose stroke risk is the most uncertain and where personalizing the anticoagulation decision is most pressing," said Dr. Daniel E. Singer of the clinical epidemiology unit, Massachusetts General Hospital, Boston, and his associates.
In addition, the ATRIA scores were especially good at predicting severe strokes, "the category of stroke that we are most interested in avoiding," the investigators noted.
Dr. Singer and his colleagues first used large health-plan databases to identify 13,559 California adults diagnosed as having nonvalvular AF in 1996-1997 and followed through 2003. These study subjects accounted for 33,497 person-years of observation on warfarin and 10,927 person-years of observation off warfarin.
There were 685 thromboembolic events, including 643 ischemic strokes, in this derivation cohort. Patient age and personal history of prior stroke were the two factors found to exert the greatest effect on future stroke risk.
From these data, the investigators identified eight highly predictive variables to incorporate into their risk assessment model: age, prior stroke, female sex, diabetes, heart failure, hypertension, proteinuria, and end-stage renal disease or an estimated glomerular filtration rate less than 45 mL/min per 1.73 m2.
This risk-prediction scheme differs from existing schemes primarily in that it uses a broader range of age categories; makes age, prior stroke, and their interaction the predominant risk factors to weigh into the calculation; and adds new high-risk factors such as female sex and renal dysfunction into the calculation.
When this ATRIA risk scheme was used, many more study subjects were accurately classified as low or high risk than with other schemes, the investigators said (J. Am. Heart Assoc. 2013; 2013[doi: 10.1161/?JAHA.113.000250]).
The ATRIA stroke risk score improved on the CHADS2 (congestive heart failure, hypertension, age at least 75 years, diabetes, stroke [doubled]) stroke risk score by 26%, primarily by correctly upgrading many patients from moderate-risk to high-risk categories. And it improved on the more recently identified CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age at least 75 years [doubled], diabetes, stroke [doubled]-vascular disease, age 65-74, sex category [female]) stroke risk score by 27%, exclusively by correctly downgrading many patients from high- or moderate-risk categories to the low-risk category.
The researchers then confirmed the accuracy of the ATRIA stroke risk scheme by testing it in a validation cohort of 33,247 adults who were newly diagnosed as having AF in 2006-2009. These study subjects accounted for 26,263 person-years off warfarin and 25,306 person-years on warfarin.
There were 496 thromboembolic events, including 466 ischemic strokes, in this validation cohort.
When the new ATRIA stroke risk scheme was used, the distribution of patients into low-, moderate-, and high-risk categories was "remarkably similar" to that in the derivation cohort. Similarly, the ATRIA scores were much more accurate than those in current standard use at determining which patients were at low risk and which were at high risk for stroke.
In particular, 46% of patients in both the derivation and validation cohorts were categorized by their ATRIA score as having a less than 1% per year risk of stroke. This designation would be extremely helpful to clinicians in deciding which patients can safely forgo anticoagulation therapy, Dr. Singer and his associates said.
Similarly, the ATRIA score was markedly better than the other two risk schemes at discriminating risk for severe, as compared with minor, stroke events. This would be very helpful to clinicians in deciding which patients are most in need of anticoagulation therapy, they said.
Recent research indicates that certain biomarkers now also appear to be promising predictors of stroke in AF patients. If this proves to be true, such biomarkers can easily be added into the ATRIA scoring scheme to further improve stroke risk assessment, the investigators added.
This study was supported by the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Eliot B. and Edith C. Shoolman Fund of Massachusetts General Hospital. Dr. Singer reported ties to Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer.
A new scheme for assessing stroke risk, based on data amassed in the Anticoagulation and Risk Factors in AF, or ATRIA, cohort, performed better than the schemes currently recommended in leading clinical guidelines, according to a report published online in the Journal of the American Heart Association.
In a derivation study in which the ATRIA scheme was developed and a separate validation study in which its accuracy was confirmed, the ATRIA scores identified a substantially larger proportion of atrial fibrillation patients – 46% – as being at low risk for stroke, compared with other risk schemes currently in widespread use. This would allow clinicians to consider forgoing anticoagulant therapy in nearly half of AF patients.
The new scheme was particularly useful in calculating stroke risk in primary prevention patients, "the large group whose stroke risk is the most uncertain and where personalizing the anticoagulation decision is most pressing," said Dr. Daniel E. Singer of the clinical epidemiology unit, Massachusetts General Hospital, Boston, and his associates.
In addition, the ATRIA scores were especially good at predicting severe strokes, "the category of stroke that we are most interested in avoiding," the investigators noted.
Dr. Singer and his colleagues first used large health-plan databases to identify 13,559 California adults diagnosed as having nonvalvular AF in 1996-1997 and followed through 2003. These study subjects accounted for 33,497 person-years of observation on warfarin and 10,927 person-years of observation off warfarin.
There were 685 thromboembolic events, including 643 ischemic strokes, in this derivation cohort. Patient age and personal history of prior stroke were the two factors found to exert the greatest effect on future stroke risk.
From these data, the investigators identified eight highly predictive variables to incorporate into their risk assessment model: age, prior stroke, female sex, diabetes, heart failure, hypertension, proteinuria, and end-stage renal disease or an estimated glomerular filtration rate less than 45 mL/min per 1.73 m2.
This risk-prediction scheme differs from existing schemes primarily in that it uses a broader range of age categories; makes age, prior stroke, and their interaction the predominant risk factors to weigh into the calculation; and adds new high-risk factors such as female sex and renal dysfunction into the calculation.
When this ATRIA risk scheme was used, many more study subjects were accurately classified as low or high risk than with other schemes, the investigators said (J. Am. Heart Assoc. 2013; 2013[doi: 10.1161/?JAHA.113.000250]).
The ATRIA stroke risk score improved on the CHADS2 (congestive heart failure, hypertension, age at least 75 years, diabetes, stroke [doubled]) stroke risk score by 26%, primarily by correctly upgrading many patients from moderate-risk to high-risk categories. And it improved on the more recently identified CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age at least 75 years [doubled], diabetes, stroke [doubled]-vascular disease, age 65-74, sex category [female]) stroke risk score by 27%, exclusively by correctly downgrading many patients from high- or moderate-risk categories to the low-risk category.
The researchers then confirmed the accuracy of the ATRIA stroke risk scheme by testing it in a validation cohort of 33,247 adults who were newly diagnosed as having AF in 2006-2009. These study subjects accounted for 26,263 person-years off warfarin and 25,306 person-years on warfarin.
There were 496 thromboembolic events, including 466 ischemic strokes, in this validation cohort.
When the new ATRIA stroke risk scheme was used, the distribution of patients into low-, moderate-, and high-risk categories was "remarkably similar" to that in the derivation cohort. Similarly, the ATRIA scores were much more accurate than those in current standard use at determining which patients were at low risk and which were at high risk for stroke.
In particular, 46% of patients in both the derivation and validation cohorts were categorized by their ATRIA score as having a less than 1% per year risk of stroke. This designation would be extremely helpful to clinicians in deciding which patients can safely forgo anticoagulation therapy, Dr. Singer and his associates said.
Similarly, the ATRIA score was markedly better than the other two risk schemes at discriminating risk for severe, as compared with minor, stroke events. This would be very helpful to clinicians in deciding which patients are most in need of anticoagulation therapy, they said.
Recent research indicates that certain biomarkers now also appear to be promising predictors of stroke in AF patients. If this proves to be true, such biomarkers can easily be added into the ATRIA scoring scheme to further improve stroke risk assessment, the investigators added.
This study was supported by the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Eliot B. and Edith C. Shoolman Fund of Massachusetts General Hospital. Dr. Singer reported ties to Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer.
A new scheme for assessing stroke risk, based on data amassed in the Anticoagulation and Risk Factors in AF, or ATRIA, cohort, performed better than the schemes currently recommended in leading clinical guidelines, according to a report published online in the Journal of the American Heart Association.
In a derivation study in which the ATRIA scheme was developed and a separate validation study in which its accuracy was confirmed, the ATRIA scores identified a substantially larger proportion of atrial fibrillation patients – 46% – as being at low risk for stroke, compared with other risk schemes currently in widespread use. This would allow clinicians to consider forgoing anticoagulant therapy in nearly half of AF patients.
The new scheme was particularly useful in calculating stroke risk in primary prevention patients, "the large group whose stroke risk is the most uncertain and where personalizing the anticoagulation decision is most pressing," said Dr. Daniel E. Singer of the clinical epidemiology unit, Massachusetts General Hospital, Boston, and his associates.
In addition, the ATRIA scores were especially good at predicting severe strokes, "the category of stroke that we are most interested in avoiding," the investigators noted.
Dr. Singer and his colleagues first used large health-plan databases to identify 13,559 California adults diagnosed as having nonvalvular AF in 1996-1997 and followed through 2003. These study subjects accounted for 33,497 person-years of observation on warfarin and 10,927 person-years of observation off warfarin.
There were 685 thromboembolic events, including 643 ischemic strokes, in this derivation cohort. Patient age and personal history of prior stroke were the two factors found to exert the greatest effect on future stroke risk.
From these data, the investigators identified eight highly predictive variables to incorporate into their risk assessment model: age, prior stroke, female sex, diabetes, heart failure, hypertension, proteinuria, and end-stage renal disease or an estimated glomerular filtration rate less than 45 mL/min per 1.73 m2.
This risk-prediction scheme differs from existing schemes primarily in that it uses a broader range of age categories; makes age, prior stroke, and their interaction the predominant risk factors to weigh into the calculation; and adds new high-risk factors such as female sex and renal dysfunction into the calculation.
When this ATRIA risk scheme was used, many more study subjects were accurately classified as low or high risk than with other schemes, the investigators said (J. Am. Heart Assoc. 2013; 2013[doi: 10.1161/?JAHA.113.000250]).
The ATRIA stroke risk score improved on the CHADS2 (congestive heart failure, hypertension, age at least 75 years, diabetes, stroke [doubled]) stroke risk score by 26%, primarily by correctly upgrading many patients from moderate-risk to high-risk categories. And it improved on the more recently identified CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age at least 75 years [doubled], diabetes, stroke [doubled]-vascular disease, age 65-74, sex category [female]) stroke risk score by 27%, exclusively by correctly downgrading many patients from high- or moderate-risk categories to the low-risk category.
The researchers then confirmed the accuracy of the ATRIA stroke risk scheme by testing it in a validation cohort of 33,247 adults who were newly diagnosed as having AF in 2006-2009. These study subjects accounted for 26,263 person-years off warfarin and 25,306 person-years on warfarin.
There were 496 thromboembolic events, including 466 ischemic strokes, in this validation cohort.
When the new ATRIA stroke risk scheme was used, the distribution of patients into low-, moderate-, and high-risk categories was "remarkably similar" to that in the derivation cohort. Similarly, the ATRIA scores were much more accurate than those in current standard use at determining which patients were at low risk and which were at high risk for stroke.
In particular, 46% of patients in both the derivation and validation cohorts were categorized by their ATRIA score as having a less than 1% per year risk of stroke. This designation would be extremely helpful to clinicians in deciding which patients can safely forgo anticoagulation therapy, Dr. Singer and his associates said.
Similarly, the ATRIA score was markedly better than the other two risk schemes at discriminating risk for severe, as compared with minor, stroke events. This would be very helpful to clinicians in deciding which patients are most in need of anticoagulation therapy, they said.
Recent research indicates that certain biomarkers now also appear to be promising predictors of stroke in AF patients. If this proves to be true, such biomarkers can easily be added into the ATRIA scoring scheme to further improve stroke risk assessment, the investigators added.
This study was supported by the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Eliot B. and Edith C. Shoolman Fund of Massachusetts General Hospital. Dr. Singer reported ties to Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Major Finding: With the new stroke prediction scheme, 46% of AF patients were classified as having an extremely low (less than 1%) annual risk of developing ischemic stroke.
Data Source: A study in which the ATRIA stroke risk assessment scheme was created using a derivation cohort involving 13,559 California adults with AF, and the scheme’s accuracy was then verified in a validation cohort involving 33,247 such patients.
Disclosures: This study was supported by the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Eliot B. and Edith C. Shoolman Fund of Massachusetts General Hospital. Dr. Singer reported ties to Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, and Pfizer.
Novel drug improved walk distance in pulmonary hypertension patients
Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.
Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.
The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.
The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.
The CHEST-1 trial
In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.
The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.
The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).
Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.
In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).
In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.
Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.
There were two deaths in the riociguat group and three in the placebo group.
A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.
The PATENT-1 trial
The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.
In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.
A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.
These study subjects were randomly assigned to receive high-dose riociguat capped at 2.5 mg three times daily (254 patients), low-dose riociguat capped at 1.5 mg three times daily (63 patients), or placebo (126 patients) for 12 weeks. The analysis of data from the low-dose group was considered exploratory and was reported separately.
The primary endpoint – change from baseline in 6-minute walk distance – increased by a mean of 30 m in the high-dose group but decreased by a mean of 6 m in the placebo group in the intention-to-treat analysis. The results were similar in the per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209655]).
This treatment benefit was consistent across several subgroups of patients. In addition, the active drug significantly decreased pulmonary vascular resistance, improved mean pulmonary artery pressure and cardiac output, lengthened the interval to clinical worsening, improved NT-proBNP levels, improved WHO functional class, and improved scores on the Borg dyspnea scale.
In exploratory analyses, riociguat did not improve scores on one measure of QOL but did so on a disease-specific QOL tool.
Drug-related serious adverse events occurred in 1.4 % of patients receiving high-dose riociguat and 1% of those receiving placebo. A total of 3% of patients in the riociguat group and 7% of those in the placebo group discontinued the study drug because of adverse events.
Serious or drug-related adverse events in both groups included increased hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, hypoxemia, dyspnea, and worsening of pulmonary hypertension. There were two deaths in the riociguat group and three in the placebo group, none of which were considered to be related to the study drug.
A total of 396 of the subjects in the PATENT-1 study elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the PATENT-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed a further mean increase of 53 m in 6-minute walk distance with high-dose riociguat.
CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.
Riociguat "is poised for examination by the Food and Drug Administration as a therapy for pulmonary hypertension and, if approved, has the potential to generate substantial revenue" for the sponsor of these two clinical trials, said Dr. Stephen L. Archer.
Both CHEST-1 and PATENT-1 were sponsored by Bayer HealthCare, which also provided the statistician and editorial assistance for both trials. "In light of the financial stakes, both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients," he noted.
Although riociguat yielded only "modest" gains in exercise capacity, it looks promising and may prove to be the first effective oral therapy for inoperable Group 4 pulmonary hypertension, Dr. Archer added.
However, he noted limitations in both studies. The CHEST-1 trial was limited by its "failure to examine the effects of the study drug on the right ventricle. The 6-minute walk distance is as reflective of right ventricular or skeletal-muscle function as it is of reduction in pulmonary vascular resistance, the authors’ presumed mechanism of benefit."
PATENT-1 was limited by its modest effect size, he added. "This is particularly important, since 50% of the patients were receiving no other treatment for pulmonary arterial hypertension, and the rate of response to treatment among such patients is usually higher than the rate among patients who are receiving concomitant treatment for pulmonary arterial hypertension," Dr. Archer said.
Dr. Archer is in the department of medicine at Queen’s University, Kingston, Ont. He reported no financial conflicts of interest. These remarks were taken from his editorial accompanying Dr. Ghofrani’s reports (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMe1306684]).
Riociguat "is poised for examination by the Food and Drug Administration as a therapy for pulmonary hypertension and, if approved, has the potential to generate substantial revenue" for the sponsor of these two clinical trials, said Dr. Stephen L. Archer.
Both CHEST-1 and PATENT-1 were sponsored by Bayer HealthCare, which also provided the statistician and editorial assistance for both trials. "In light of the financial stakes, both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients," he noted.
Although riociguat yielded only "modest" gains in exercise capacity, it looks promising and may prove to be the first effective oral therapy for inoperable Group 4 pulmonary hypertension, Dr. Archer added.
However, he noted limitations in both studies. The CHEST-1 trial was limited by its "failure to examine the effects of the study drug on the right ventricle. The 6-minute walk distance is as reflective of right ventricular or skeletal-muscle function as it is of reduction in pulmonary vascular resistance, the authors’ presumed mechanism of benefit."
PATENT-1 was limited by its modest effect size, he added. "This is particularly important, since 50% of the patients were receiving no other treatment for pulmonary arterial hypertension, and the rate of response to treatment among such patients is usually higher than the rate among patients who are receiving concomitant treatment for pulmonary arterial hypertension," Dr. Archer said.
Dr. Archer is in the department of medicine at Queen’s University, Kingston, Ont. He reported no financial conflicts of interest. These remarks were taken from his editorial accompanying Dr. Ghofrani’s reports (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMe1306684]).
Riociguat "is poised for examination by the Food and Drug Administration as a therapy for pulmonary hypertension and, if approved, has the potential to generate substantial revenue" for the sponsor of these two clinical trials, said Dr. Stephen L. Archer.
Both CHEST-1 and PATENT-1 were sponsored by Bayer HealthCare, which also provided the statistician and editorial assistance for both trials. "In light of the financial stakes, both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients," he noted.
Although riociguat yielded only "modest" gains in exercise capacity, it looks promising and may prove to be the first effective oral therapy for inoperable Group 4 pulmonary hypertension, Dr. Archer added.
However, he noted limitations in both studies. The CHEST-1 trial was limited by its "failure to examine the effects of the study drug on the right ventricle. The 6-minute walk distance is as reflective of right ventricular or skeletal-muscle function as it is of reduction in pulmonary vascular resistance, the authors’ presumed mechanism of benefit."
PATENT-1 was limited by its modest effect size, he added. "This is particularly important, since 50% of the patients were receiving no other treatment for pulmonary arterial hypertension, and the rate of response to treatment among such patients is usually higher than the rate among patients who are receiving concomitant treatment for pulmonary arterial hypertension," Dr. Archer said.
Dr. Archer is in the department of medicine at Queen’s University, Kingston, Ont. He reported no financial conflicts of interest. These remarks were taken from his editorial accompanying Dr. Ghofrani’s reports (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMe1306684]).
Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.
Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.
The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.
The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.
The CHEST-1 trial
In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.
The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.
The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).
Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.
In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).
In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.
Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.
There were two deaths in the riociguat group and three in the placebo group.
A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.
The PATENT-1 trial
The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.
In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.
A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.
These study subjects were randomly assigned to receive high-dose riociguat capped at 2.5 mg three times daily (254 patients), low-dose riociguat capped at 1.5 mg three times daily (63 patients), or placebo (126 patients) for 12 weeks. The analysis of data from the low-dose group was considered exploratory and was reported separately.
The primary endpoint – change from baseline in 6-minute walk distance – increased by a mean of 30 m in the high-dose group but decreased by a mean of 6 m in the placebo group in the intention-to-treat analysis. The results were similar in the per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209655]).
This treatment benefit was consistent across several subgroups of patients. In addition, the active drug significantly decreased pulmonary vascular resistance, improved mean pulmonary artery pressure and cardiac output, lengthened the interval to clinical worsening, improved NT-proBNP levels, improved WHO functional class, and improved scores on the Borg dyspnea scale.
In exploratory analyses, riociguat did not improve scores on one measure of QOL but did so on a disease-specific QOL tool.
Drug-related serious adverse events occurred in 1.4 % of patients receiving high-dose riociguat and 1% of those receiving placebo. A total of 3% of patients in the riociguat group and 7% of those in the placebo group discontinued the study drug because of adverse events.
Serious or drug-related adverse events in both groups included increased hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, hypoxemia, dyspnea, and worsening of pulmonary hypertension. There were two deaths in the riociguat group and three in the placebo group, none of which were considered to be related to the study drug.
A total of 396 of the subjects in the PATENT-1 study elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the PATENT-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed a further mean increase of 53 m in 6-minute walk distance with high-dose riociguat.
CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.
Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.
Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.
The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.
The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.
The CHEST-1 trial
In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.
The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.
The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).
Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.
In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).
In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.
Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.
There were two deaths in the riociguat group and three in the placebo group.
A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.
The PATENT-1 trial
The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.
In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.
A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.
These study subjects were randomly assigned to receive high-dose riociguat capped at 2.5 mg three times daily (254 patients), low-dose riociguat capped at 1.5 mg three times daily (63 patients), or placebo (126 patients) for 12 weeks. The analysis of data from the low-dose group was considered exploratory and was reported separately.
The primary endpoint – change from baseline in 6-minute walk distance – increased by a mean of 30 m in the high-dose group but decreased by a mean of 6 m in the placebo group in the intention-to-treat analysis. The results were similar in the per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209655]).
This treatment benefit was consistent across several subgroups of patients. In addition, the active drug significantly decreased pulmonary vascular resistance, improved mean pulmonary artery pressure and cardiac output, lengthened the interval to clinical worsening, improved NT-proBNP levels, improved WHO functional class, and improved scores on the Borg dyspnea scale.
In exploratory analyses, riociguat did not improve scores on one measure of QOL but did so on a disease-specific QOL tool.
Drug-related serious adverse events occurred in 1.4 % of patients receiving high-dose riociguat and 1% of those receiving placebo. A total of 3% of patients in the riociguat group and 7% of those in the placebo group discontinued the study drug because of adverse events.
Serious or drug-related adverse events in both groups included increased hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, hypoxemia, dyspnea, and worsening of pulmonary hypertension. There were two deaths in the riociguat group and three in the placebo group, none of which were considered to be related to the study drug.
A total of 396 of the subjects in the PATENT-1 study elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the PATENT-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed a further mean increase of 53 m in 6-minute walk distance with high-dose riociguat.
CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: Riociguat significantly improved 6-minute walk distance by a mean of 39 m in patients with thromboembolic pulmonary hypertension and by a mean of 30 m in patients with pulmonary arterial hypertension.
Data source: Two separate, international, phase III, randomized controlled trials assessing the safety and efficacy of riociguat for thromboembolic pulmonary hypertension (261 patients) and pulmonary arterial hypertension (443 patients).
Disclosures: CHEST-1 and PATENT-1 were funded by Bayer HealthCare. Dr. Ghofrani reported ties to Actelion, Bayer, and other companies. His associates reported ties to numerous industry sources.
Racial discrepancy in breast cancer survival examined
The disparity between black women and white women in breast cancer survival has not changed appreciably since the early 1990s, and it appears to be related primarily to differences between the two racial groups at presentation rather than to treatment differences, according to a report in the July 24/31 issue of JAMA.
These are the findings of a large, population-based study using an innovative statistical approach to tease out the complex interactions among demographic, clinical, and treatment differences between the races.
"Our results suggest that it may be difficult to eliminate the racial disparity in survival ... unless differences in presentation can be reduced," said Dr. Jeffrey H. Silber of the Center for Outcomes Research at Children’s Hospital of Philadelphia and his associates.
The researchers analyzed information from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess the racial disparity in 5-year breast cancer survival among women older than 65 years at diagnosis in 1991-2005.To do so, they used rigorous matching methods in three sequential analyses to compare 7,375 black patients with white control subjects selected from a pool of 99,898 white patients.
The black women first were compared with white women who had similar demographic traits (age, year of diagnosis, and SEER site), then with white patients who had similar clinical presentations (comorbidities, tumor stage, and other tumor factors), and finally with white patients who had similar treatment (specifics of surgery, radiotherapy, and chemotherapy).
"The three matched white groups sequentially remove aspects of the [racial] disparity while leaving other aspects in place, so as to develop an understanding of how the disparity occurs," the investigators noted (JAMA 2013;310:389-97).
There were four major findings:
First, 5-year breast cancer survival improved somewhat in both races over time, but the disparity between black women and white women remained constant.
Second, when the women were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life. In other words, compared with white women of the same age, year of diagnosis, and geographical location, black women still had a significantly lower 5-year breast cancer survival. Thus, demographic differences explain only a small part of the racial disparity.
Third, when the women were matched for clinical traits at presentation, this disparity in 5-year survival dropped to 4.4%, which represents approximately 1 year. This is a smaller but still significant difference between black women and white women who present with the same clinical picture.
Fourth, when the women were matched for treatment factors, this disparity only decreased slightly. "Hence, treatment differences explained only 0.81% of the 12.9% difference in 5-year survival," Dr. Silber and his associates said.
Most of the disparity in survival could be attributed to the poorer health of black women at presentation. Black women were markedly less likely than were white women to have seen a primary care provider during the preceding year and were significantly less likely to have undergone recent screening for breast cancer, colon cancer, or high cholesterol.
Black women also were significantly more likely than white women to have comorbid conditions. "Some of the effectiveness of cancer treatment ... may be blunted by other health problems" or by the treatment of those health problems, the investigators said.
Finally, black women were more likely than were white women to present with advanced breast cancer and worse biological features, such as larger tumor size and less favorable receptor status. The mean interval between diagnosis and the first treatment also was significantly longer for black women than for white women, they added.
This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.
The conclusion of Silber et al. that treatment differences account for only a small fraction of the racial disparity in breast cancer survival may be questioned for several reasons, said Dr. Jeanne S. Mandelblatt, Vanessa B. Sheppard, Ph.D., and Dr. Alfred I. Neugut.
This analysis did not include any information regarding hormone therapy, even though most older women of both races have estrogen receptor–positive tumors, and hormone therapy can improve survival by 30% in such patients. "Differential patterns of hormone therapy use or adherence by race would lead to underestimation of the association between treatment and survival differences," they said.
In addition, this study did not address treatment doses, intensity, and adherence, all of which have been shown to differ by race and to affect survival. And the SEER-Medicare database isn’t able to capture differences in the quality of treatment, adherence to treatment, and patient-physician communication, all of which may contribute to black women having a major difference from white women in the experience of cancer treatment.
Dr. Mandelblatt is in the Cancer Prevention and Control Program at Georgetown Lombardi Comprehensive Cancer Center, Washington; Dr. Sheppard is in the Breast Cancer Program at Georgetown University, Washington; and Dr. Neugut is in the departments of medicine and epidemiology at the Herbert Irving Comprehensive Cancer Center–Columbia University, New York. They commented in an editorial responding to Dr. Silber and his associates’ article (JAMA 2013;310:376-7). This work was supported by the National Cancer Institute, the National Institutes of Health, and the Department of Defense Breast Cancer Center of Excellence Award. The three physicians said they had no financial disclosures.
The conclusion of Silber et al. that treatment differences account for only a small fraction of the racial disparity in breast cancer survival may be questioned for several reasons, said Dr. Jeanne S. Mandelblatt, Vanessa B. Sheppard, Ph.D., and Dr. Alfred I. Neugut.
This analysis did not include any information regarding hormone therapy, even though most older women of both races have estrogen receptor–positive tumors, and hormone therapy can improve survival by 30% in such patients. "Differential patterns of hormone therapy use or adherence by race would lead to underestimation of the association between treatment and survival differences," they said.
In addition, this study did not address treatment doses, intensity, and adherence, all of which have been shown to differ by race and to affect survival. And the SEER-Medicare database isn’t able to capture differences in the quality of treatment, adherence to treatment, and patient-physician communication, all of which may contribute to black women having a major difference from white women in the experience of cancer treatment.
Dr. Mandelblatt is in the Cancer Prevention and Control Program at Georgetown Lombardi Comprehensive Cancer Center, Washington; Dr. Sheppard is in the Breast Cancer Program at Georgetown University, Washington; and Dr. Neugut is in the departments of medicine and epidemiology at the Herbert Irving Comprehensive Cancer Center–Columbia University, New York. They commented in an editorial responding to Dr. Silber and his associates’ article (JAMA 2013;310:376-7). This work was supported by the National Cancer Institute, the National Institutes of Health, and the Department of Defense Breast Cancer Center of Excellence Award. The three physicians said they had no financial disclosures.
The conclusion of Silber et al. that treatment differences account for only a small fraction of the racial disparity in breast cancer survival may be questioned for several reasons, said Dr. Jeanne S. Mandelblatt, Vanessa B. Sheppard, Ph.D., and Dr. Alfred I. Neugut.
This analysis did not include any information regarding hormone therapy, even though most older women of both races have estrogen receptor–positive tumors, and hormone therapy can improve survival by 30% in such patients. "Differential patterns of hormone therapy use or adherence by race would lead to underestimation of the association between treatment and survival differences," they said.
In addition, this study did not address treatment doses, intensity, and adherence, all of which have been shown to differ by race and to affect survival. And the SEER-Medicare database isn’t able to capture differences in the quality of treatment, adherence to treatment, and patient-physician communication, all of which may contribute to black women having a major difference from white women in the experience of cancer treatment.
Dr. Mandelblatt is in the Cancer Prevention and Control Program at Georgetown Lombardi Comprehensive Cancer Center, Washington; Dr. Sheppard is in the Breast Cancer Program at Georgetown University, Washington; and Dr. Neugut is in the departments of medicine and epidemiology at the Herbert Irving Comprehensive Cancer Center–Columbia University, New York. They commented in an editorial responding to Dr. Silber and his associates’ article (JAMA 2013;310:376-7). This work was supported by the National Cancer Institute, the National Institutes of Health, and the Department of Defense Breast Cancer Center of Excellence Award. The three physicians said they had no financial disclosures.
The disparity between black women and white women in breast cancer survival has not changed appreciably since the early 1990s, and it appears to be related primarily to differences between the two racial groups at presentation rather than to treatment differences, according to a report in the July 24/31 issue of JAMA.
These are the findings of a large, population-based study using an innovative statistical approach to tease out the complex interactions among demographic, clinical, and treatment differences between the races.
"Our results suggest that it may be difficult to eliminate the racial disparity in survival ... unless differences in presentation can be reduced," said Dr. Jeffrey H. Silber of the Center for Outcomes Research at Children’s Hospital of Philadelphia and his associates.
The researchers analyzed information from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess the racial disparity in 5-year breast cancer survival among women older than 65 years at diagnosis in 1991-2005.To do so, they used rigorous matching methods in three sequential analyses to compare 7,375 black patients with white control subjects selected from a pool of 99,898 white patients.
The black women first were compared with white women who had similar demographic traits (age, year of diagnosis, and SEER site), then with white patients who had similar clinical presentations (comorbidities, tumor stage, and other tumor factors), and finally with white patients who had similar treatment (specifics of surgery, radiotherapy, and chemotherapy).
"The three matched white groups sequentially remove aspects of the [racial] disparity while leaving other aspects in place, so as to develop an understanding of how the disparity occurs," the investigators noted (JAMA 2013;310:389-97).
There were four major findings:
First, 5-year breast cancer survival improved somewhat in both races over time, but the disparity between black women and white women remained constant.
Second, when the women were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life. In other words, compared with white women of the same age, year of diagnosis, and geographical location, black women still had a significantly lower 5-year breast cancer survival. Thus, demographic differences explain only a small part of the racial disparity.
Third, when the women were matched for clinical traits at presentation, this disparity in 5-year survival dropped to 4.4%, which represents approximately 1 year. This is a smaller but still significant difference between black women and white women who present with the same clinical picture.
Fourth, when the women were matched for treatment factors, this disparity only decreased slightly. "Hence, treatment differences explained only 0.81% of the 12.9% difference in 5-year survival," Dr. Silber and his associates said.
Most of the disparity in survival could be attributed to the poorer health of black women at presentation. Black women were markedly less likely than were white women to have seen a primary care provider during the preceding year and were significantly less likely to have undergone recent screening for breast cancer, colon cancer, or high cholesterol.
Black women also were significantly more likely than white women to have comorbid conditions. "Some of the effectiveness of cancer treatment ... may be blunted by other health problems" or by the treatment of those health problems, the investigators said.
Finally, black women were more likely than were white women to present with advanced breast cancer and worse biological features, such as larger tumor size and less favorable receptor status. The mean interval between diagnosis and the first treatment also was significantly longer for black women than for white women, they added.
This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.
The disparity between black women and white women in breast cancer survival has not changed appreciably since the early 1990s, and it appears to be related primarily to differences between the two racial groups at presentation rather than to treatment differences, according to a report in the July 24/31 issue of JAMA.
These are the findings of a large, population-based study using an innovative statistical approach to tease out the complex interactions among demographic, clinical, and treatment differences between the races.
"Our results suggest that it may be difficult to eliminate the racial disparity in survival ... unless differences in presentation can be reduced," said Dr. Jeffrey H. Silber of the Center for Outcomes Research at Children’s Hospital of Philadelphia and his associates.
The researchers analyzed information from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess the racial disparity in 5-year breast cancer survival among women older than 65 years at diagnosis in 1991-2005.To do so, they used rigorous matching methods in three sequential analyses to compare 7,375 black patients with white control subjects selected from a pool of 99,898 white patients.
The black women first were compared with white women who had similar demographic traits (age, year of diagnosis, and SEER site), then with white patients who had similar clinical presentations (comorbidities, tumor stage, and other tumor factors), and finally with white patients who had similar treatment (specifics of surgery, radiotherapy, and chemotherapy).
"The three matched white groups sequentially remove aspects of the [racial] disparity while leaving other aspects in place, so as to develop an understanding of how the disparity occurs," the investigators noted (JAMA 2013;310:389-97).
There were four major findings:
First, 5-year breast cancer survival improved somewhat in both races over time, but the disparity between black women and white women remained constant.
Second, when the women were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life. In other words, compared with white women of the same age, year of diagnosis, and geographical location, black women still had a significantly lower 5-year breast cancer survival. Thus, demographic differences explain only a small part of the racial disparity.
Third, when the women were matched for clinical traits at presentation, this disparity in 5-year survival dropped to 4.4%, which represents approximately 1 year. This is a smaller but still significant difference between black women and white women who present with the same clinical picture.
Fourth, when the women were matched for treatment factors, this disparity only decreased slightly. "Hence, treatment differences explained only 0.81% of the 12.9% difference in 5-year survival," Dr. Silber and his associates said.
Most of the disparity in survival could be attributed to the poorer health of black women at presentation. Black women were markedly less likely than were white women to have seen a primary care provider during the preceding year and were significantly less likely to have undergone recent screening for breast cancer, colon cancer, or high cholesterol.
Black women also were significantly more likely than white women to have comorbid conditions. "Some of the effectiveness of cancer treatment ... may be blunted by other health problems" or by the treatment of those health problems, the investigators said.
Finally, black women were more likely than were white women to present with advanced breast cancer and worse biological features, such as larger tumor size and less favorable receptor status. The mean interval between diagnosis and the first treatment also was significantly longer for black women than for white women, they added.
This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.
FROM JAMA
Major finding: When breast cancer patients were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life.
Data source: A population-based study comparing survival outcomes between 7,375 black women and matched control white women aged 65 years and older when diagnosed as having breast cancer in 1991-2005.
Disclosures: This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.
TTE, though ‘appropriate,’ changes care in only 32%
Transthoracic echocardiography was deemed to have been "appropriate" according to appropriate use criteria in nearly 92% of 535 cases in a single-center retrospective study reported online July 22 in JAMA Internal Medicine.
However, the TTE findings led to an active change in care in only 32% of those cases. In nearly half (47%) of cases, the TTE results resulted in simple continuation of current care, and there was no change in care for the remaining 21% of cases, said Dr. Susan A. Matulevicius and her associates at the University of Texas Southwest Medical Center, Dallas.
"The discrepancy between appropriateness and clinical impact is striking and suggests that the appropriate use criteria guidelines as currently implemented are unlikely to facilitate optimal use of TTE," the investigators noted.
The use of TTE has doubled during the past decade and now comprises half of all cardiac imaging services among Medicare beneficiaries. That represents more than $1.1 billion of the total Medicare expenditures for diagnostic imaging during one year, they said.
The American College of Cardiology, American Society of Echocardiography, and other professional groups developed appropriate use criteria for TTE in 2007 (J. Am.Coll. Cardiol. 2007;50:187-204) and updated them in 2011 (J. Am. Soc. Echocardiogr. 2011;24:229-67), but to date, no large study has assessed whether these efforts, or indeed whether the TTE results themselves, actually affect clinical care. Dr. Matulevicius and her colleagues said.
They reviewed the electronic health records for all TTEs performed during 1 month (April 2011) at their medical center, to assess the appropriateness and the clinical impact of the procedures.
The study population was 59% female and 41% male, and the mean age was 58 years. Approximately 55% of the subjects were white, 21% were black, and 8% were Hispanic.
Two general cardiologists who were blinded to the TTE results and to the patients’ clinical course independently reviewed the 535 cases, classifying them as appropriate (91.8%), inappropriate (4.3%), or uncertain (3.9%), according to the updated appropriate use criteria.
Two other noninvasive cardiologists who were blinded to these classifications independently assessed the clinical impact of each TTE and categorized the results as prompting an active change in care (32%), a continuation of current care (47%), or no change in care (21%).
The results of the TTE prompted an active change in clinical care in only 32% of cases. The most common changes were further diagnostic testing (29% of cases) and subspecialty consultation (26%), Dr. Matulevicius and her associates said (JAMA Intern. Med. 2013 July 22 [doi:10.1001/jamainternmed.2013.8972]).
In addition, there was no significant difference between the proportion of appropriate TTEs that led to a change in clinical care (32%) and the proportion of inappropriate TTEs that led to a change in clinical care (22%).
The researchers also conducted an exploratory analysis to determine, by consensus of the reviewing cardiologists, whether the TTEs that led to active change had been very useful, useful, neutral, not useful, or misused as guides to patient care.
Only 19% of all TTEs were judged to be very useful or useful. Another 6% were deemed not useful or misused. The majority (about 75%) were categorized as neutral in this analysis.
These findings are in line with those of previous small studies at other institutions. They suggest that the appropriate use criteria have failed to have much impact on physician decision making and have not curbed the massive growth of TTE use, the investigators added.
"In our study, 114 TTEs in 1 month led to no change in care, which equates to more than 1,300 TTEs on an annual basis. If our findings are corroborated in other settings and centers, 21% (or $230 million) of the $1.1 billion of Medicare expenditures on echocardiography could have been saved if these TTEs had not been performed.
"Better metrics for identifying patients or scenarios when TTE is likely to result in no change in care must be developed," they said.
Certain common indications that at present are considered to be appropriate but have minimal impact on clinical care should be targeted. "For example, initial evaluation of reasonably suspected valvular or structural heart disease (appropriate use criteria 34) and serial reevaluations in a patient undergoing therapy with cardiotoxic agents (appropriate use criteria 91) were the most common "appropriate" TTE indications but resulted in active change in care in fewer than 15% of studies.
"Alternative strategies, including performance of limited echocardiography or screening with plasma biomarkers, such as sensitive troponin and natriuretic peptide levels, may help to improve efficiency of TTE screening for these indications," Dr. Matulevicius and her associates said.
This study was supported by the University of Texas, the National Center for Advancing Translational Sciences, and the National Institutes of Health. No relevant financial conflicts of interest were reported.
This study is commendable, but simply designating a TTE as leading to no change in clinical care or to a continuation of existing care can be misleading. These descriptions imply that there was a total disregard for or ignorance of the TTE results, said Dr. William Armstrong and Dr. Kim A. Eagle.
In this study, TTE was performed in 24 patients receiving cardiotoxic agents, and the response to the TTE results was to continue existing care in 21 of them. But even though management did not change, continued TTE screening represents highly appropriate and highly beneficial state-of-the-art care for such patients, they noted.
Similarly, TTE is "the only realistic method for confirming the presence or absence" of suspected pulmonary hypertension. When this disorder is a legitimate concern but is not found to be present on TTE scanning, "no change" in care is entirely appropriate, Drs. Armstrong and Eagle said.
Dr. Armstrong and Dr. Eagle are in the division of cardiology at the University of Michigan Medical Center, Ann Arbor. They reported no financial conflicts of interest. These remarks were taken from their invited commentary accompanying Dr. Matulevicius’s report (JAMA Intern. Med. 2013 July 22 [doi:10.1001/jamainternmed.2013.7273]).
This study is commendable, but simply designating a TTE as leading to no change in clinical care or to a continuation of existing care can be misleading. These descriptions imply that there was a total disregard for or ignorance of the TTE results, said Dr. William Armstrong and Dr. Kim A. Eagle.
In this study, TTE was performed in 24 patients receiving cardiotoxic agents, and the response to the TTE results was to continue existing care in 21 of them. But even though management did not change, continued TTE screening represents highly appropriate and highly beneficial state-of-the-art care for such patients, they noted.
Similarly, TTE is "the only realistic method for confirming the presence or absence" of suspected pulmonary hypertension. When this disorder is a legitimate concern but is not found to be present on TTE scanning, "no change" in care is entirely appropriate, Drs. Armstrong and Eagle said.
Dr. Armstrong and Dr. Eagle are in the division of cardiology at the University of Michigan Medical Center, Ann Arbor. They reported no financial conflicts of interest. These remarks were taken from their invited commentary accompanying Dr. Matulevicius’s report (JAMA Intern. Med. 2013 July 22 [doi:10.1001/jamainternmed.2013.7273]).
This study is commendable, but simply designating a TTE as leading to no change in clinical care or to a continuation of existing care can be misleading. These descriptions imply that there was a total disregard for or ignorance of the TTE results, said Dr. William Armstrong and Dr. Kim A. Eagle.
In this study, TTE was performed in 24 patients receiving cardiotoxic agents, and the response to the TTE results was to continue existing care in 21 of them. But even though management did not change, continued TTE screening represents highly appropriate and highly beneficial state-of-the-art care for such patients, they noted.
Similarly, TTE is "the only realistic method for confirming the presence or absence" of suspected pulmonary hypertension. When this disorder is a legitimate concern but is not found to be present on TTE scanning, "no change" in care is entirely appropriate, Drs. Armstrong and Eagle said.
Dr. Armstrong and Dr. Eagle are in the division of cardiology at the University of Michigan Medical Center, Ann Arbor. They reported no financial conflicts of interest. These remarks were taken from their invited commentary accompanying Dr. Matulevicius’s report (JAMA Intern. Med. 2013 July 22 [doi:10.1001/jamainternmed.2013.7273]).
Transthoracic echocardiography was deemed to have been "appropriate" according to appropriate use criteria in nearly 92% of 535 cases in a single-center retrospective study reported online July 22 in JAMA Internal Medicine.
However, the TTE findings led to an active change in care in only 32% of those cases. In nearly half (47%) of cases, the TTE results resulted in simple continuation of current care, and there was no change in care for the remaining 21% of cases, said Dr. Susan A. Matulevicius and her associates at the University of Texas Southwest Medical Center, Dallas.
"The discrepancy between appropriateness and clinical impact is striking and suggests that the appropriate use criteria guidelines as currently implemented are unlikely to facilitate optimal use of TTE," the investigators noted.
The use of TTE has doubled during the past decade and now comprises half of all cardiac imaging services among Medicare beneficiaries. That represents more than $1.1 billion of the total Medicare expenditures for diagnostic imaging during one year, they said.
The American College of Cardiology, American Society of Echocardiography, and other professional groups developed appropriate use criteria for TTE in 2007 (J. Am.Coll. Cardiol. 2007;50:187-204) and updated them in 2011 (J. Am. Soc. Echocardiogr. 2011;24:229-67), but to date, no large study has assessed whether these efforts, or indeed whether the TTE results themselves, actually affect clinical care. Dr. Matulevicius and her colleagues said.
They reviewed the electronic health records for all TTEs performed during 1 month (April 2011) at their medical center, to assess the appropriateness and the clinical impact of the procedures.
The study population was 59% female and 41% male, and the mean age was 58 years. Approximately 55% of the subjects were white, 21% were black, and 8% were Hispanic.
Two general cardiologists who were blinded to the TTE results and to the patients’ clinical course independently reviewed the 535 cases, classifying them as appropriate (91.8%), inappropriate (4.3%), or uncertain (3.9%), according to the updated appropriate use criteria.
Two other noninvasive cardiologists who were blinded to these classifications independently assessed the clinical impact of each TTE and categorized the results as prompting an active change in care (32%), a continuation of current care (47%), or no change in care (21%).
The results of the TTE prompted an active change in clinical care in only 32% of cases. The most common changes were further diagnostic testing (29% of cases) and subspecialty consultation (26%), Dr. Matulevicius and her associates said (JAMA Intern. Med. 2013 July 22 [doi:10.1001/jamainternmed.2013.8972]).
In addition, there was no significant difference between the proportion of appropriate TTEs that led to a change in clinical care (32%) and the proportion of inappropriate TTEs that led to a change in clinical care (22%).
The researchers also conducted an exploratory analysis to determine, by consensus of the reviewing cardiologists, whether the TTEs that led to active change had been very useful, useful, neutral, not useful, or misused as guides to patient care.
Only 19% of all TTEs were judged to be very useful or useful. Another 6% were deemed not useful or misused. The majority (about 75%) were categorized as neutral in this analysis.
These findings are in line with those of previous small studies at other institutions. They suggest that the appropriate use criteria have failed to have much impact on physician decision making and have not curbed the massive growth of TTE use, the investigators added.
"In our study, 114 TTEs in 1 month led to no change in care, which equates to more than 1,300 TTEs on an annual basis. If our findings are corroborated in other settings and centers, 21% (or $230 million) of the $1.1 billion of Medicare expenditures on echocardiography could have been saved if these TTEs had not been performed.
"Better metrics for identifying patients or scenarios when TTE is likely to result in no change in care must be developed," they said.
Certain common indications that at present are considered to be appropriate but have minimal impact on clinical care should be targeted. "For example, initial evaluation of reasonably suspected valvular or structural heart disease (appropriate use criteria 34) and serial reevaluations in a patient undergoing therapy with cardiotoxic agents (appropriate use criteria 91) were the most common "appropriate" TTE indications but resulted in active change in care in fewer than 15% of studies.
"Alternative strategies, including performance of limited echocardiography or screening with plasma biomarkers, such as sensitive troponin and natriuretic peptide levels, may help to improve efficiency of TTE screening for these indications," Dr. Matulevicius and her associates said.
This study was supported by the University of Texas, the National Center for Advancing Translational Sciences, and the National Institutes of Health. No relevant financial conflicts of interest were reported.
Transthoracic echocardiography was deemed to have been "appropriate" according to appropriate use criteria in nearly 92% of 535 cases in a single-center retrospective study reported online July 22 in JAMA Internal Medicine.
However, the TTE findings led to an active change in care in only 32% of those cases. In nearly half (47%) of cases, the TTE results resulted in simple continuation of current care, and there was no change in care for the remaining 21% of cases, said Dr. Susan A. Matulevicius and her associates at the University of Texas Southwest Medical Center, Dallas.
"The discrepancy between appropriateness and clinical impact is striking and suggests that the appropriate use criteria guidelines as currently implemented are unlikely to facilitate optimal use of TTE," the investigators noted.
The use of TTE has doubled during the past decade and now comprises half of all cardiac imaging services among Medicare beneficiaries. That represents more than $1.1 billion of the total Medicare expenditures for diagnostic imaging during one year, they said.
The American College of Cardiology, American Society of Echocardiography, and other professional groups developed appropriate use criteria for TTE in 2007 (J. Am.Coll. Cardiol. 2007;50:187-204) and updated them in 2011 (J. Am. Soc. Echocardiogr. 2011;24:229-67), but to date, no large study has assessed whether these efforts, or indeed whether the TTE results themselves, actually affect clinical care. Dr. Matulevicius and her colleagues said.
They reviewed the electronic health records for all TTEs performed during 1 month (April 2011) at their medical center, to assess the appropriateness and the clinical impact of the procedures.
The study population was 59% female and 41% male, and the mean age was 58 years. Approximately 55% of the subjects were white, 21% were black, and 8% were Hispanic.
Two general cardiologists who were blinded to the TTE results and to the patients’ clinical course independently reviewed the 535 cases, classifying them as appropriate (91.8%), inappropriate (4.3%), or uncertain (3.9%), according to the updated appropriate use criteria.
Two other noninvasive cardiologists who were blinded to these classifications independently assessed the clinical impact of each TTE and categorized the results as prompting an active change in care (32%), a continuation of current care (47%), or no change in care (21%).
The results of the TTE prompted an active change in clinical care in only 32% of cases. The most common changes were further diagnostic testing (29% of cases) and subspecialty consultation (26%), Dr. Matulevicius and her associates said (JAMA Intern. Med. 2013 July 22 [doi:10.1001/jamainternmed.2013.8972]).
In addition, there was no significant difference between the proportion of appropriate TTEs that led to a change in clinical care (32%) and the proportion of inappropriate TTEs that led to a change in clinical care (22%).
The researchers also conducted an exploratory analysis to determine, by consensus of the reviewing cardiologists, whether the TTEs that led to active change had been very useful, useful, neutral, not useful, or misused as guides to patient care.
Only 19% of all TTEs were judged to be very useful or useful. Another 6% were deemed not useful or misused. The majority (about 75%) were categorized as neutral in this analysis.
These findings are in line with those of previous small studies at other institutions. They suggest that the appropriate use criteria have failed to have much impact on physician decision making and have not curbed the massive growth of TTE use, the investigators added.
"In our study, 114 TTEs in 1 month led to no change in care, which equates to more than 1,300 TTEs on an annual basis. If our findings are corroborated in other settings and centers, 21% (or $230 million) of the $1.1 billion of Medicare expenditures on echocardiography could have been saved if these TTEs had not been performed.
"Better metrics for identifying patients or scenarios when TTE is likely to result in no change in care must be developed," they said.
Certain common indications that at present are considered to be appropriate but have minimal impact on clinical care should be targeted. "For example, initial evaluation of reasonably suspected valvular or structural heart disease (appropriate use criteria 34) and serial reevaluations in a patient undergoing therapy with cardiotoxic agents (appropriate use criteria 91) were the most common "appropriate" TTE indications but resulted in active change in care in fewer than 15% of studies.
"Alternative strategies, including performance of limited echocardiography or screening with plasma biomarkers, such as sensitive troponin and natriuretic peptide levels, may help to improve efficiency of TTE screening for these indications," Dr. Matulevicius and her associates said.
This study was supported by the University of Texas, the National Center for Advancing Translational Sciences, and the National Institutes of Health. No relevant financial conflicts of interest were reported.
FROM JAMA INTERNAL MEDICINE
Major finding: TTE findings led to an active change in care in only 32% of cases and were considered useful or very useful in fewer than 20% of those.
Data source: A single-center case series involving 535 TTE scans performed during 1 year.
Disclosures: This study was supported by the University of Texas, the National Center for Advancing Translational Sciences, and the National Institutes of Health. No relevant financial conflicts of interest were reported.
Fungal meningitis can masquerade as ischemic stroke
The recent outbreak of fungal meningitis caused by spinal injections of contaminated methylprednisolone illustrates that the disease can present as ischemic stroke, according to a report published online July 22 in JAMA Neurology.
Three such cases occurred in elderly patients who had clear risk factors for stroke and no fever or meningeal signs; whose exposure to the contaminated injection was as remote as 4 weeks earlier; and whose early MRI scans indicated stroke rather than infection, said Dr. Kirk Kleinfeld and his associates at Vanderbilt University Medical Center, Nashville, Tenn.
The investigators described these cases in detail so as to alert clinicians to this confusing presentation, which would enable them to initiate antifungal therapy as soon as possible. In two of these cases, the diagnosis was delayed and the patients died. In the third case, once clinical suspicion of fungal meningitis had been aroused, empiric antifungal therapy appears to have saved the patient’s life, they noted.
"An awareness of the presentation and vascular sequelae of fungal meningitis in immunocompetent patients should lead to earlier treatment and improved outcomes prior to a definitive diagnosis," Dr. Kleinfeld and his colleagues wrote.
In the first case, a 78-year-old man presented with acute-onset, left-sided weakness and dysarthria. He was afebrile and had no meningeal signs, and his laboratory workup showed only mild leukocytosis. He had hyperlipidemia, hypertension, and atrial fibrillation, and an MRI scan showed a small-vessel ischemic infarct of the right anterior superior pons/lower midbrain.
The patient failed to improve with standard poststroke care. When his left-sided weakness worsened on day 3, another MRI showed that the infarct had extended and a new one had formed in the right thalamus. The next day he became unresponsive, and repeated imaging showed enlargement and evolution of those infarcts plus formation of an occlusion of the right superior cerebellar artery. The patient died on day 6.
An autopsy was performed when it was noted that the patient had received an epidural steroid injection 2 weeks earlier to treat low-back pain. It "revealed small areas of focal cortical and pontine subarachnoid hemorrhage, as well as fungal cerebral vasculitis with aneurysm formation." Infection with Exserohilum species was identified, the investigators reported (JAMA Neurol. 2013 July 22 [doi: 10.1001/jamaneurol.2013.3586]).
In the second case, a 78-year-old woman presented with subacute vertigo, nausea, and headache, and was found on examination to have one-sided dysmetria and mild ataxia. Her medical history included hypertension, hyperlipidemia, and coronary artery disease, and the initial laboratory workup revealed type 2 diabetes. The authors noted that an MRI scan showed "ischemic infarcts of the left lateral pons, superior cerebellar peduncle, and superior cerebellum suggestive of a large-vessel (superior cerebellar artery) etiology."
A hypercoagulable panel revealed lupus anticoagulant and elevated antiphospholipid protein antibodies. Anticoagulation therapy was given. The patient failed to improve, and on day 4 she developed a low-grade fever and mild encephalopathy. A repeat MRI showed a new ischemic pontine stroke.
The patient’s mental status failed to improve, and it was noted that she had received an epidural steroid injection 2 weeks earlier to treat low-back pain. The patient underwent lumbar puncture to identify any fungal infection, and intravenous antibiotics and voriconazole were administered beginning on day 15. However, the patient died on day 50.
"An autopsy revealed a left superior cerebellar artery mycotic aneurysm with vascular infiltration of the arterial wall by hyphal fungal forms," which were thought to represent Exserohilum species based on polymerase chain reaction studies, the investigators reported.
In the third case, a 70-year-old woman presented with headache, difficulty balancing, nuchal rigidity, and mild fever. She had hyperlipidemia, and physical examination showed mild dysarthria and bilateral dysmetria. An MRI scan revealed acute small-vessel strokes in the right thalamus and internal capsule.
Because the patient had chronic back pain and the clinicians’ suspicions were raised regarding fungal meningitis, it was found that she had undergone an epidural steroid injection 1 month earlier. A lumbar puncture was performed to identify possible fungal infection, and treatment with intravenous antibiotics and voriconazole was initiated.
The patient became encephalopathic on day 7, and a repeat MRI showed a new small-vessel stroke involving the left internal capsule. With continued voriconazole therapy, the patient’s mental status and her cerebrospinal fluid cell counts slowly improved. She survived and was discharged 37 days later.
"We suspect that [the early antifungal treatment] halted the further vascular progression of her infection," Dr. Kleinfeld and his associates wrote.
All three patients received methylprednisolone from contaminated lots at medical facilities that were identified by the Centers for Disease Control and Prevention as recipients of contaminated lots.
These cases show that clinicians should consider an atypical pathogenesis when small-vessel infarctions expand locally or when new infarctions develop in the same vascular territory. They also demonstrate the angioinvasive nature of some fungal species such as Exserohilum, which can lead to progressive vascular occlusion, the investigators said.
No relevant financial conflicts of interest were reported.
The recent outbreak of fungal meningitis caused by spinal injections of contaminated methylprednisolone illustrates that the disease can present as ischemic stroke, according to a report published online July 22 in JAMA Neurology.
Three such cases occurred in elderly patients who had clear risk factors for stroke and no fever or meningeal signs; whose exposure to the contaminated injection was as remote as 4 weeks earlier; and whose early MRI scans indicated stroke rather than infection, said Dr. Kirk Kleinfeld and his associates at Vanderbilt University Medical Center, Nashville, Tenn.
The investigators described these cases in detail so as to alert clinicians to this confusing presentation, which would enable them to initiate antifungal therapy as soon as possible. In two of these cases, the diagnosis was delayed and the patients died. In the third case, once clinical suspicion of fungal meningitis had been aroused, empiric antifungal therapy appears to have saved the patient’s life, they noted.
"An awareness of the presentation and vascular sequelae of fungal meningitis in immunocompetent patients should lead to earlier treatment and improved outcomes prior to a definitive diagnosis," Dr. Kleinfeld and his colleagues wrote.
In the first case, a 78-year-old man presented with acute-onset, left-sided weakness and dysarthria. He was afebrile and had no meningeal signs, and his laboratory workup showed only mild leukocytosis. He had hyperlipidemia, hypertension, and atrial fibrillation, and an MRI scan showed a small-vessel ischemic infarct of the right anterior superior pons/lower midbrain.
The patient failed to improve with standard poststroke care. When his left-sided weakness worsened on day 3, another MRI showed that the infarct had extended and a new one had formed in the right thalamus. The next day he became unresponsive, and repeated imaging showed enlargement and evolution of those infarcts plus formation of an occlusion of the right superior cerebellar artery. The patient died on day 6.
An autopsy was performed when it was noted that the patient had received an epidural steroid injection 2 weeks earlier to treat low-back pain. It "revealed small areas of focal cortical and pontine subarachnoid hemorrhage, as well as fungal cerebral vasculitis with aneurysm formation." Infection with Exserohilum species was identified, the investigators reported (JAMA Neurol. 2013 July 22 [doi: 10.1001/jamaneurol.2013.3586]).
In the second case, a 78-year-old woman presented with subacute vertigo, nausea, and headache, and was found on examination to have one-sided dysmetria and mild ataxia. Her medical history included hypertension, hyperlipidemia, and coronary artery disease, and the initial laboratory workup revealed type 2 diabetes. The authors noted that an MRI scan showed "ischemic infarcts of the left lateral pons, superior cerebellar peduncle, and superior cerebellum suggestive of a large-vessel (superior cerebellar artery) etiology."
A hypercoagulable panel revealed lupus anticoagulant and elevated antiphospholipid protein antibodies. Anticoagulation therapy was given. The patient failed to improve, and on day 4 she developed a low-grade fever and mild encephalopathy. A repeat MRI showed a new ischemic pontine stroke.
The patient’s mental status failed to improve, and it was noted that she had received an epidural steroid injection 2 weeks earlier to treat low-back pain. The patient underwent lumbar puncture to identify any fungal infection, and intravenous antibiotics and voriconazole were administered beginning on day 15. However, the patient died on day 50.
"An autopsy revealed a left superior cerebellar artery mycotic aneurysm with vascular infiltration of the arterial wall by hyphal fungal forms," which were thought to represent Exserohilum species based on polymerase chain reaction studies, the investigators reported.
In the third case, a 70-year-old woman presented with headache, difficulty balancing, nuchal rigidity, and mild fever. She had hyperlipidemia, and physical examination showed mild dysarthria and bilateral dysmetria. An MRI scan revealed acute small-vessel strokes in the right thalamus and internal capsule.
Because the patient had chronic back pain and the clinicians’ suspicions were raised regarding fungal meningitis, it was found that she had undergone an epidural steroid injection 1 month earlier. A lumbar puncture was performed to identify possible fungal infection, and treatment with intravenous antibiotics and voriconazole was initiated.
The patient became encephalopathic on day 7, and a repeat MRI showed a new small-vessel stroke involving the left internal capsule. With continued voriconazole therapy, the patient’s mental status and her cerebrospinal fluid cell counts slowly improved. She survived and was discharged 37 days later.
"We suspect that [the early antifungal treatment] halted the further vascular progression of her infection," Dr. Kleinfeld and his associates wrote.
All three patients received methylprednisolone from contaminated lots at medical facilities that were identified by the Centers for Disease Control and Prevention as recipients of contaminated lots.
These cases show that clinicians should consider an atypical pathogenesis when small-vessel infarctions expand locally or when new infarctions develop in the same vascular territory. They also demonstrate the angioinvasive nature of some fungal species such as Exserohilum, which can lead to progressive vascular occlusion, the investigators said.
No relevant financial conflicts of interest were reported.
The recent outbreak of fungal meningitis caused by spinal injections of contaminated methylprednisolone illustrates that the disease can present as ischemic stroke, according to a report published online July 22 in JAMA Neurology.
Three such cases occurred in elderly patients who had clear risk factors for stroke and no fever or meningeal signs; whose exposure to the contaminated injection was as remote as 4 weeks earlier; and whose early MRI scans indicated stroke rather than infection, said Dr. Kirk Kleinfeld and his associates at Vanderbilt University Medical Center, Nashville, Tenn.
The investigators described these cases in detail so as to alert clinicians to this confusing presentation, which would enable them to initiate antifungal therapy as soon as possible. In two of these cases, the diagnosis was delayed and the patients died. In the third case, once clinical suspicion of fungal meningitis had been aroused, empiric antifungal therapy appears to have saved the patient’s life, they noted.
"An awareness of the presentation and vascular sequelae of fungal meningitis in immunocompetent patients should lead to earlier treatment and improved outcomes prior to a definitive diagnosis," Dr. Kleinfeld and his colleagues wrote.
In the first case, a 78-year-old man presented with acute-onset, left-sided weakness and dysarthria. He was afebrile and had no meningeal signs, and his laboratory workup showed only mild leukocytosis. He had hyperlipidemia, hypertension, and atrial fibrillation, and an MRI scan showed a small-vessel ischemic infarct of the right anterior superior pons/lower midbrain.
The patient failed to improve with standard poststroke care. When his left-sided weakness worsened on day 3, another MRI showed that the infarct had extended and a new one had formed in the right thalamus. The next day he became unresponsive, and repeated imaging showed enlargement and evolution of those infarcts plus formation of an occlusion of the right superior cerebellar artery. The patient died on day 6.
An autopsy was performed when it was noted that the patient had received an epidural steroid injection 2 weeks earlier to treat low-back pain. It "revealed small areas of focal cortical and pontine subarachnoid hemorrhage, as well as fungal cerebral vasculitis with aneurysm formation." Infection with Exserohilum species was identified, the investigators reported (JAMA Neurol. 2013 July 22 [doi: 10.1001/jamaneurol.2013.3586]).
In the second case, a 78-year-old woman presented with subacute vertigo, nausea, and headache, and was found on examination to have one-sided dysmetria and mild ataxia. Her medical history included hypertension, hyperlipidemia, and coronary artery disease, and the initial laboratory workup revealed type 2 diabetes. The authors noted that an MRI scan showed "ischemic infarcts of the left lateral pons, superior cerebellar peduncle, and superior cerebellum suggestive of a large-vessel (superior cerebellar artery) etiology."
A hypercoagulable panel revealed lupus anticoagulant and elevated antiphospholipid protein antibodies. Anticoagulation therapy was given. The patient failed to improve, and on day 4 she developed a low-grade fever and mild encephalopathy. A repeat MRI showed a new ischemic pontine stroke.
The patient’s mental status failed to improve, and it was noted that she had received an epidural steroid injection 2 weeks earlier to treat low-back pain. The patient underwent lumbar puncture to identify any fungal infection, and intravenous antibiotics and voriconazole were administered beginning on day 15. However, the patient died on day 50.
"An autopsy revealed a left superior cerebellar artery mycotic aneurysm with vascular infiltration of the arterial wall by hyphal fungal forms," which were thought to represent Exserohilum species based on polymerase chain reaction studies, the investigators reported.
In the third case, a 70-year-old woman presented with headache, difficulty balancing, nuchal rigidity, and mild fever. She had hyperlipidemia, and physical examination showed mild dysarthria and bilateral dysmetria. An MRI scan revealed acute small-vessel strokes in the right thalamus and internal capsule.
Because the patient had chronic back pain and the clinicians’ suspicions were raised regarding fungal meningitis, it was found that she had undergone an epidural steroid injection 1 month earlier. A lumbar puncture was performed to identify possible fungal infection, and treatment with intravenous antibiotics and voriconazole was initiated.
The patient became encephalopathic on day 7, and a repeat MRI showed a new small-vessel stroke involving the left internal capsule. With continued voriconazole therapy, the patient’s mental status and her cerebrospinal fluid cell counts slowly improved. She survived and was discharged 37 days later.
"We suspect that [the early antifungal treatment] halted the further vascular progression of her infection," Dr. Kleinfeld and his associates wrote.
All three patients received methylprednisolone from contaminated lots at medical facilities that were identified by the Centers for Disease Control and Prevention as recipients of contaminated lots.
These cases show that clinicians should consider an atypical pathogenesis when small-vessel infarctions expand locally or when new infarctions develop in the same vascular territory. They also demonstrate the angioinvasive nature of some fungal species such as Exserohilum, which can lead to progressive vascular occlusion, the investigators said.
No relevant financial conflicts of interest were reported.
FROM JAMA NEUROLOGY
Major finding: Of three patients with fungal meningitis, one was diagnosed quickly enough after a series of what appeared to be strokes to be treated successfully with intravenous antibiotics and voriconazole and was discharged 37 days after initial admission. The other two patients died 6 and 50 days after hospital admission.
Data source: A case series in which three elderly patients whose low-back pain had been treated with contaminated epidural steroid injections developed fungal meningitis that masqueraded as stroke.
Disclosures: No relevant financial conflicts of interest were reported.
Radium-223 prolongs survival in metastatic prostate cancer
Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.
Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).
The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.
The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.
These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).
All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.
The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).
A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.
These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.
Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.
In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.
The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.
This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.
The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.
The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.
A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.
The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.
This study demonstrates a clear survival advantage with a compound that has "remarkable tolerability," imparting "some long-awaited momentum to research on the use of alpha emitters," said Dr. Neha Vapiwala and Dr. Eli Glatstein.
Given radium-223’s ability to both complement and contend with existing treatments, "the first-line role of taxanes in metastatic castration-resistant prostate cancer may be reexamined, and the viability of alpha particles in medicine may be newly explored," they noted.
Dr. Vapiwala and Dr. Glatstein are in the department of radiation oncology at the University of Pennsylvania, Philadelphia. They reported no relevant financial conflicts of interest. These remarks were taken from their editorial accompanying Dr. Parker’s report (N. Engl. J. Med. 2013 July 18 [doi:10.1056/NEJMe1304041]).
This study demonstrates a clear survival advantage with a compound that has "remarkable tolerability," imparting "some long-awaited momentum to research on the use of alpha emitters," said Dr. Neha Vapiwala and Dr. Eli Glatstein.
Given radium-223’s ability to both complement and contend with existing treatments, "the first-line role of taxanes in metastatic castration-resistant prostate cancer may be reexamined, and the viability of alpha particles in medicine may be newly explored," they noted.
Dr. Vapiwala and Dr. Glatstein are in the department of radiation oncology at the University of Pennsylvania, Philadelphia. They reported no relevant financial conflicts of interest. These remarks were taken from their editorial accompanying Dr. Parker’s report (N. Engl. J. Med. 2013 July 18 [doi:10.1056/NEJMe1304041]).
This study demonstrates a clear survival advantage with a compound that has "remarkable tolerability," imparting "some long-awaited momentum to research on the use of alpha emitters," said Dr. Neha Vapiwala and Dr. Eli Glatstein.
Given radium-223’s ability to both complement and contend with existing treatments, "the first-line role of taxanes in metastatic castration-resistant prostate cancer may be reexamined, and the viability of alpha particles in medicine may be newly explored," they noted.
Dr. Vapiwala and Dr. Glatstein are in the department of radiation oncology at the University of Pennsylvania, Philadelphia. They reported no relevant financial conflicts of interest. These remarks were taken from their editorial accompanying Dr. Parker’s report (N. Engl. J. Med. 2013 July 18 [doi:10.1056/NEJMe1304041]).
Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.
Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).
The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.
The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.
These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).
All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.
The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).
A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.
These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.
Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.
In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.
The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.
This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.
The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.
The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.
A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.
The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.
Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.
Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).
The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.
The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.
These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).
All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.
The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).
A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.
These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.
Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.
In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.
The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.
This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.
The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.
The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.
A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.
The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: The primary end point, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group.
Data source: An international phase III randomized placebo-controlled trial involving 921 men who had castration-resistant prostate cancer with symptomatic bone metastases.
Disclosures: The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.
High-risk smokers benefit most from CT screening for lung cancer
Low-dose computed tomography screening for lung cancer prevents the greatest number of deaths if it is reserved for smokers at highest risk of dying from the disease within 5 years, and it prevents very few deaths among those at lowest risk, according to a report published online July 18 in the New England Journal of Medicine.
When smokers were stratified into quintiles based on 5-year risk of death, 161 patients in the highest-risk quintile would need to be screened using low-dose CT to prevent 1 lung cancer death. In contrast, among the smokers in the lowest-risk quintile, 5,276 would need to be screened to prevent 1 lung cancer death, said Stephanie A. Kovalchik, Ph.D., of the National Cancer Institute and her associates.
These findings provide the empirical evidence that the medical community has been seeking to identify patients who would reap the most benefit from targeted screening – a benefit that would clearly outweigh the harm of the relatively frequent false-positive results with low-dose CT screening.
At present, screening guidelines all recommend low-dose CT screening for patients who meet the NLST (National Lung Screening Trial) entry criteria, but some experts argue that further refinement of screening criteria would be appropriate. The observations in this study "argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria, to increase the efficiency of low-dose CT screening," the investigators said.
Dr. Kovalchik and her colleagues examined whether the benefits and harms of low-dose CT scanning in the NLST differed according to the study subjects’ prescreening risk of lung cancer death, which was determined at enrollment using a validated prediction model. Risk factors included in this model were age, body mass index, family history of lung cancer, pack-years of smoking, years since smoking cessation (among patients who had quit), presence or absence of emphysema, sex, and race.
The NLST was a large randomized clinical trial that compared the efficacy of this screening technique against that of chest radiography in 53,454 smokers aged 55-74 years who had a minimum of 30 pack-years of smoking.
For their study, Dr. Kovalchik and her associates assessed outcomes in 26,604 NLST participants who had undergone three annual CT scans and 26,554 who had undergone three annual radiographs in the trial’s intention-to-treat population.
The primary end point was the rate of death from lung cancer during a median of 5.5 years of follow-up. This end point was reached by 354 subjects in the CT group, compared with 442 in the radiography group.
The rate of lung cancer deaths was 24.6 per 10,000 person-years among subjects screened by CT, compared with 30.9 per 10,000 person-years among those screened by radiography. This reflects a 20% relative reduction in lung cancer deaths with low-dose CT screening, the investigators reported (N. Engl. J. Med. 2013 July 18 [doi: 10.1056/NEJMoa1301851]).
The researchers developed an absolute risk-prediction model for lung-cancer mortality that accounted for a participant’s specific risk characteristics and life expectancy by incorporating Cox proportional-hazards models of death from lung cancer and competing causes of death. Predictors of lung-cancer death were selected from a set of previously identified demographic and clinical risk factors for lung cancer (including smoking history) using Lasso regression. The prediction model was externally validated with outcome data from 15,114 NLST-eligible and 22,649 NLST-ineligible smokers aged 55-74 years who were enrolled in the radiography group of the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial. The participants were stratified into five quintiles for the predicted 5-year risk of death from lung cancer.
"Participants at highest risk for lung cancer death accounted for a disproportionate share of the benefits of low-dose CT screening. For example, 77 of 88 CT-prevented lung cancer deaths (88%) occurred among the 60% of participants with a 5-year risk of lung-cancer death of 0.85% or more, whereas only 1% of prevented lung-cancer deaths occurred among the 20% of participants at lowest risk," the researchers said.
Restricting screening to the 60% of participants at highest risk for death from lung cancer within 5 years (more than 0.85%), as compared with the entire CT group, captured 88% of CT-preventable lung-cancer deaths, reduced the number of participants who would need to be screened to prevent one lung-cancer death from 302 to 161, and reduced the number of false-positive results per CT-prevented lung cancer death from 108 to 65. In contrast, the 20% of participants at lowest risk for lung cancer death accounted for almost none of the CT-prevented lung cancer deaths, the researchers said.
"These observations argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria to increase the efficiency of low-dose CT screening. ... [T]ailoring of low-dose CT screening to a patient’s predicted risk of lung cancer death could narrow the NLST-eligible population without a loss in the potential public health benefits of screening or a disproportionate increase in the potential harms," they wrote.
Dr. Kovalchik and her colleagues noted that this screening technique was of limited efficacy in one important subgroup of smokers: those who had coexisting pulmonary disorders. Further study of the benefits and harms of low-dose CT screening in such patients is needed.
This study was funded by the National Cancer Institute. No relevant financial conflicts of interest were reported.
Low-dose computed tomography screening for lung cancer prevents the greatest number of deaths if it is reserved for smokers at highest risk of dying from the disease within 5 years, and it prevents very few deaths among those at lowest risk, according to a report published online July 18 in the New England Journal of Medicine.
When smokers were stratified into quintiles based on 5-year risk of death, 161 patients in the highest-risk quintile would need to be screened using low-dose CT to prevent 1 lung cancer death. In contrast, among the smokers in the lowest-risk quintile, 5,276 would need to be screened to prevent 1 lung cancer death, said Stephanie A. Kovalchik, Ph.D., of the National Cancer Institute and her associates.
These findings provide the empirical evidence that the medical community has been seeking to identify patients who would reap the most benefit from targeted screening – a benefit that would clearly outweigh the harm of the relatively frequent false-positive results with low-dose CT screening.
At present, screening guidelines all recommend low-dose CT screening for patients who meet the NLST (National Lung Screening Trial) entry criteria, but some experts argue that further refinement of screening criteria would be appropriate. The observations in this study "argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria, to increase the efficiency of low-dose CT screening," the investigators said.
Dr. Kovalchik and her colleagues examined whether the benefits and harms of low-dose CT scanning in the NLST differed according to the study subjects’ prescreening risk of lung cancer death, which was determined at enrollment using a validated prediction model. Risk factors included in this model were age, body mass index, family history of lung cancer, pack-years of smoking, years since smoking cessation (among patients who had quit), presence or absence of emphysema, sex, and race.
The NLST was a large randomized clinical trial that compared the efficacy of this screening technique against that of chest radiography in 53,454 smokers aged 55-74 years who had a minimum of 30 pack-years of smoking.
For their study, Dr. Kovalchik and her associates assessed outcomes in 26,604 NLST participants who had undergone three annual CT scans and 26,554 who had undergone three annual radiographs in the trial’s intention-to-treat population.
The primary end point was the rate of death from lung cancer during a median of 5.5 years of follow-up. This end point was reached by 354 subjects in the CT group, compared with 442 in the radiography group.
The rate of lung cancer deaths was 24.6 per 10,000 person-years among subjects screened by CT, compared with 30.9 per 10,000 person-years among those screened by radiography. This reflects a 20% relative reduction in lung cancer deaths with low-dose CT screening, the investigators reported (N. Engl. J. Med. 2013 July 18 [doi: 10.1056/NEJMoa1301851]).
The researchers developed an absolute risk-prediction model for lung-cancer mortality that accounted for a participant’s specific risk characteristics and life expectancy by incorporating Cox proportional-hazards models of death from lung cancer and competing causes of death. Predictors of lung-cancer death were selected from a set of previously identified demographic and clinical risk factors for lung cancer (including smoking history) using Lasso regression. The prediction model was externally validated with outcome data from 15,114 NLST-eligible and 22,649 NLST-ineligible smokers aged 55-74 years who were enrolled in the radiography group of the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial. The participants were stratified into five quintiles for the predicted 5-year risk of death from lung cancer.
"Participants at highest risk for lung cancer death accounted for a disproportionate share of the benefits of low-dose CT screening. For example, 77 of 88 CT-prevented lung cancer deaths (88%) occurred among the 60% of participants with a 5-year risk of lung-cancer death of 0.85% or more, whereas only 1% of prevented lung-cancer deaths occurred among the 20% of participants at lowest risk," the researchers said.
Restricting screening to the 60% of participants at highest risk for death from lung cancer within 5 years (more than 0.85%), as compared with the entire CT group, captured 88% of CT-preventable lung-cancer deaths, reduced the number of participants who would need to be screened to prevent one lung-cancer death from 302 to 161, and reduced the number of false-positive results per CT-prevented lung cancer death from 108 to 65. In contrast, the 20% of participants at lowest risk for lung cancer death accounted for almost none of the CT-prevented lung cancer deaths, the researchers said.
"These observations argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria to increase the efficiency of low-dose CT screening. ... [T]ailoring of low-dose CT screening to a patient’s predicted risk of lung cancer death could narrow the NLST-eligible population without a loss in the potential public health benefits of screening or a disproportionate increase in the potential harms," they wrote.
Dr. Kovalchik and her colleagues noted that this screening technique was of limited efficacy in one important subgroup of smokers: those who had coexisting pulmonary disorders. Further study of the benefits and harms of low-dose CT screening in such patients is needed.
This study was funded by the National Cancer Institute. No relevant financial conflicts of interest were reported.
Low-dose computed tomography screening for lung cancer prevents the greatest number of deaths if it is reserved for smokers at highest risk of dying from the disease within 5 years, and it prevents very few deaths among those at lowest risk, according to a report published online July 18 in the New England Journal of Medicine.
When smokers were stratified into quintiles based on 5-year risk of death, 161 patients in the highest-risk quintile would need to be screened using low-dose CT to prevent 1 lung cancer death. In contrast, among the smokers in the lowest-risk quintile, 5,276 would need to be screened to prevent 1 lung cancer death, said Stephanie A. Kovalchik, Ph.D., of the National Cancer Institute and her associates.
These findings provide the empirical evidence that the medical community has been seeking to identify patients who would reap the most benefit from targeted screening – a benefit that would clearly outweigh the harm of the relatively frequent false-positive results with low-dose CT screening.
At present, screening guidelines all recommend low-dose CT screening for patients who meet the NLST (National Lung Screening Trial) entry criteria, but some experts argue that further refinement of screening criteria would be appropriate. The observations in this study "argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria, to increase the efficiency of low-dose CT screening," the investigators said.
Dr. Kovalchik and her colleagues examined whether the benefits and harms of low-dose CT scanning in the NLST differed according to the study subjects’ prescreening risk of lung cancer death, which was determined at enrollment using a validated prediction model. Risk factors included in this model were age, body mass index, family history of lung cancer, pack-years of smoking, years since smoking cessation (among patients who had quit), presence or absence of emphysema, sex, and race.
The NLST was a large randomized clinical trial that compared the efficacy of this screening technique against that of chest radiography in 53,454 smokers aged 55-74 years who had a minimum of 30 pack-years of smoking.
For their study, Dr. Kovalchik and her associates assessed outcomes in 26,604 NLST participants who had undergone three annual CT scans and 26,554 who had undergone three annual radiographs in the trial’s intention-to-treat population.
The primary end point was the rate of death from lung cancer during a median of 5.5 years of follow-up. This end point was reached by 354 subjects in the CT group, compared with 442 in the radiography group.
The rate of lung cancer deaths was 24.6 per 10,000 person-years among subjects screened by CT, compared with 30.9 per 10,000 person-years among those screened by radiography. This reflects a 20% relative reduction in lung cancer deaths with low-dose CT screening, the investigators reported (N. Engl. J. Med. 2013 July 18 [doi: 10.1056/NEJMoa1301851]).
The researchers developed an absolute risk-prediction model for lung-cancer mortality that accounted for a participant’s specific risk characteristics and life expectancy by incorporating Cox proportional-hazards models of death from lung cancer and competing causes of death. Predictors of lung-cancer death were selected from a set of previously identified demographic and clinical risk factors for lung cancer (including smoking history) using Lasso regression. The prediction model was externally validated with outcome data from 15,114 NLST-eligible and 22,649 NLST-ineligible smokers aged 55-74 years who were enrolled in the radiography group of the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial. The participants were stratified into five quintiles for the predicted 5-year risk of death from lung cancer.
"Participants at highest risk for lung cancer death accounted for a disproportionate share of the benefits of low-dose CT screening. For example, 77 of 88 CT-prevented lung cancer deaths (88%) occurred among the 60% of participants with a 5-year risk of lung-cancer death of 0.85% or more, whereas only 1% of prevented lung-cancer deaths occurred among the 20% of participants at lowest risk," the researchers said.
Restricting screening to the 60% of participants at highest risk for death from lung cancer within 5 years (more than 0.85%), as compared with the entire CT group, captured 88% of CT-preventable lung-cancer deaths, reduced the number of participants who would need to be screened to prevent one lung-cancer death from 302 to 161, and reduced the number of false-positive results per CT-prevented lung cancer death from 108 to 65. In contrast, the 20% of participants at lowest risk for lung cancer death accounted for almost none of the CT-prevented lung cancer deaths, the researchers said.
"These observations argue for the use of individualized risk assessment of lung cancer death instead of the NLST entry criteria to increase the efficiency of low-dose CT screening. ... [T]ailoring of low-dose CT screening to a patient’s predicted risk of lung cancer death could narrow the NLST-eligible population without a loss in the potential public health benefits of screening or a disproportionate increase in the potential harms," they wrote.
Dr. Kovalchik and her colleagues noted that this screening technique was of limited efficacy in one important subgroup of smokers: those who had coexisting pulmonary disorders. Further study of the benefits and harms of low-dose CT screening in such patients is needed.
This study was funded by the National Cancer Institute. No relevant financial conflicts of interest were reported.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: The rate of lung cancer deaths was 24.6 per 10,000 person-years among subjects screened by CT, compared with 30.9 per 10,000 person-years among those screened by radiography, which reflects a 20% relative reduction.
Data source: A secondary analysis of data on 26,604 NLST participants who had three annual low-dose lung CTs and 26,554 who had three chest radiographs to screen for lung cancer, all of whom were followed for 5 years.
Disclosures: This study was funded by the National Cancer Institute. No relevant financial conflicts of interest were reported.