Mary Ann Moon

Adding evolocumab to both moderate- and high-intensity statin therapy lowered low-density lipoprotein cholesterol even further in an international phase III clinical trial reported online May 13 in JAMA.

Evolocumab, a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), showed robust LDL cholesterol–lowering properties in preliminary studies and was well tolerated. In this industry-sponsored, phase III trial, evolocumab significantly reduced LDL cholesterol (LDL-C) in a substantially larger portion of patients, compared with both placebo and additive ezetimibe, with comparable rates of adverse events, said Dr. Jennifer G. Robinson, who is professor of both epidemiology and medicine as well as director of the lipid research clinic and codirector of the prevention intervention center at the University of Iowa College of Public Health, Iowa City, and her associates.

This is the first study to demonstrate that adding evolocumab allows most (86%-94%) patients to achieve LDL-C levels of less than 70 mg/dL regardless of background statin type or dose, they noted.

The double-blind trial involved 1,899 adults up to 80 years of age (mean age, 60 years) residing in Australia, Belgium, Canada, the Czech Republic, Denmark, France, Germany, Hong Kong, Hungary, Italy, the Netherlands, Russia, Spain, Sweden, Switzerland, the United Kingdom, and the United States. At enrollment, 29% were already taking intensive statin therapy, 41% were taking nonintensive statin therapy, and 30% were not taking statins.

Nearly half of the study participants were women; 23% had coronary artery disease, 10% had other atherosclerotic cardiovascular disease, and 16% had diabetes mellitus. These participants were randomly assigned to 1 of 24 treatment groups for 12 weeks, in which they took oral atorvastatin, rosuvastatin, or simvastatin in a variety of doses, plus either subcutaneous evolocumab or placebo injections on different schedules or oral ezetimibe or oral placebo.

Every group of patients who received additive evolocumab, whether at dosing every-2 weeks or at monthly dosing, showed significant lowering of LDL-cholesterol beyond what was achieved with background statin therapy. Compared with placebo, the reduction from baseline LDL-cholesterol level ranged from 66% to 75%.

In comparison, the reduction from baseline with ezetimibe never exceeded 24%.

With additive evolocumab, 86%-94% of patients achieved LDL-cholesterol levels of less than 70 mg/dL. In contrast, only 17%-62% of patients receiving additive ezetimibe achieved such low levels, Dr. Robinson and her associates said (JAMA 2014;311:1870-82).

Adding evolocumab also improved non–high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein B, triglyceride, and HDL-cholesterol profiles, beyond the benefits of statin therapy alone.

The rates of adverse events that lead to discontinuation of the study drug were 1.9% with evolocumab, 1.8% with ezetimibe, and 2.2% with placebo, and the rates of serious adverse events were 2.1%, 0.9%, and 2.3%, respectively.

The next step in assessing evolocumab will be to determine whether these lowering of LDL cholesterol levels translate into reductions in atherosclerotic CVD events. And, given the short-term duration of treatment in this trial, future research also must address longer-term safety and clinical outcomes, the investigators said.

Adding evolocumab to both moderate- and high-intensity statin therapy lowered low-density lipoprotein cholesterol even further in an international phase III clinical trial reported online May 13 in JAMA.

Evolocumab, a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), showed robust LDL cholesterol–lowering properties in preliminary studies and was well tolerated. In this industry-sponsored, phase III trial, evolocumab significantly reduced LDL cholesterol (LDL-C) in a substantially larger portion of patients, compared with both placebo and additive ezetimibe, with comparable rates of adverse events, said Dr. Jennifer G. Robinson, who is professor of both epidemiology and medicine as well as director of the lipid research clinic and codirector of the prevention intervention center at the University of Iowa College of Public Health, Iowa City, and her associates.

This is the first study to demonstrate that adding evolocumab allows most (86%-94%) patients to achieve LDL-C levels of less than 70 mg/dL regardless of background statin type or dose, they noted.

The double-blind trial involved 1,899 adults up to 80 years of age (mean age, 60 years) residing in Australia, Belgium, Canada, the Czech Republic, Denmark, France, Germany, Hong Kong, Hungary, Italy, the Netherlands, Russia, Spain, Sweden, Switzerland, the United Kingdom, and the United States. At enrollment, 29% were already taking intensive statin therapy, 41% were taking nonintensive statin therapy, and 30% were not taking statins.

Nearly half of the study participants were women; 23% had coronary artery disease, 10% had other atherosclerotic cardiovascular disease, and 16% had diabetes mellitus. These participants were randomly assigned to 1 of 24 treatment groups for 12 weeks, in which they took oral atorvastatin, rosuvastatin, or simvastatin in a variety of doses, plus either subcutaneous evolocumab or placebo injections on different schedules or oral ezetimibe or oral placebo.

Every group of patients who received additive evolocumab, whether at dosing every-2 weeks or at monthly dosing, showed significant lowering of LDL-cholesterol beyond what was achieved with background statin therapy. Compared with placebo, the reduction from baseline LDL-cholesterol level ranged from 66% to 75%.

In comparison, the reduction from baseline with ezetimibe never exceeded 24%.

With additive evolocumab, 86%-94% of patients achieved LDL-cholesterol levels of less than 70 mg/dL. In contrast, only 17%-62% of patients receiving additive ezetimibe achieved such low levels, Dr. Robinson and her associates said (JAMA 2014;311:1870-82).

Adding evolocumab also improved non–high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein B, triglyceride, and HDL-cholesterol profiles, beyond the benefits of statin therapy alone.

The rates of adverse events that lead to discontinuation of the study drug were 1.9% with evolocumab, 1.8% with ezetimibe, and 2.2% with placebo, and the rates of serious adverse events were 2.1%, 0.9%, and 2.3%, respectively.

The next step in assessing evolocumab will be to determine whether these lowering of LDL cholesterol levels translate into reductions in atherosclerotic CVD events. And, given the short-term duration of treatment in this trial, future research also must address longer-term safety and clinical outcomes, the investigators said.

Adding evolocumab to both moderate- and high-intensity statin therapy lowered low-density lipoprotein cholesterol even further in an international phase III clinical trial reported online May 13 in JAMA.

Evolocumab, a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), showed robust LDL cholesterol–lowering properties in preliminary studies and was well tolerated. In this industry-sponsored, phase III trial, evolocumab significantly reduced LDL cholesterol (LDL-C) in a substantially larger portion of patients, compared with both placebo and additive ezetimibe, with comparable rates of adverse events, said Dr. Jennifer G. Robinson, who is professor of both epidemiology and medicine as well as director of the lipid research clinic and codirector of the prevention intervention center at the University of Iowa College of Public Health, Iowa City, and her associates.

This is the first study to demonstrate that adding evolocumab allows most (86%-94%) patients to achieve LDL-C levels of less than 70 mg/dL regardless of background statin type or dose, they noted.

The double-blind trial involved 1,899 adults up to 80 years of age (mean age, 60 years) residing in Australia, Belgium, Canada, the Czech Republic, Denmark, France, Germany, Hong Kong, Hungary, Italy, the Netherlands, Russia, Spain, Sweden, Switzerland, the United Kingdom, and the United States. At enrollment, 29% were already taking intensive statin therapy, 41% were taking nonintensive statin therapy, and 30% were not taking statins.

Nearly half of the study participants were women; 23% had coronary artery disease, 10% had other atherosclerotic cardiovascular disease, and 16% had diabetes mellitus. These participants were randomly assigned to 1 of 24 treatment groups for 12 weeks, in which they took oral atorvastatin, rosuvastatin, or simvastatin in a variety of doses, plus either subcutaneous evolocumab or placebo injections on different schedules or oral ezetimibe or oral placebo.

Every group of patients who received additive evolocumab, whether at dosing every-2 weeks or at monthly dosing, showed significant lowering of LDL-cholesterol beyond what was achieved with background statin therapy. Compared with placebo, the reduction from baseline LDL-cholesterol level ranged from 66% to 75%.

In comparison, the reduction from baseline with ezetimibe never exceeded 24%.

With additive evolocumab, 86%-94% of patients achieved LDL-cholesterol levels of less than 70 mg/dL. In contrast, only 17%-62% of patients receiving additive ezetimibe achieved such low levels, Dr. Robinson and her associates said (JAMA 2014;311:1870-82).

Adding evolocumab also improved non–high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein B, triglyceride, and HDL-cholesterol profiles, beyond the benefits of statin therapy alone.

The rates of adverse events that lead to discontinuation of the study drug were 1.9% with evolocumab, 1.8% with ezetimibe, and 2.2% with placebo, and the rates of serious adverse events were 2.1%, 0.9%, and 2.3%, respectively.

The next step in assessing evolocumab will be to determine whether these lowering of LDL cholesterol levels translate into reductions in atherosclerotic CVD events. And, given the short-term duration of treatment in this trial, future research also must address longer-term safety and clinical outcomes, the investigators said.

Adults with schizophrenia showed an impaired ability to detect and understand sarcasm and lying in a video test depicting contextual clues such as facial expressions, vocal inflections, and body language, according to a published report.

People with schizophrenia consistently show deficits in theory of mind reasoning, defined as the ability to attribute mental states such as beliefs and intentions to other people. Most studies of this impairment use written short stories or cartoon vignettes to assess patients’ social perception abilities – tests that aren’t representative of real-world encounters and don’t include contextual clues, said Briana Cassetta and Vina Goghari, Ph.D., of the Clinical Neuroscience of Schizophrenia Laboratory and the department of psychology, University of Calgary (Alta.).

They assessed 30 adults with schizophrenia or schizoaffective disorder, 28 first-degree relatives who did not have schizophrenia or schizoaffective disorder, and 27 healthy control subjects matched for age and sex. The authors used two parts of TASIT (The Awareness of Social Inference Test), which uses videotaped vignettes of professional actors presenting a series of sincere, lying, and sarcastic exchanges such as might be encountered in daily life. The people with schizophrenia showed an intact ability to understand sincere exchanges but consistently performed poorly at comprehending sarcasm and lying, compared with both control groups, the investigators reported (Psychiatry Res. 2014 [doi: 10.1016/psychres.2014.03.043]).

In this study, the unaffected relatives of schizophrenia patients attained scores that were comparable to those of healthy controls, providing further support for the idea that these theory of mind deficits are disease specific, Ms. Cassetta and Dr. Goghari noted.

Future research regarding theory of mind "may benefit from utilizing tasks that incorporate dynamic social cues that are available in everyday social communication, in order to obtain a more accurate assessment of [participants’] abilities," they added.

This study was supported by the Canadian Institutes of Health Research, the University of Calgary, the Social Sciences and Humanities Research Council of Canada, and Alberta Innovates Health Solutions. No financial conflicts of interest were reported.

Adults with schizophrenia showed an impaired ability to detect and understand sarcasm and lying in a video test depicting contextual clues such as facial expressions, vocal inflections, and body language, according to a published report.

People with schizophrenia consistently show deficits in theory of mind reasoning, defined as the ability to attribute mental states such as beliefs and intentions to other people. Most studies of this impairment use written short stories or cartoon vignettes to assess patients’ social perception abilities – tests that aren’t representative of real-world encounters and don’t include contextual clues, said Briana Cassetta and Vina Goghari, Ph.D., of the Clinical Neuroscience of Schizophrenia Laboratory and the department of psychology, University of Calgary (Alta.).

They assessed 30 adults with schizophrenia or schizoaffective disorder, 28 first-degree relatives who did not have schizophrenia or schizoaffective disorder, and 27 healthy control subjects matched for age and sex. The authors used two parts of TASIT (The Awareness of Social Inference Test), which uses videotaped vignettes of professional actors presenting a series of sincere, lying, and sarcastic exchanges such as might be encountered in daily life. The people with schizophrenia showed an intact ability to understand sincere exchanges but consistently performed poorly at comprehending sarcasm and lying, compared with both control groups, the investigators reported (Psychiatry Res. 2014 [doi: 10.1016/psychres.2014.03.043]).

In this study, the unaffected relatives of schizophrenia patients attained scores that were comparable to those of healthy controls, providing further support for the idea that these theory of mind deficits are disease specific, Ms. Cassetta and Dr. Goghari noted.

Future research regarding theory of mind "may benefit from utilizing tasks that incorporate dynamic social cues that are available in everyday social communication, in order to obtain a more accurate assessment of [participants’] abilities," they added.

This study was supported by the Canadian Institutes of Health Research, the University of Calgary, the Social Sciences and Humanities Research Council of Canada, and Alberta Innovates Health Solutions. No financial conflicts of interest were reported.

Adults with schizophrenia showed an impaired ability to detect and understand sarcasm and lying in a video test depicting contextual clues such as facial expressions, vocal inflections, and body language, according to a published report.

People with schizophrenia consistently show deficits in theory of mind reasoning, defined as the ability to attribute mental states such as beliefs and intentions to other people. Most studies of this impairment use written short stories or cartoon vignettes to assess patients’ social perception abilities – tests that aren’t representative of real-world encounters and don’t include contextual clues, said Briana Cassetta and Vina Goghari, Ph.D., of the Clinical Neuroscience of Schizophrenia Laboratory and the department of psychology, University of Calgary (Alta.).

They assessed 30 adults with schizophrenia or schizoaffective disorder, 28 first-degree relatives who did not have schizophrenia or schizoaffective disorder, and 27 healthy control subjects matched for age and sex. The authors used two parts of TASIT (The Awareness of Social Inference Test), which uses videotaped vignettes of professional actors presenting a series of sincere, lying, and sarcastic exchanges such as might be encountered in daily life. The people with schizophrenia showed an intact ability to understand sincere exchanges but consistently performed poorly at comprehending sarcasm and lying, compared with both control groups, the investigators reported (Psychiatry Res. 2014 [doi: 10.1016/psychres.2014.03.043]).

In this study, the unaffected relatives of schizophrenia patients attained scores that were comparable to those of healthy controls, providing further support for the idea that these theory of mind deficits are disease specific, Ms. Cassetta and Dr. Goghari noted.

Future research regarding theory of mind "may benefit from utilizing tasks that incorporate dynamic social cues that are available in everyday social communication, in order to obtain a more accurate assessment of [participants’] abilities," they added.

This study was supported by the Canadian Institutes of Health Research, the University of Calgary, the Social Sciences and Humanities Research Council of Canada, and Alberta Innovates Health Solutions. No financial conflicts of interest were reported.

Cerebral vascular damage from small-vessel disease appears to aggravate the deposition of amyloid, particularly in patients carrying the apolipoprotein E e4 genotype, according to a report published online May 12 in JAMA Neurology.

This and other findings from a cross-sectional cohort study involving 914 Dutch patients with Alzheimer’s disease (AD) or vascular dementia support "the hypothesis that the pathways of small-vessel disease and AD pathology are interconnected." In addition, the ApoE e4 genotype seems to upregulate this association, said Dr. Maartje I. Kester of the Alzheimer center, department of neurology, Vrije University Medical Center, Amsterdam, and her associates.

"Small-vessel disease could provoke amyloid pathology, while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage," they noted.

Dr. Kester and her colleagues explored the relationship between small-vessel disease pathology and AD pathology by assessing MRI images of microbleeds, white-matter hyperintensities, and lacunes and correlating these with CSF (cerebrospinal fluid) levels of beta-amyloid 42, total tau, and p-tau. They performed these analyses in 914 patients participating in the Amsterdam Dementia Cohort who had all undergone brain MRI and CSF assessments as part of that study.

For their study, Dr. Kester and her associates included 547 patients diagnosed as having AD, 30 patients diagnosed as having vascular dementia, and 337 patients with subjective memory complaints but no dementia, who served as control subjects.

The researchers found that both microbleeds and white-matter intensities were associated with lower CSF levels of beta-amyloid 42, "indicating a direct relationship between [small-vessel disease] and AD pathology." The effects on CSF beta-amyloid 42 levels were largest in patients who carried the ApoE e4 genotype, suggesting "an inducing role" of this genotype "in the relation between AD and vascular pathology," the investigators said.

"It is conceivable that [cerebral amyloid angiopathy], which is commonly seen in patients with AD and is associated with parenchymal amyloid, may lead to ischemic vascular events in the brain like [white-matter hyperintensities], microinfarcts, and [microbleeds]. Conversely, ischemic changes could accelerate the rate of amyloid deposition, and vessel wall stiffness may impair perivascular drainage of cerebral amyloid, both leading to more deposition," Dr. Kester and her associates wrote (JAMA Neurol. 2014 May 12 [doi:10.1001/jamaneurol.2014.754]).

Lacunes appeared to represent a different type of pathology. "We found a positive association between [beta-amyloid 42] and lacunes in patients with [vascular dementia], indicating that lacunes are associated with lower amounts of amyloid in the brain. Lacunes and AD pathology seem to lead independently to cognitive decline, while a combination of enough additive damage leads to clinical (vascular) dementia," they added.

One limitation of the study is that the number of patients with vascular dementia was fairly small. "However pure [vascular dementia] is a rare disorder and large data sets are difficult to attain," Dr. Kester and her associates wrote.

This study was supported in part by Alzheimer Nederland and Stichting Dioraphte. Dr. Kester reported no financial conflicts of interest; her associates reported ties to numerous industry sources.

Cerebral vascular damage from small-vessel disease appears to aggravate the deposition of amyloid, particularly in patients carrying the apolipoprotein E e4 genotype, according to a report published online May 12 in JAMA Neurology.

This and other findings from a cross-sectional cohort study involving 914 Dutch patients with Alzheimer’s disease (AD) or vascular dementia support "the hypothesis that the pathways of small-vessel disease and AD pathology are interconnected." In addition, the ApoE e4 genotype seems to upregulate this association, said Dr. Maartje I. Kester of the Alzheimer center, department of neurology, Vrije University Medical Center, Amsterdam, and her associates.

"Small-vessel disease could provoke amyloid pathology, while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage," they noted.

Dr. Kester and her colleagues explored the relationship between small-vessel disease pathology and AD pathology by assessing MRI images of microbleeds, white-matter hyperintensities, and lacunes and correlating these with CSF (cerebrospinal fluid) levels of beta-amyloid 42, total tau, and p-tau. They performed these analyses in 914 patients participating in the Amsterdam Dementia Cohort who had all undergone brain MRI and CSF assessments as part of that study.

For their study, Dr. Kester and her associates included 547 patients diagnosed as having AD, 30 patients diagnosed as having vascular dementia, and 337 patients with subjective memory complaints but no dementia, who served as control subjects.

The researchers found that both microbleeds and white-matter intensities were associated with lower CSF levels of beta-amyloid 42, "indicating a direct relationship between [small-vessel disease] and AD pathology." The effects on CSF beta-amyloid 42 levels were largest in patients who carried the ApoE e4 genotype, suggesting "an inducing role" of this genotype "in the relation between AD and vascular pathology," the investigators said.

"It is conceivable that [cerebral amyloid angiopathy], which is commonly seen in patients with AD and is associated with parenchymal amyloid, may lead to ischemic vascular events in the brain like [white-matter hyperintensities], microinfarcts, and [microbleeds]. Conversely, ischemic changes could accelerate the rate of amyloid deposition, and vessel wall stiffness may impair perivascular drainage of cerebral amyloid, both leading to more deposition," Dr. Kester and her associates wrote (JAMA Neurol. 2014 May 12 [doi:10.1001/jamaneurol.2014.754]).

Lacunes appeared to represent a different type of pathology. "We found a positive association between [beta-amyloid 42] and lacunes in patients with [vascular dementia], indicating that lacunes are associated with lower amounts of amyloid in the brain. Lacunes and AD pathology seem to lead independently to cognitive decline, while a combination of enough additive damage leads to clinical (vascular) dementia," they added.

One limitation of the study is that the number of patients with vascular dementia was fairly small. "However pure [vascular dementia] is a rare disorder and large data sets are difficult to attain," Dr. Kester and her associates wrote.

This study was supported in part by Alzheimer Nederland and Stichting Dioraphte. Dr. Kester reported no financial conflicts of interest; her associates reported ties to numerous industry sources.

Cerebral vascular damage from small-vessel disease appears to aggravate the deposition of amyloid, particularly in patients carrying the apolipoprotein E e4 genotype, according to a report published online May 12 in JAMA Neurology.

This and other findings from a cross-sectional cohort study involving 914 Dutch patients with Alzheimer’s disease (AD) or vascular dementia support "the hypothesis that the pathways of small-vessel disease and AD pathology are interconnected." In addition, the ApoE e4 genotype seems to upregulate this association, said Dr. Maartje I. Kester of the Alzheimer center, department of neurology, Vrije University Medical Center, Amsterdam, and her associates.

"Small-vessel disease could provoke amyloid pathology, while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage," they noted.

Dr. Kester and her colleagues explored the relationship between small-vessel disease pathology and AD pathology by assessing MRI images of microbleeds, white-matter hyperintensities, and lacunes and correlating these with CSF (cerebrospinal fluid) levels of beta-amyloid 42, total tau, and p-tau. They performed these analyses in 914 patients participating in the Amsterdam Dementia Cohort who had all undergone brain MRI and CSF assessments as part of that study.

For their study, Dr. Kester and her associates included 547 patients diagnosed as having AD, 30 patients diagnosed as having vascular dementia, and 337 patients with subjective memory complaints but no dementia, who served as control subjects.

The researchers found that both microbleeds and white-matter intensities were associated with lower CSF levels of beta-amyloid 42, "indicating a direct relationship between [small-vessel disease] and AD pathology." The effects on CSF beta-amyloid 42 levels were largest in patients who carried the ApoE e4 genotype, suggesting "an inducing role" of this genotype "in the relation between AD and vascular pathology," the investigators said.

"It is conceivable that [cerebral amyloid angiopathy], which is commonly seen in patients with AD and is associated with parenchymal amyloid, may lead to ischemic vascular events in the brain like [white-matter hyperintensities], microinfarcts, and [microbleeds]. Conversely, ischemic changes could accelerate the rate of amyloid deposition, and vessel wall stiffness may impair perivascular drainage of cerebral amyloid, both leading to more deposition," Dr. Kester and her associates wrote (JAMA Neurol. 2014 May 12 [doi:10.1001/jamaneurol.2014.754]).

Lacunes appeared to represent a different type of pathology. "We found a positive association between [beta-amyloid 42] and lacunes in patients with [vascular dementia], indicating that lacunes are associated with lower amounts of amyloid in the brain. Lacunes and AD pathology seem to lead independently to cognitive decline, while a combination of enough additive damage leads to clinical (vascular) dementia," they added.

One limitation of the study is that the number of patients with vascular dementia was fairly small. "However pure [vascular dementia] is a rare disorder and large data sets are difficult to attain," Dr. Kester and her associates wrote.

This study was supported in part by Alzheimer Nederland and Stichting Dioraphte. Dr. Kester reported no financial conflicts of interest; her associates reported ties to numerous industry sources.

The incidence of adverse events related to circumcision varies according to the age of the patient, increasing substantially in boys and adolescent males, compared with infants, according to a report published online May 12 in JAMA Pediatrics.

In the largest study by far of circumcisions in the United States, the rate of associated adverse events was 20-fold higher among boys who underwent the procedure between 1 and 9 years of age, and 10-fold higher among boys who had it after 10 years of age, than among boys who were circumcised during infancy, said Charbel El Bcheraoui, Ph.D., of the office of surveillance epidemiology and laboratory services at the Centers for Disease Control & Prevention, and associates.

Until now, studies of circumcision-related adverse events "were based on small samples, a single clinical site or state, cross-sectional data, or nonrepresentative cohorts," the investigators said. Their study, which included approximately 1.4 million circumcisions across the country, is the first to compare rates of adverse events across all age groups from neonates to adults, said Dr. El Bcheraoui, who is also of the Institute for Health Metrics and Evaluation at the University of Washington, Seattle, and colleagues.

To determine the risks associated with circumcision, the investigators analyzed information in a database representing 120 million inpatient hospitalizations at urban and rural, academic and nonacademic, medical centers of all sizes in every region of the country, as well as representing 870,000 outpatient medical providers. They reviewed 1,400,920 reimbursement claims for circumcisions to males of all ages during a 10-year period.

Of these, 95.3% procedures were done during infancy, 2.0% were done at ages 1-9 years, and 2.7% were done at ages 10 years and older.

The researchers identified ICD codes for adverse events that were likely related to circumcision, namely, partial or complete amputation of the penis; open wound on the penis; suturing of a penile laceration; reconstruction of the penis; replantation of the penis; division of penile adhesions; lysis or excision of postcircumcision penile adhesions; repair of incomplete circumcision; vascular disorder of the penis, including death or decay of tissue caused by insufficient blood supply; penile inflammation or edema; urethral or other penile strictures; and suturing of an incised penile artery.

The incidence of adverse events was 0.4% among boys circumcised during infancy, 9.06% among those circumcised at ages 1-9 years, and 5.31% among boys, adolescents, and adults circumcised at age 10 years or older, the investigators reported (JAMA Ped. 2014 May 12 [doi:10.1001/jamapediatrics.2013.5414]).

The most common adverse events were related to correctional procedures and bleeding.

The incidence of the most severe adverse event – penile amputation – was highest, at 0.17%, in the 10-and-older group. The total number of amputations was 71. The database doesn’t distinguish between partial and complete amputations, so the exact number of each type is not known.

It is possible that this analysis was affected by some confounding by indication, because older males in the United States are more likely to undergo circumcision for medical indications (infections or adhesions) than for cultural or religious reasons. "Future studies will need to carefully adjust for this potential source of confounding," Dr. El Bcheraoui and associates noted.

Dr. El Bcheraoui and associates reported no financial conflicts of interest.

The incidence of adverse events related to circumcision varies according to the age of the patient, increasing substantially in boys and adolescent males, compared with infants, according to a report published online May 12 in JAMA Pediatrics.

In the largest study by far of circumcisions in the United States, the rate of associated adverse events was 20-fold higher among boys who underwent the procedure between 1 and 9 years of age, and 10-fold higher among boys who had it after 10 years of age, than among boys who were circumcised during infancy, said Charbel El Bcheraoui, Ph.D., of the office of surveillance epidemiology and laboratory services at the Centers for Disease Control & Prevention, and associates.

Until now, studies of circumcision-related adverse events "were based on small samples, a single clinical site or state, cross-sectional data, or nonrepresentative cohorts," the investigators said. Their study, which included approximately 1.4 million circumcisions across the country, is the first to compare rates of adverse events across all age groups from neonates to adults, said Dr. El Bcheraoui, who is also of the Institute for Health Metrics and Evaluation at the University of Washington, Seattle, and colleagues.

To determine the risks associated with circumcision, the investigators analyzed information in a database representing 120 million inpatient hospitalizations at urban and rural, academic and nonacademic, medical centers of all sizes in every region of the country, as well as representing 870,000 outpatient medical providers. They reviewed 1,400,920 reimbursement claims for circumcisions to males of all ages during a 10-year period.

Of these, 95.3% procedures were done during infancy, 2.0% were done at ages 1-9 years, and 2.7% were done at ages 10 years and older.

The researchers identified ICD codes for adverse events that were likely related to circumcision, namely, partial or complete amputation of the penis; open wound on the penis; suturing of a penile laceration; reconstruction of the penis; replantation of the penis; division of penile adhesions; lysis or excision of postcircumcision penile adhesions; repair of incomplete circumcision; vascular disorder of the penis, including death or decay of tissue caused by insufficient blood supply; penile inflammation or edema; urethral or other penile strictures; and suturing of an incised penile artery.

The incidence of adverse events was 0.4% among boys circumcised during infancy, 9.06% among those circumcised at ages 1-9 years, and 5.31% among boys, adolescents, and adults circumcised at age 10 years or older, the investigators reported (JAMA Ped. 2014 May 12 [doi:10.1001/jamapediatrics.2013.5414]).

The most common adverse events were related to correctional procedures and bleeding.

The incidence of the most severe adverse event – penile amputation – was highest, at 0.17%, in the 10-and-older group. The total number of amputations was 71. The database doesn’t distinguish between partial and complete amputations, so the exact number of each type is not known.

It is possible that this analysis was affected by some confounding by indication, because older males in the United States are more likely to undergo circumcision for medical indications (infections or adhesions) than for cultural or religious reasons. "Future studies will need to carefully adjust for this potential source of confounding," Dr. El Bcheraoui and associates noted.

Dr. El Bcheraoui and associates reported no financial conflicts of interest.

The incidence of adverse events related to circumcision varies according to the age of the patient, increasing substantially in boys and adolescent males, compared with infants, according to a report published online May 12 in JAMA Pediatrics.

In the largest study by far of circumcisions in the United States, the rate of associated adverse events was 20-fold higher among boys who underwent the procedure between 1 and 9 years of age, and 10-fold higher among boys who had it after 10 years of age, than among boys who were circumcised during infancy, said Charbel El Bcheraoui, Ph.D., of the office of surveillance epidemiology and laboratory services at the Centers for Disease Control & Prevention, and associates.

Until now, studies of circumcision-related adverse events "were based on small samples, a single clinical site or state, cross-sectional data, or nonrepresentative cohorts," the investigators said. Their study, which included approximately 1.4 million circumcisions across the country, is the first to compare rates of adverse events across all age groups from neonates to adults, said Dr. El Bcheraoui, who is also of the Institute for Health Metrics and Evaluation at the University of Washington, Seattle, and colleagues.

To determine the risks associated with circumcision, the investigators analyzed information in a database representing 120 million inpatient hospitalizations at urban and rural, academic and nonacademic, medical centers of all sizes in every region of the country, as well as representing 870,000 outpatient medical providers. They reviewed 1,400,920 reimbursement claims for circumcisions to males of all ages during a 10-year period.

Of these, 95.3% procedures were done during infancy, 2.0% were done at ages 1-9 years, and 2.7% were done at ages 10 years and older.

The researchers identified ICD codes for adverse events that were likely related to circumcision, namely, partial or complete amputation of the penis; open wound on the penis; suturing of a penile laceration; reconstruction of the penis; replantation of the penis; division of penile adhesions; lysis or excision of postcircumcision penile adhesions; repair of incomplete circumcision; vascular disorder of the penis, including death or decay of tissue caused by insufficient blood supply; penile inflammation or edema; urethral or other penile strictures; and suturing of an incised penile artery.

The incidence of adverse events was 0.4% among boys circumcised during infancy, 9.06% among those circumcised at ages 1-9 years, and 5.31% among boys, adolescents, and adults circumcised at age 10 years or older, the investigators reported (JAMA Ped. 2014 May 12 [doi:10.1001/jamapediatrics.2013.5414]).

The most common adverse events were related to correctional procedures and bleeding.

The incidence of the most severe adverse event – penile amputation – was highest, at 0.17%, in the 10-and-older group. The total number of amputations was 71. The database doesn’t distinguish between partial and complete amputations, so the exact number of each type is not known.

It is possible that this analysis was affected by some confounding by indication, because older males in the United States are more likely to undergo circumcision for medical indications (infections or adhesions) than for cultural or religious reasons. "Future studies will need to carefully adjust for this potential source of confounding," Dr. El Bcheraoui and associates noted.

Dr. El Bcheraoui and associates reported no financial conflicts of interest.

An analysis of recently available registry data including HER2 status for breast cancer patients confirms higher proportions of more aggressive breast cancer subtypes among younger women, black women, and Hispanic women, and notable differences in clinical presentation across subtypes, investigators reported in the Journal of the National Cancer Institute.

Although the reasons underlying these ethnic and age differences are not yet clear, the new data "are directly relevant to individualized treatment decisions that influence clinical outcomes," said Nadia Howlader of the National Cancer Institute, Bethesda, Md., and her colleagues.

They analyzed nationally representative data from 17 population-based Surveillance, Epidemiology, and End Results (SEER) registries, identifying 36,810 women diagnosed as having invasive breast cancer in 2010, the first year for which SEER data regarding tumor HER2 status were available. In addition to information on tumor receptor status, stage, and grade, the database includes information on patient age, race/ethnicity, and socioeconomic status.

Ms. Howlader, a mathematical statistician in the division of cancer control and population sciences, and her associates found that 72.7% of these breast cancers were HR-positive (expressing either estrogen receptors or progesterone receptors) and HER2-negative (not expressing human epidermal growth factor 2-neu); 12.2% were triple-negative (negative for estrogen, progesterone, and HER2 receptors); 10.3% were HR-positive and HER2-positive; and 4.6% were HR-negative but HER2-positive (J. Natl. Cancer Inst. 2014 April 28 [doi: 10.1093/jnci/dju055]).

The receptor status was unknown for 12% of the invasive breast cancer cases in the registries.

Compared with HR-positive and HER2-negative patients, those diagnosed with the other three subtypes were somewhat more likely to be younger, belong to minority racial or ethnic groups, live in counties with higher poverty levels, and have later-stage and higher Bloom-Richardson grade disease, the investigators reported.

Non-Hispanic black women had the highest incidence rates of triple-negative breast cancer across all age groups, with the difference in rates reaching its widest point at ages 60-64 and 65-69 years, when non-Hispanic black women were much more likely to be diagnosed with this subtype than were the other racial/ethnic groups. Triple-negative cancers were substantially more likely to be high-grade tumors (75% vs. 17%) and to present at an advanced stage than was the predominant HR-positive HER2-negative subtype.

The HER2-overexpressing tumors were less common subtypes with fewer observed variations by race/ethnicity, compared with both the HR-positive and HER2-negative, and triple-negative subtypes.

Compared with the predominant HR-positive and HER2-negative subtype, the proportion of women with the other three subtypes decreased with advancing age; these subtypes comprised 35% of case patients under age 50, but represented only 20% of case patients among those aged 75 years and older, the investigators reported.

"Understanding of the biological basis for differences in breast cancer subtype incidence and mortality across population groups is limited and warrants continued intensive study," the authors wrote. SEER data will continue to support this research, Ms. Howlader and her colleagues said.

This study was supported by the National Cancer Institute and the participating SEER registries. Ms. Howlader and her associates reported no financial conflicts of interest.

An analysis of recently available registry data including HER2 status for breast cancer patients confirms higher proportions of more aggressive breast cancer subtypes among younger women, black women, and Hispanic women, and notable differences in clinical presentation across subtypes, investigators reported in the Journal of the National Cancer Institute.

Although the reasons underlying these ethnic and age differences are not yet clear, the new data "are directly relevant to individualized treatment decisions that influence clinical outcomes," said Nadia Howlader of the National Cancer Institute, Bethesda, Md., and her colleagues.

They analyzed nationally representative data from 17 population-based Surveillance, Epidemiology, and End Results (SEER) registries, identifying 36,810 women diagnosed as having invasive breast cancer in 2010, the first year for which SEER data regarding tumor HER2 status were available. In addition to information on tumor receptor status, stage, and grade, the database includes information on patient age, race/ethnicity, and socioeconomic status.

Ms. Howlader, a mathematical statistician in the division of cancer control and population sciences, and her associates found that 72.7% of these breast cancers were HR-positive (expressing either estrogen receptors or progesterone receptors) and HER2-negative (not expressing human epidermal growth factor 2-neu); 12.2% were triple-negative (negative for estrogen, progesterone, and HER2 receptors); 10.3% were HR-positive and HER2-positive; and 4.6% were HR-negative but HER2-positive (J. Natl. Cancer Inst. 2014 April 28 [doi: 10.1093/jnci/dju055]).

The receptor status was unknown for 12% of the invasive breast cancer cases in the registries.

Compared with HR-positive and HER2-negative patients, those diagnosed with the other three subtypes were somewhat more likely to be younger, belong to minority racial or ethnic groups, live in counties with higher poverty levels, and have later-stage and higher Bloom-Richardson grade disease, the investigators reported.

Non-Hispanic black women had the highest incidence rates of triple-negative breast cancer across all age groups, with the difference in rates reaching its widest point at ages 60-64 and 65-69 years, when non-Hispanic black women were much more likely to be diagnosed with this subtype than were the other racial/ethnic groups. Triple-negative cancers were substantially more likely to be high-grade tumors (75% vs. 17%) and to present at an advanced stage than was the predominant HR-positive HER2-negative subtype.

The HER2-overexpressing tumors were less common subtypes with fewer observed variations by race/ethnicity, compared with both the HR-positive and HER2-negative, and triple-negative subtypes.

Compared with the predominant HR-positive and HER2-negative subtype, the proportion of women with the other three subtypes decreased with advancing age; these subtypes comprised 35% of case patients under age 50, but represented only 20% of case patients among those aged 75 years and older, the investigators reported.

"Understanding of the biological basis for differences in breast cancer subtype incidence and mortality across population groups is limited and warrants continued intensive study," the authors wrote. SEER data will continue to support this research, Ms. Howlader and her colleagues said.

This study was supported by the National Cancer Institute and the participating SEER registries. Ms. Howlader and her associates reported no financial conflicts of interest.

An analysis of recently available registry data including HER2 status for breast cancer patients confirms higher proportions of more aggressive breast cancer subtypes among younger women, black women, and Hispanic women, and notable differences in clinical presentation across subtypes, investigators reported in the Journal of the National Cancer Institute.

Although the reasons underlying these ethnic and age differences are not yet clear, the new data "are directly relevant to individualized treatment decisions that influence clinical outcomes," said Nadia Howlader of the National Cancer Institute, Bethesda, Md., and her colleagues.

They analyzed nationally representative data from 17 population-based Surveillance, Epidemiology, and End Results (SEER) registries, identifying 36,810 women diagnosed as having invasive breast cancer in 2010, the first year for which SEER data regarding tumor HER2 status were available. In addition to information on tumor receptor status, stage, and grade, the database includes information on patient age, race/ethnicity, and socioeconomic status.

Ms. Howlader, a mathematical statistician in the division of cancer control and population sciences, and her associates found that 72.7% of these breast cancers were HR-positive (expressing either estrogen receptors or progesterone receptors) and HER2-negative (not expressing human epidermal growth factor 2-neu); 12.2% were triple-negative (negative for estrogen, progesterone, and HER2 receptors); 10.3% were HR-positive and HER2-positive; and 4.6% were HR-negative but HER2-positive (J. Natl. Cancer Inst. 2014 April 28 [doi: 10.1093/jnci/dju055]).

The receptor status was unknown for 12% of the invasive breast cancer cases in the registries.

Compared with HR-positive and HER2-negative patients, those diagnosed with the other three subtypes were somewhat more likely to be younger, belong to minority racial or ethnic groups, live in counties with higher poverty levels, and have later-stage and higher Bloom-Richardson grade disease, the investigators reported.

Non-Hispanic black women had the highest incidence rates of triple-negative breast cancer across all age groups, with the difference in rates reaching its widest point at ages 60-64 and 65-69 years, when non-Hispanic black women were much more likely to be diagnosed with this subtype than were the other racial/ethnic groups. Triple-negative cancers were substantially more likely to be high-grade tumors (75% vs. 17%) and to present at an advanced stage than was the predominant HR-positive HER2-negative subtype.

The HER2-overexpressing tumors were less common subtypes with fewer observed variations by race/ethnicity, compared with both the HR-positive and HER2-negative, and triple-negative subtypes.

Compared with the predominant HR-positive and HER2-negative subtype, the proportion of women with the other three subtypes decreased with advancing age; these subtypes comprised 35% of case patients under age 50, but represented only 20% of case patients among those aged 75 years and older, the investigators reported.

"Understanding of the biological basis for differences in breast cancer subtype incidence and mortality across population groups is limited and warrants continued intensive study," the authors wrote. SEER data will continue to support this research, Ms. Howlader and her colleagues said.

This study was supported by the National Cancer Institute and the participating SEER registries. Ms. Howlader and her associates reported no financial conflicts of interest.

An analysis of recently available registry data including HER2 status for breast cancer patients confirms higher proportions of more aggressive breast cancer subtypes among younger women, black women, and Hispanic women, and notable differences in clinical presentation across subtypes, investigators reported in the Journal of the National Cancer Institute.

Although the reasons underlying these ethnic and age differences are not yet clear, the new data "are directly relevant to individualized treatment decisions that influence clinical outcomes," said Nadia Howlader of the National Cancer Institute, Bethesda, Md., and her colleagues.

They analyzed nationally representative data from 17 population-based Surveillance, Epidemiology, and End Results (SEER) registries, identifying 36,810 women diagnosed as having invasive breast cancer in 2010, the first year for which SEER data regarding tumor HER2 status were available. In addition to information on tumor receptor status, stage, and grade, the database includes information on patient age, race/ethnicity, and socioeconomic status.

Ms. Howlader, a mathematical statistician in the division of cancer control and population sciences, and her associates found that 72.7% of these breast cancers were HR-positive (expressing either estrogen receptors or progesterone receptors) and HER2-negative (not expressing human epidermal growth factor 2-neu); 12.2% were triple-negative (negative for estrogen, progesterone, and HER2 receptors); 10.3% were HR-positive and HER2-positive; and 4.6% were HR-negative but HER2-positive (J. Natl. Cancer Inst. 2014 April 28 [doi: 10.1093/jnci/dju055]).

The receptor status was unknown for 12% of the invasive breast cancer cases in the registries.

Compared with HR-positive and HER2-negative patients, those diagnosed with the other three subtypes were somewhat more likely to be younger, belong to minority racial or ethnic groups, live in counties with higher poverty levels, and have later-stage and higher Bloom-Richardson grade disease, the investigators reported.

Non-Hispanic black women had the highest incidence rates of triple-negative breast cancer across all age groups, with the difference in rates reaching its widest point at ages 60-64 and 65-69 years, when non-Hispanic black women were much more likely to be diagnosed with this subtype than were the other racial/ethnic groups. Triple-negative cancers were substantially more likely to be high-grade tumors (75% vs. 17%) and to present at an advanced stage than was the predominant HR-positive HER2-negative subtype.

The HER2-overexpressing tumors were less common subtypes with fewer observed variations by race/ethnicity, compared with both the HR-positive and HER2-negative, and triple-negative subtypes.

Compared with the predominant HR-positive and HER2-negative subtype, the proportion of women with the other three subtypes decreased with advancing age; these subtypes comprised 35% of case patients under age 50, but represented only 20% of case patients among those aged 75 years and older, the investigators reported.

"Understanding of the biological basis for differences in breast cancer subtype incidence and mortality across population groups is limited and warrants continued intensive study," the authors wrote. SEER data will continue to support this research, Ms. Howlader and her colleagues said.

This study was supported by the National Cancer Institute and the participating SEER registries. Ms. Howlader and her associates reported no financial conflicts of interest.

An analysis of recently available registry data including HER2 status for breast cancer patients confirms higher proportions of more aggressive breast cancer subtypes among younger women, black women, and Hispanic women, and notable differences in clinical presentation across subtypes, investigators reported in the Journal of the National Cancer Institute.

Although the reasons underlying these ethnic and age differences are not yet clear, the new data "are directly relevant to individualized treatment decisions that influence clinical outcomes," said Nadia Howlader of the National Cancer Institute, Bethesda, Md., and her colleagues.

They analyzed nationally representative data from 17 population-based Surveillance, Epidemiology, and End Results (SEER) registries, identifying 36,810 women diagnosed as having invasive breast cancer in 2010, the first year for which SEER data regarding tumor HER2 status were available. In addition to information on tumor receptor status, stage, and grade, the database includes information on patient age, race/ethnicity, and socioeconomic status.

Ms. Howlader, a mathematical statistician in the division of cancer control and population sciences, and her associates found that 72.7% of these breast cancers were HR-positive (expressing either estrogen receptors or progesterone receptors) and HER2-negative (not expressing human epidermal growth factor 2-neu); 12.2% were triple-negative (negative for estrogen, progesterone, and HER2 receptors); 10.3% were HR-positive and HER2-positive; and 4.6% were HR-negative but HER2-positive (J. Natl. Cancer Inst. 2014 April 28 [doi: 10.1093/jnci/dju055]).

The receptor status was unknown for 12% of the invasive breast cancer cases in the registries.

Compared with HR-positive and HER2-negative patients, those diagnosed with the other three subtypes were somewhat more likely to be younger, belong to minority racial or ethnic groups, live in counties with higher poverty levels, and have later-stage and higher Bloom-Richardson grade disease, the investigators reported.

Non-Hispanic black women had the highest incidence rates of triple-negative breast cancer across all age groups, with the difference in rates reaching its widest point at ages 60-64 and 65-69 years, when non-Hispanic black women were much more likely to be diagnosed with this subtype than were the other racial/ethnic groups. Triple-negative cancers were substantially more likely to be high-grade tumors (75% vs. 17%) and to present at an advanced stage than was the predominant HR-positive HER2-negative subtype.

The HER2-overexpressing tumors were less common subtypes with fewer observed variations by race/ethnicity, compared with both the HR-positive and HER2-negative, and triple-negative subtypes.

Compared with the predominant HR-positive and HER2-negative subtype, the proportion of women with the other three subtypes decreased with advancing age; these subtypes comprised 35% of case patients under age 50, but represented only 20% of case patients among those aged 75 years and older, the investigators reported.

"Understanding of the biological basis for differences in breast cancer subtype incidence and mortality across population groups is limited and warrants continued intensive study," the authors wrote. SEER data will continue to support this research, Ms. Howlader and her colleagues said.

This study was supported by the National Cancer Institute and the participating SEER registries. Ms. Howlader and her associates reported no financial conflicts of interest.

An analysis of recently available registry data including HER2 status for breast cancer patients confirms higher proportions of more aggressive breast cancer subtypes among younger women, black women, and Hispanic women, and notable differences in clinical presentation across subtypes, investigators reported in the Journal of the National Cancer Institute.

Although the reasons underlying these ethnic and age differences are not yet clear, the new data "are directly relevant to individualized treatment decisions that influence clinical outcomes," said Nadia Howlader of the National Cancer Institute, Bethesda, Md., and her colleagues.

They analyzed nationally representative data from 17 population-based Surveillance, Epidemiology, and End Results (SEER) registries, identifying 36,810 women diagnosed as having invasive breast cancer in 2010, the first year for which SEER data regarding tumor HER2 status were available. In addition to information on tumor receptor status, stage, and grade, the database includes information on patient age, race/ethnicity, and socioeconomic status.

Ms. Howlader, a mathematical statistician in the division of cancer control and population sciences, and her associates found that 72.7% of these breast cancers were HR-positive (expressing either estrogen receptors or progesterone receptors) and HER2-negative (not expressing human epidermal growth factor 2-neu); 12.2% were triple-negative (negative for estrogen, progesterone, and HER2 receptors); 10.3% were HR-positive and HER2-positive; and 4.6% were HR-negative but HER2-positive (J. Natl. Cancer Inst. 2014 April 28 [doi: 10.1093/jnci/dju055]).

The receptor status was unknown for 12% of the invasive breast cancer cases in the registries.

Compared with HR-positive and HER2-negative patients, those diagnosed with the other three subtypes were somewhat more likely to be younger, belong to minority racial or ethnic groups, live in counties with higher poverty levels, and have later-stage and higher Bloom-Richardson grade disease, the investigators reported.

Non-Hispanic black women had the highest incidence rates of triple-negative breast cancer across all age groups, with the difference in rates reaching its widest point at ages 60-64 and 65-69 years, when non-Hispanic black women were much more likely to be diagnosed with this subtype than were the other racial/ethnic groups. Triple-negative cancers were substantially more likely to be high-grade tumors (75% vs. 17%) and to present at an advanced stage than was the predominant HR-positive HER2-negative subtype.

The HER2-overexpressing tumors were less common subtypes with fewer observed variations by race/ethnicity, compared with both the HR-positive and HER2-negative, and triple-negative subtypes.

Compared with the predominant HR-positive and HER2-negative subtype, the proportion of women with the other three subtypes decreased with advancing age; these subtypes comprised 35% of case patients under age 50, but represented only 20% of case patients among those aged 75 years and older, the investigators reported.

"Understanding of the biological basis for differences in breast cancer subtype incidence and mortality across population groups is limited and warrants continued intensive study," the authors wrote. SEER data will continue to support this research, Ms. Howlader and her colleagues said.

This study was supported by the National Cancer Institute and the participating SEER registries. Ms. Howlader and her associates reported no financial conflicts of interest.

Letermovir prevented cytomegalovirus infection in a small, short-term phase II clinical trial involving adults who had undergone allogeneic hematopoietic-cell transplantation, according to a report published online May 8 in the New England Journal of Medicine.

The efficacy of the new drug, "a highly potent anti-CMV agent with a novel mechanism of action targeting the viral terminase subunit pUL56," increased with increasing dosage. Its safety profile was comparable to that of placebo in this industry-sponsored study, with none of the hematologic or renal toxicities associated with other anti-CMV drugs, said Dr. Roy F. Chemaly of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates.

CDC

The investigators tested three daily oral doses of letermovir against placebo at nine transplantation centers in Germany and 10 in the United States over an 18-month period. All the patients had recently received allogeneic transplants from matched related or unrelated donors and had tested negative for CMV viremia. They were randomly assigned to receive 60 mg (33 patients), 120 mg (31 patients), or 240 mg (34 patients) of active drug or matching placebo (33 patients) for 12 weeks.

At the conclusion of treatment, the rate of virologic failure was "markedly" lower in the 240-mg group (6%) than in the 120-mg group (19%) and the 60-mg group (21%); the rate of virologic failure was significantly lower in all three active-treatment groups than in the placebo group (36%). It was discovered that 15 patients given letermovir and 5 given placebo already had active, occult CMV infections at the start of treatment, which had not been detected on viremia testing. When these cases were excluded from a post hoc analysis, rates of virologic failure were 0% with 240-mg letermovir, 6% with 120-mg letermovir, and 15% with 60-mg letermovir, compared with 24% with placebo, the investigators said (N. Engl. J. Med. 2014 May 8 [doi:10.1056/NEJMoa1309533]).

The rate of adverse events considered to be possibly treatment related was lower with letermovir (17%) than with placebo (33%), as was the rate of serious adverse events (31% vs 36%). Patients discontinued the study drug twice as often in the placebo group (58%) as in the active-treatment groups (26%). There was no indication of renal or hematologic toxicity, and the incidence of graft-versus-host disease was similar among the four study groups. In particular, the incidence of neutropenia was nearly identical between letermovir (7%) and placebo (6%) – much lower than the rates as high as 58% reported with other anti-CMV agents, Dr. Chemaly and his associates said.

"These results are consistent with those of a previous phase II proof-of-concept trial involving a small number of recipients of solid-organ transplants," they added.

This study was funded by AiCuris, maker of letermovir. Dr. Chemaly reported receiving grants from AiCuris, Chimerix, ViroPharma, GlaxoSmithKline, and Gilead, and receiving personal fees from Astellas and Merck; his associates reported ties to numerous industry sources.

Letermovir prevented cytomegalovirus infection in a small, short-term phase II clinical trial involving adults who had undergone allogeneic hematopoietic-cell transplantation, according to a report published online May 8 in the New England Journal of Medicine.

The efficacy of the new drug, "a highly potent anti-CMV agent with a novel mechanism of action targeting the viral terminase subunit pUL56," increased with increasing dosage. Its safety profile was comparable to that of placebo in this industry-sponsored study, with none of the hematologic or renal toxicities associated with other anti-CMV drugs, said Dr. Roy F. Chemaly of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates.

CDC

The investigators tested three daily oral doses of letermovir against placebo at nine transplantation centers in Germany and 10 in the United States over an 18-month period. All the patients had recently received allogeneic transplants from matched related or unrelated donors and had tested negative for CMV viremia. They were randomly assigned to receive 60 mg (33 patients), 120 mg (31 patients), or 240 mg (34 patients) of active drug or matching placebo (33 patients) for 12 weeks.

At the conclusion of treatment, the rate of virologic failure was "markedly" lower in the 240-mg group (6%) than in the 120-mg group (19%) and the 60-mg group (21%); the rate of virologic failure was significantly lower in all three active-treatment groups than in the placebo group (36%). It was discovered that 15 patients given letermovir and 5 given placebo already had active, occult CMV infections at the start of treatment, which had not been detected on viremia testing. When these cases were excluded from a post hoc analysis, rates of virologic failure were 0% with 240-mg letermovir, 6% with 120-mg letermovir, and 15% with 60-mg letermovir, compared with 24% with placebo, the investigators said (N. Engl. J. Med. 2014 May 8 [doi:10.1056/NEJMoa1309533]).

The rate of adverse events considered to be possibly treatment related was lower with letermovir (17%) than with placebo (33%), as was the rate of serious adverse events (31% vs 36%). Patients discontinued the study drug twice as often in the placebo group (58%) as in the active-treatment groups (26%). There was no indication of renal or hematologic toxicity, and the incidence of graft-versus-host disease was similar among the four study groups. In particular, the incidence of neutropenia was nearly identical between letermovir (7%) and placebo (6%) – much lower than the rates as high as 58% reported with other anti-CMV agents, Dr. Chemaly and his associates said.

"These results are consistent with those of a previous phase II proof-of-concept trial involving a small number of recipients of solid-organ transplants," they added.

This study was funded by AiCuris, maker of letermovir. Dr. Chemaly reported receiving grants from AiCuris, Chimerix, ViroPharma, GlaxoSmithKline, and Gilead, and receiving personal fees from Astellas and Merck; his associates reported ties to numerous industry sources.

Letermovir prevented cytomegalovirus infection in a small, short-term phase II clinical trial involving adults who had undergone allogeneic hematopoietic-cell transplantation, according to a report published online May 8 in the New England Journal of Medicine.

The efficacy of the new drug, "a highly potent anti-CMV agent with a novel mechanism of action targeting the viral terminase subunit pUL56," increased with increasing dosage. Its safety profile was comparable to that of placebo in this industry-sponsored study, with none of the hematologic or renal toxicities associated with other anti-CMV drugs, said Dr. Roy F. Chemaly of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates.

CDC

The investigators tested three daily oral doses of letermovir against placebo at nine transplantation centers in Germany and 10 in the United States over an 18-month period. All the patients had recently received allogeneic transplants from matched related or unrelated donors and had tested negative for CMV viremia. They were randomly assigned to receive 60 mg (33 patients), 120 mg (31 patients), or 240 mg (34 patients) of active drug or matching placebo (33 patients) for 12 weeks.

At the conclusion of treatment, the rate of virologic failure was "markedly" lower in the 240-mg group (6%) than in the 120-mg group (19%) and the 60-mg group (21%); the rate of virologic failure was significantly lower in all three active-treatment groups than in the placebo group (36%). It was discovered that 15 patients given letermovir and 5 given placebo already had active, occult CMV infections at the start of treatment, which had not been detected on viremia testing. When these cases were excluded from a post hoc analysis, rates of virologic failure were 0% with 240-mg letermovir, 6% with 120-mg letermovir, and 15% with 60-mg letermovir, compared with 24% with placebo, the investigators said (N. Engl. J. Med. 2014 May 8 [doi:10.1056/NEJMoa1309533]).

The rate of adverse events considered to be possibly treatment related was lower with letermovir (17%) than with placebo (33%), as was the rate of serious adverse events (31% vs 36%). Patients discontinued the study drug twice as often in the placebo group (58%) as in the active-treatment groups (26%). There was no indication of renal or hematologic toxicity, and the incidence of graft-versus-host disease was similar among the four study groups. In particular, the incidence of neutropenia was nearly identical between letermovir (7%) and placebo (6%) – much lower than the rates as high as 58% reported with other anti-CMV agents, Dr. Chemaly and his associates said.

"These results are consistent with those of a previous phase II proof-of-concept trial involving a small number of recipients of solid-organ transplants," they added.

This study was funded by AiCuris, maker of letermovir. Dr. Chemaly reported receiving grants from AiCuris, Chimerix, ViroPharma, GlaxoSmithKline, and Gilead, and receiving personal fees from Astellas and Merck; his associates reported ties to numerous industry sources.

The benefits of aspirin therapy for primary prevention of cardiovascular disease outweigh the risks in patients who have coronary artery calcification scores of 100 or more, while the opposite is true in those who have scores of 0, according to a subanalysis of the MESA study published online May 6 in Circulation: Cardiovascular Quality and Outcomes.

In addition, the coronary artery calcium (CAC) score, a highly specific marker of the atherosclerotic plaque burden in the coronary arteries that is obtained via chest CT, predicts the risk/benefit ratio of aspirin therapy independently of traditional risk factors. These findings indicate that it can be used to guide aspirin therapy regardless of whether patients "qualify" for it according to AHA guidelines, said Dr. Michael D. Miedema of the Minneapolis Heart Institute and his associates.

At present, aspirin therapy for primary prevention is recommended only for patients at elevated risk for a cardiovascular event because its risks, particularly that of bleeding, are considered to outweigh the benefits. This means aspirin prevention is withheld from lower-risk patients "who represent the majority of the primary prevention population and in whom a large proportion of CVD events occur."

Dr. Miedema and his colleagues assessed whether CAC could be used to fine-tune risk assessment and thus allow treatment of more patients, preventing more cardiovascular events while avoiding unnecessary exposure of patients in whom risk truly exceeds benefit.

They analyzed data from the Multi-Ethnic Study of Atherosclerosis, a longitudinal epidemiologic study involving 6,814 men and women aged 45-84 years at baseline in 2000 who were followed at six U.S. medical centers for a median of 7.6 years.

For their study, Dr. Miedema and his associates included 4,229 of these individuals in whom CAC scores were obtained at enrollment, none of whom had clinical CVD or diabetes at that time. A total of 56% had a CAC score of 0, 18% had a CAC score of 100 or more, and the remaining 26% had intermediate CAC scores of 1-99.

Compared with patients who had a CAC score of 0, those with CAC scores of 100 or higher had more than a ninefold higher risk (hazard ratio, 9.03) for a coronary heart disease event, defined as nonfatal MI, resuscitated cardiac arrest, or CHD death; and more than a sixfold higher risk (HR, 6.57) for a CVD event, defined as a CHD event or stroke, during follow-up. This difference remained robust after the data were adjusted to account for traditional risk factors, in both men and women, and regardless of patient age (Circ. Cardiovasc. Qual. Outcomes 2014 May 6 [doi:10.1161/circoutcomes.113.000690]).

The findings indicate that CAC score can be used to guide aspirin therapy, at least in the 74% of patients whose scores fall at the extreme ends of the spectrum rather than in the intermediate range, the researchers noted.

This study was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Miedema and his associates reported no financial conflicts of interest.

The benefits of aspirin therapy for primary prevention of cardiovascular disease outweigh the risks in patients who have coronary artery calcification scores of 100 or more, while the opposite is true in those who have scores of 0, according to a subanalysis of the MESA study published online May 6 in Circulation: Cardiovascular Quality and Outcomes.

In addition, the coronary artery calcium (CAC) score, a highly specific marker of the atherosclerotic plaque burden in the coronary arteries that is obtained via chest CT, predicts the risk/benefit ratio of aspirin therapy independently of traditional risk factors. These findings indicate that it can be used to guide aspirin therapy regardless of whether patients "qualify" for it according to AHA guidelines, said Dr. Michael D. Miedema of the Minneapolis Heart Institute and his associates.

At present, aspirin therapy for primary prevention is recommended only for patients at elevated risk for a cardiovascular event because its risks, particularly that of bleeding, are considered to outweigh the benefits. This means aspirin prevention is withheld from lower-risk patients "who represent the majority of the primary prevention population and in whom a large proportion of CVD events occur."

Dr. Miedema and his colleagues assessed whether CAC could be used to fine-tune risk assessment and thus allow treatment of more patients, preventing more cardiovascular events while avoiding unnecessary exposure of patients in whom risk truly exceeds benefit.

They analyzed data from the Multi-Ethnic Study of Atherosclerosis, a longitudinal epidemiologic study involving 6,814 men and women aged 45-84 years at baseline in 2000 who were followed at six U.S. medical centers for a median of 7.6 years.

For their study, Dr. Miedema and his associates included 4,229 of these individuals in whom CAC scores were obtained at enrollment, none of whom had clinical CVD or diabetes at that time. A total of 56% had a CAC score of 0, 18% had a CAC score of 100 or more, and the remaining 26% had intermediate CAC scores of 1-99.

Compared with patients who had a CAC score of 0, those with CAC scores of 100 or higher had more than a ninefold higher risk (hazard ratio, 9.03) for a coronary heart disease event, defined as nonfatal MI, resuscitated cardiac arrest, or CHD death; and more than a sixfold higher risk (HR, 6.57) for a CVD event, defined as a CHD event or stroke, during follow-up. This difference remained robust after the data were adjusted to account for traditional risk factors, in both men and women, and regardless of patient age (Circ. Cardiovasc. Qual. Outcomes 2014 May 6 [doi:10.1161/circoutcomes.113.000690]).

The findings indicate that CAC score can be used to guide aspirin therapy, at least in the 74% of patients whose scores fall at the extreme ends of the spectrum rather than in the intermediate range, the researchers noted.

This study was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Miedema and his associates reported no financial conflicts of interest.

The benefits of aspirin therapy for primary prevention of cardiovascular disease outweigh the risks in patients who have coronary artery calcification scores of 100 or more, while the opposite is true in those who have scores of 0, according to a subanalysis of the MESA study published online May 6 in Circulation: Cardiovascular Quality and Outcomes.

In addition, the coronary artery calcium (CAC) score, a highly specific marker of the atherosclerotic plaque burden in the coronary arteries that is obtained via chest CT, predicts the risk/benefit ratio of aspirin therapy independently of traditional risk factors. These findings indicate that it can be used to guide aspirin therapy regardless of whether patients "qualify" for it according to AHA guidelines, said Dr. Michael D. Miedema of the Minneapolis Heart Institute and his associates.

At present, aspirin therapy for primary prevention is recommended only for patients at elevated risk for a cardiovascular event because its risks, particularly that of bleeding, are considered to outweigh the benefits. This means aspirin prevention is withheld from lower-risk patients "who represent the majority of the primary prevention population and in whom a large proportion of CVD events occur."

Dr. Miedema and his colleagues assessed whether CAC could be used to fine-tune risk assessment and thus allow treatment of more patients, preventing more cardiovascular events while avoiding unnecessary exposure of patients in whom risk truly exceeds benefit.

They analyzed data from the Multi-Ethnic Study of Atherosclerosis, a longitudinal epidemiologic study involving 6,814 men and women aged 45-84 years at baseline in 2000 who were followed at six U.S. medical centers for a median of 7.6 years.

For their study, Dr. Miedema and his associates included 4,229 of these individuals in whom CAC scores were obtained at enrollment, none of whom had clinical CVD or diabetes at that time. A total of 56% had a CAC score of 0, 18% had a CAC score of 100 or more, and the remaining 26% had intermediate CAC scores of 1-99.

Compared with patients who had a CAC score of 0, those with CAC scores of 100 or higher had more than a ninefold higher risk (hazard ratio, 9.03) for a coronary heart disease event, defined as nonfatal MI, resuscitated cardiac arrest, or CHD death; and more than a sixfold higher risk (HR, 6.57) for a CVD event, defined as a CHD event or stroke, during follow-up. This difference remained robust after the data were adjusted to account for traditional risk factors, in both men and women, and regardless of patient age (Circ. Cardiovasc. Qual. Outcomes 2014 May 6 [doi:10.1161/circoutcomes.113.000690]).

The findings indicate that CAC score can be used to guide aspirin therapy, at least in the 74% of patients whose scores fall at the extreme ends of the spectrum rather than in the intermediate range, the researchers noted.

This study was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Miedema and his associates reported no financial conflicts of interest.

Physical activity improves specific components of heart-rate variability in a dose-dependent manner among older adults, according to a report published May 6 in Circulation.

This suggests that "any physical activity is better than none, and more is [even] better" for men and women aged 65 and older, said Luisa Soares-Miranda, Ph.D., of the Research Centre in Physical Activity, Health, and Leisure, University of Porto (Portugal), and her associates (Circulation 2014 May 6 [doi:10.1161/CIRCULATIONAHA.113.005361]).

©Monkey Business/Fotolia.com

They analyzed data regarding 985 participants in the population-based Cardiovascular Health Study, in which older men and women (average age 71.5 years) residing in four U.S. communities at baseline during 1989-1990 were followed for 10 years for cardiovascular events.

For their study, Dr. Soares-Miranda and her colleagues reviewed 24-hour Holter monitor recordings obtained in a subset of those participants at enrollment and at 5-year follow-up. The individuals completed detailed questionnaires about the frequency and duration of their usual activities, including walking, gardening, swimming, aerobics, golfing, dancing, and riding an exercise cycle.

Activity level showed a linear association with higher 24-hour standard deviation of all normal-to-normal-intervals (SDNN), higher ultra-low-frequency power (ULF), and fewer episodes of erratic heart-rate variability on Holter monitoring, all of which reduce the risk of MI and heart failure.

"For example ... the higher values of SDNN that we observed in the highest versus lowest quartile of leisure-time activity would correspond to an approximately 11% lower risk of cardiac events," the investigators said.

In addition, people who increased their walking distance or pace during the first 5 years of follow-up showed significantly higher SDNN and ULF and significantly fewer episodes of heart-rate variability than did those who maintained or decreased their walking distance or pace, said Dr. Soares-Miranda, also of Harvard School of Public Health, Boston.

These findings suggest not only that regular physical activity in later life is beneficial but also that certain benefits may be lost when physical activity is reduced or stopped – "supporting the need to maintain modest physical activity throughout the aging process," they added.

This study was supported by the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Portuguese Foundation for Science and Technology. Dr. Soares-Miranda and her associates reported no financial conflicts of interest.

Physical activity improves specific components of heart-rate variability in a dose-dependent manner among older adults, according to a report published May 6 in Circulation.

This suggests that "any physical activity is better than none, and more is [even] better" for men and women aged 65 and older, said Luisa Soares-Miranda, Ph.D., of the Research Centre in Physical Activity, Health, and Leisure, University of Porto (Portugal), and her associates (Circulation 2014 May 6 [doi:10.1161/CIRCULATIONAHA.113.005361]).

©Monkey Business/Fotolia.com

They analyzed data regarding 985 participants in the population-based Cardiovascular Health Study, in which older men and women (average age 71.5 years) residing in four U.S. communities at baseline during 1989-1990 were followed for 10 years for cardiovascular events.

For their study, Dr. Soares-Miranda and her colleagues reviewed 24-hour Holter monitor recordings obtained in a subset of those participants at enrollment and at 5-year follow-up. The individuals completed detailed questionnaires about the frequency and duration of their usual activities, including walking, gardening, swimming, aerobics, golfing, dancing, and riding an exercise cycle.

Activity level showed a linear association with higher 24-hour standard deviation of all normal-to-normal-intervals (SDNN), higher ultra-low-frequency power (ULF), and fewer episodes of erratic heart-rate variability on Holter monitoring, all of which reduce the risk of MI and heart failure.

"For example ... the higher values of SDNN that we observed in the highest versus lowest quartile of leisure-time activity would correspond to an approximately 11% lower risk of cardiac events," the investigators said.

In addition, people who increased their walking distance or pace during the first 5 years of follow-up showed significantly higher SDNN and ULF and significantly fewer episodes of heart-rate variability than did those who maintained or decreased their walking distance or pace, said Dr. Soares-Miranda, also of Harvard School of Public Health, Boston.

These findings suggest not only that regular physical activity in later life is beneficial but also that certain benefits may be lost when physical activity is reduced or stopped – "supporting the need to maintain modest physical activity throughout the aging process," they added.

This study was supported by the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Portuguese Foundation for Science and Technology. Dr. Soares-Miranda and her associates reported no financial conflicts of interest.

Physical activity improves specific components of heart-rate variability in a dose-dependent manner among older adults, according to a report published May 6 in Circulation.

This suggests that "any physical activity is better than none, and more is [even] better" for men and women aged 65 and older, said Luisa Soares-Miranda, Ph.D., of the Research Centre in Physical Activity, Health, and Leisure, University of Porto (Portugal), and her associates (Circulation 2014 May 6 [doi:10.1161/CIRCULATIONAHA.113.005361]).

©Monkey Business/Fotolia.com

They analyzed data regarding 985 participants in the population-based Cardiovascular Health Study, in which older men and women (average age 71.5 years) residing in four U.S. communities at baseline during 1989-1990 were followed for 10 years for cardiovascular events.

For their study, Dr. Soares-Miranda and her colleagues reviewed 24-hour Holter monitor recordings obtained in a subset of those participants at enrollment and at 5-year follow-up. The individuals completed detailed questionnaires about the frequency and duration of their usual activities, including walking, gardening, swimming, aerobics, golfing, dancing, and riding an exercise cycle.

Activity level showed a linear association with higher 24-hour standard deviation of all normal-to-normal-intervals (SDNN), higher ultra-low-frequency power (ULF), and fewer episodes of erratic heart-rate variability on Holter monitoring, all of which reduce the risk of MI and heart failure.

"For example ... the higher values of SDNN that we observed in the highest versus lowest quartile of leisure-time activity would correspond to an approximately 11% lower risk of cardiac events," the investigators said.

In addition, people who increased their walking distance or pace during the first 5 years of follow-up showed significantly higher SDNN and ULF and significantly fewer episodes of heart-rate variability than did those who maintained or decreased their walking distance or pace, said Dr. Soares-Miranda, also of Harvard School of Public Health, Boston.

These findings suggest not only that regular physical activity in later life is beneficial but also that certain benefits may be lost when physical activity is reduced or stopped – "supporting the need to maintain modest physical activity throughout the aging process," they added.

This study was supported by the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Portuguese Foundation for Science and Technology. Dr. Soares-Miranda and her associates reported no financial conflicts of interest.

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the posttest.

The massive Women’s Health Initiative estrogen plus progestin clinical trial netted more than $37 billion in savings in the 10 years after it was published, largely by curtailing postmenopausal women’s use of combined hormone therapy, which in turn prevented 126,000 cases of breast cancer and 76,000 cardiovascular events, according to a report published online May 5 in Annals of Internal Medicine.

"The net health yield for women in the United States was approximately 145,000 more quality-of-life-years than would have occurred in the absence of the trial," said Joshua A. Roth, Ph.D., of the public health sciences division, Fred Hutchinson Cancer Research Center and Group Health Research Institute, Seattle, and his associates.

So even though the 2002 trial was one of the most expensive publicly funded studies ever – costing the National Institutes of Health an estimated $260 million in 2012 U.S. dollars – it yielded clinical and economic returns of approximately $140 for every dollar invested in it, they noted.

"Our findings suggest that large public research investments can yield considerable clinical and economic value when targeted to address research questions with great clinical relevance and public health effect," the investigators wrote.

One of the primary debates regarding public funding of research concerns its overall "returns" to society. To estimate the returns of the WHI-EP trial, Dr. Roth and his colleagues developed several mathematical models so they could simulate the 10-year health outcomes of American women aged 50-79 years if the study had never taken place – that is, if it had never been reported that combined hormone therapy (HT) raised the risks of cardiovascular disease, venous thromboembolism, and breast cancer (albeit reducing the risks of fracture and colon cancer).

Publication of those results led to an immediate 50% decrease in the use of combined HT and a continuing decline of 5%-10% per year thereafter, the researchers said.

They compared disease incidence, survival rates, and direct medical expenditures between a "WHI scenario" and a "no WHI scenario" to calculate the net economic and clinical returns of the trial through the year 2012.

Approximately 39.1 million women were eligible for combined HT during the study period. An estimated 5.2 million used combined HT in the WHI scenario, but 9.5 million would have used it if there had never been a WHI, given the usage trends during the years preceding the trial.

Relative to the no-WHI scenario, there were 126,000 fewer cases of breast cancer, 76,000 fewer cases of cardiovascular disease (CVD), and 80,000 fewer cases of venous thromboembolism in the WHI scenario. On the other side of the scale, there also were 263,000 more osteoporotic fractures and 15,000 more cases of colorectal cancer.

"Compared with the no-WHI scenario, the WHI scenario resulted in $35.2 billion in direct medical expenditure savings. Most of the savings came from fewer combined HT users and associated office visits ($26.2 billion), decreased breast cancer incidence ($4.5 billion), and decreased CVD incidence ($2.2 billion), offsetting increases in expenditures for greater fracture incidence ($4.8 billion) and colorectal cancer ($1.0 billion)," Dr. Roth and his associates said (Ann. Intern. Med. 2014;160:594-602).

The WHI scenario, compared with the no-WHI scenario, yielded 145,000 QALYs (quality-adjusted life-years), mainly because of the improved quality of life of women who avoided breast cancer and CVD. This greatly offset the reductions in QALYs that would have been due to increased fractures in the no-WHI scenario.

The net economic return of the WHI was calculated to be $37.1 billion. Savings from reduced use of combined HT drove the early economic value of the trial, and later value was driven by a combination of combined HT expenditure savings and QALY gains.

"This level of value was robust across plausible uncertainty ranges, and remained greater than $20 billion in all simulations that we evaluated," they wrote.

"Our analysis of the economic return from the WHI-EP trial suggests that, in certain circumstances, public investments in large prospective trials with high clinical and public health relevance could provide a similarly large positive rate of return in the long term," the investigators added.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the posttest.

The massive Women’s Health Initiative estrogen plus progestin clinical trial netted more than $37 billion in savings in the 10 years after it was published, largely by curtailing postmenopausal women’s use of combined hormone therapy, which in turn prevented 126,000 cases of breast cancer and 76,000 cardiovascular events, according to a report published online May 5 in Annals of Internal Medicine.

"The net health yield for women in the United States was approximately 145,000 more quality-of-life-years than would have occurred in the absence of the trial," said Joshua A. Roth, Ph.D., of the public health sciences division, Fred Hutchinson Cancer Research Center and Group Health Research Institute, Seattle, and his associates.

So even though the 2002 trial was one of the most expensive publicly funded studies ever – costing the National Institutes of Health an estimated $260 million in 2012 U.S. dollars – it yielded clinical and economic returns of approximately $140 for every dollar invested in it, they noted.

"Our findings suggest that large public research investments can yield considerable clinical and economic value when targeted to address research questions with great clinical relevance and public health effect," the investigators wrote.

One of the primary debates regarding public funding of research concerns its overall "returns" to society. To estimate the returns of the WHI-EP trial, Dr. Roth and his colleagues developed several mathematical models so they could simulate the 10-year health outcomes of American women aged 50-79 years if the study had never taken place – that is, if it had never been reported that combined hormone therapy (HT) raised the risks of cardiovascular disease, venous thromboembolism, and breast cancer (albeit reducing the risks of fracture and colon cancer).

Publication of those results led to an immediate 50% decrease in the use of combined HT and a continuing decline of 5%-10% per year thereafter, the researchers said.

They compared disease incidence, survival rates, and direct medical expenditures between a "WHI scenario" and a "no WHI scenario" to calculate the net economic and clinical returns of the trial through the year 2012.

Approximately 39.1 million women were eligible for combined HT during the study period. An estimated 5.2 million used combined HT in the WHI scenario, but 9.5 million would have used it if there had never been a WHI, given the usage trends during the years preceding the trial.

Relative to the no-WHI scenario, there were 126,000 fewer cases of breast cancer, 76,000 fewer cases of cardiovascular disease (CVD), and 80,000 fewer cases of venous thromboembolism in the WHI scenario. On the other side of the scale, there also were 263,000 more osteoporotic fractures and 15,000 more cases of colorectal cancer.

"Compared with the no-WHI scenario, the WHI scenario resulted in $35.2 billion in direct medical expenditure savings. Most of the savings came from fewer combined HT users and associated office visits ($26.2 billion), decreased breast cancer incidence ($4.5 billion), and decreased CVD incidence ($2.2 billion), offsetting increases in expenditures for greater fracture incidence ($4.8 billion) and colorectal cancer ($1.0 billion)," Dr. Roth and his associates said (Ann. Intern. Med. 2014;160:594-602).

The WHI scenario, compared with the no-WHI scenario, yielded 145,000 QALYs (quality-adjusted life-years), mainly because of the improved quality of life of women who avoided breast cancer and CVD. This greatly offset the reductions in QALYs that would have been due to increased fractures in the no-WHI scenario.

The net economic return of the WHI was calculated to be $37.1 billion. Savings from reduced use of combined HT drove the early economic value of the trial, and later value was driven by a combination of combined HT expenditure savings and QALY gains.

"This level of value was robust across plausible uncertainty ranges, and remained greater than $20 billion in all simulations that we evaluated," they wrote.

"Our analysis of the economic return from the WHI-EP trial suggests that, in certain circumstances, public investments in large prospective trials with high clinical and public health relevance could provide a similarly large positive rate of return in the long term," the investigators added.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the posttest.

The massive Women’s Health Initiative estrogen plus progestin clinical trial netted more than $37 billion in savings in the 10 years after it was published, largely by curtailing postmenopausal women’s use of combined hormone therapy, which in turn prevented 126,000 cases of breast cancer and 76,000 cardiovascular events, according to a report published online May 5 in Annals of Internal Medicine.

"The net health yield for women in the United States was approximately 145,000 more quality-of-life-years than would have occurred in the absence of the trial," said Joshua A. Roth, Ph.D., of the public health sciences division, Fred Hutchinson Cancer Research Center and Group Health Research Institute, Seattle, and his associates.

So even though the 2002 trial was one of the most expensive publicly funded studies ever – costing the National Institutes of Health an estimated $260 million in 2012 U.S. dollars – it yielded clinical and economic returns of approximately $140 for every dollar invested in it, they noted.

"Our findings suggest that large public research investments can yield considerable clinical and economic value when targeted to address research questions with great clinical relevance and public health effect," the investigators wrote.

One of the primary debates regarding public funding of research concerns its overall "returns" to society. To estimate the returns of the WHI-EP trial, Dr. Roth and his colleagues developed several mathematical models so they could simulate the 10-year health outcomes of American women aged 50-79 years if the study had never taken place – that is, if it had never been reported that combined hormone therapy (HT) raised the risks of cardiovascular disease, venous thromboembolism, and breast cancer (albeit reducing the risks of fracture and colon cancer).

Publication of those results led to an immediate 50% decrease in the use of combined HT and a continuing decline of 5%-10% per year thereafter, the researchers said.

They compared disease incidence, survival rates, and direct medical expenditures between a "WHI scenario" and a "no WHI scenario" to calculate the net economic and clinical returns of the trial through the year 2012.

Approximately 39.1 million women were eligible for combined HT during the study period. An estimated 5.2 million used combined HT in the WHI scenario, but 9.5 million would have used it if there had never been a WHI, given the usage trends during the years preceding the trial.

Relative to the no-WHI scenario, there were 126,000 fewer cases of breast cancer, 76,000 fewer cases of cardiovascular disease (CVD), and 80,000 fewer cases of venous thromboembolism in the WHI scenario. On the other side of the scale, there also were 263,000 more osteoporotic fractures and 15,000 more cases of colorectal cancer.

"Compared with the no-WHI scenario, the WHI scenario resulted in $35.2 billion in direct medical expenditure savings. Most of the savings came from fewer combined HT users and associated office visits ($26.2 billion), decreased breast cancer incidence ($4.5 billion), and decreased CVD incidence ($2.2 billion), offsetting increases in expenditures for greater fracture incidence ($4.8 billion) and colorectal cancer ($1.0 billion)," Dr. Roth and his associates said (Ann. Intern. Med. 2014;160:594-602).

The WHI scenario, compared with the no-WHI scenario, yielded 145,000 QALYs (quality-adjusted life-years), mainly because of the improved quality of life of women who avoided breast cancer and CVD. This greatly offset the reductions in QALYs that would have been due to increased fractures in the no-WHI scenario.

The net economic return of the WHI was calculated to be $37.1 billion. Savings from reduced use of combined HT drove the early economic value of the trial, and later value was driven by a combination of combined HT expenditure savings and QALY gains.

"This level of value was robust across plausible uncertainty ranges, and remained greater than $20 billion in all simulations that we evaluated," they wrote.

"Our analysis of the economic return from the WHI-EP trial suggests that, in certain circumstances, public investments in large prospective trials with high clinical and public health relevance could provide a similarly large positive rate of return in the long term," the investigators added.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.