Sara Freeman

Concussion in athletes was detected with greater accuracy when a simple vision test was added to other established tests in a prospective study of 217 members of the men’s football, women’s soccer, and women’s lacrosse teams at the University of Florida.

All concussive cases were correctly identified when the King-Devick (K-D) test was used in conjunction with the Balance Error Scoring System (BESS), which is part of the Sports Concussion Assessment Tool 3 (SCAT3), Dr. Laura Balcer and her associates reported Feb. 26 in an abstract released in advance of the annual meeting of the American Academy of Neurology in Philadelphia.

Furthermore, differences between baseline assessments and postinjury assessment showed that the K-D test identified a higher percentage of athletes with worsened scores than did the Standardized Assessment of Concussion (SAC) test (79% vs. 52%).

Using the K-D and SAC tests together also was better than using either of the tests alone, with 89% of concussions identified.

In a statement issued by the AAN, Dr. Balcer of the departments of population health and neurology at New York University noted that "the visual pathways are commonly affected in concussion. [And] adding a vision based test to evaluate athletes on the sidelines may allow us to better detect more athletes with concussion more quickly. This is particularly important since not all athletes reliably report their symptoms of concussion."

The findings add to previous work by Dr. Balcer and her colleagues in a similarly sized cohort of athletes from the University of Pennsylvania varsity football, sprint football, and women’s and men’s soccer and basketball teams (J. Neurol. Sci. 2011;309:34-9), and lend further support for the use of the K-D test as a rapid screening tool to assess players’ concussion during sporting events.

Up to 3.8 million sports-related concussive injuries have been estimated to occur in the United States each year, with diagnosis based on a variety of symptoms and signs that may include headache, unsteadiness, confusion, or behavior that is out of character for the individual concerned. It is important to be able to assess head injuries quickly, as concussion may be a result of a more serious neurological injury that needs emergency hospital treatment.

Unlike other tests for concussion that ideally need to be administered by a medical professional, anyone can administer the K-D test. This, together with the fact it takes less than 1 minute to complete, makes it ideal to use on the sidelines as an objective means of whether a concussive injury warrants more urgent attention.

The K-D test was developed in 1976 and assesses saccade, or the quick, simultaneous movement of both eyes in the same direction, as well as subjects’ language and level of concentration. It involves subjects’ quickly reading aloud a series of single-digit numbers shown to them on three test cards of increasing complexity. Subjects read the test cards from left to right and a stopwatch is used to record the time it takes them to complete each one. A time score is then obtained as the sum of all three test card times.

For the present study, the University of Florida sports teams administered several tests for concussion at the beginning of their seasons and again if concussion was suspected during the season. Thirty athletes experienced a first concussion during their athletic season.

The researchers found that worsening symptom severity scores obtained using the Post-Concussion Scale correlated strongly with increasing time to complete the K-D test (P less than .001).

"Among specific symptoms, light and noise sensitivities were particularly well correlated with K-D worsening," Dr. Balcer and her colleagues wrote in their abstract.

Furthermore, athletes who took longer to complete the K-D test at baseline had worse baseline score for visual motor speed assessed using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scale, which was conducted as part of routine clinical practice for concussion management but not diagnoses.

"The implications are that adding a vision-based test to sideline concussion assessment enables us to have a group of tests – a composite – that, when used together, can potentially help identify athletes with concussion," Dr. Balcer commented in an interview.

"A group of tests also helps add to clinical diagnosis of concussion immediately post injury by testing the brain’s many pathways that can be affected, including vision, cognition, and balance," she said.

"While no one test or group of tests can substitute for the fact that concussion is a clinical diagnosis, based on the judgment of the health care provider, trainer, parent, or athlete, having quick sideline tools that can be easily administered by laypeople adds an important element to how we identify concussions among youth athletes," Dr. Balcer observed. Young athletes are a particular group for which athletic trainers and physicians are not usually available on the sidelines.

The K-D test is relevant to any sporting activity in which there is likely to be physical contact between players or there is a chance of head injury or collision. In addition to football, soccer, and lacrosse, its use has been tested in sports such as boxing (Neurology 2011;76:1456-62), basketball (J. Neurol. Sci. 2011;309:34-9), ice hockey (J. Neurol. Sci. 2013;328:28-31), and rugby (J. Neurol. Sci. 2013;326:59-63).

The study was partly supported by the National Institutes of Health. Dr. Balcer declared no relevant conflicts of interest.

Concussion in athletes was detected with greater accuracy when a simple vision test was added to other established tests in a prospective study of 217 members of the men’s football, women’s soccer, and women’s lacrosse teams at the University of Florida.

All concussive cases were correctly identified when the King-Devick (K-D) test was used in conjunction with the Balance Error Scoring System (BESS), which is part of the Sports Concussion Assessment Tool 3 (SCAT3), Dr. Laura Balcer and her associates reported Feb. 26 in an abstract released in advance of the annual meeting of the American Academy of Neurology in Philadelphia.

Furthermore, differences between baseline assessments and postinjury assessment showed that the K-D test identified a higher percentage of athletes with worsened scores than did the Standardized Assessment of Concussion (SAC) test (79% vs. 52%).

Using the K-D and SAC tests together also was better than using either of the tests alone, with 89% of concussions identified.

In a statement issued by the AAN, Dr. Balcer of the departments of population health and neurology at New York University noted that "the visual pathways are commonly affected in concussion. [And] adding a vision based test to evaluate athletes on the sidelines may allow us to better detect more athletes with concussion more quickly. This is particularly important since not all athletes reliably report their symptoms of concussion."

The findings add to previous work by Dr. Balcer and her colleagues in a similarly sized cohort of athletes from the University of Pennsylvania varsity football, sprint football, and women’s and men’s soccer and basketball teams (J. Neurol. Sci. 2011;309:34-9), and lend further support for the use of the K-D test as a rapid screening tool to assess players’ concussion during sporting events.

Up to 3.8 million sports-related concussive injuries have been estimated to occur in the United States each year, with diagnosis based on a variety of symptoms and signs that may include headache, unsteadiness, confusion, or behavior that is out of character for the individual concerned. It is important to be able to assess head injuries quickly, as concussion may be a result of a more serious neurological injury that needs emergency hospital treatment.

Unlike other tests for concussion that ideally need to be administered by a medical professional, anyone can administer the K-D test. This, together with the fact it takes less than 1 minute to complete, makes it ideal to use on the sidelines as an objective means of whether a concussive injury warrants more urgent attention.

The K-D test was developed in 1976 and assesses saccade, or the quick, simultaneous movement of both eyes in the same direction, as well as subjects’ language and level of concentration. It involves subjects’ quickly reading aloud a series of single-digit numbers shown to them on three test cards of increasing complexity. Subjects read the test cards from left to right and a stopwatch is used to record the time it takes them to complete each one. A time score is then obtained as the sum of all three test card times.

For the present study, the University of Florida sports teams administered several tests for concussion at the beginning of their seasons and again if concussion was suspected during the season. Thirty athletes experienced a first concussion during their athletic season.

The researchers found that worsening symptom severity scores obtained using the Post-Concussion Scale correlated strongly with increasing time to complete the K-D test (P less than .001).

"Among specific symptoms, light and noise sensitivities were particularly well correlated with K-D worsening," Dr. Balcer and her colleagues wrote in their abstract.

Furthermore, athletes who took longer to complete the K-D test at baseline had worse baseline score for visual motor speed assessed using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scale, which was conducted as part of routine clinical practice for concussion management but not diagnoses.

"The implications are that adding a vision-based test to sideline concussion assessment enables us to have a group of tests – a composite – that, when used together, can potentially help identify athletes with concussion," Dr. Balcer commented in an interview.

"A group of tests also helps add to clinical diagnosis of concussion immediately post injury by testing the brain’s many pathways that can be affected, including vision, cognition, and balance," she said.

"While no one test or group of tests can substitute for the fact that concussion is a clinical diagnosis, based on the judgment of the health care provider, trainer, parent, or athlete, having quick sideline tools that can be easily administered by laypeople adds an important element to how we identify concussions among youth athletes," Dr. Balcer observed. Young athletes are a particular group for which athletic trainers and physicians are not usually available on the sidelines.

The K-D test is relevant to any sporting activity in which there is likely to be physical contact between players or there is a chance of head injury or collision. In addition to football, soccer, and lacrosse, its use has been tested in sports such as boxing (Neurology 2011;76:1456-62), basketball (J. Neurol. Sci. 2011;309:34-9), ice hockey (J. Neurol. Sci. 2013;328:28-31), and rugby (J. Neurol. Sci. 2013;326:59-63).

The study was partly supported by the National Institutes of Health. Dr. Balcer declared no relevant conflicts of interest.

Concussion in athletes was detected with greater accuracy when a simple vision test was added to other established tests in a prospective study of 217 members of the men’s football, women’s soccer, and women’s lacrosse teams at the University of Florida.

All concussive cases were correctly identified when the King-Devick (K-D) test was used in conjunction with the Balance Error Scoring System (BESS), which is part of the Sports Concussion Assessment Tool 3 (SCAT3), Dr. Laura Balcer and her associates reported Feb. 26 in an abstract released in advance of the annual meeting of the American Academy of Neurology in Philadelphia.

Furthermore, differences between baseline assessments and postinjury assessment showed that the K-D test identified a higher percentage of athletes with worsened scores than did the Standardized Assessment of Concussion (SAC) test (79% vs. 52%).

Using the K-D and SAC tests together also was better than using either of the tests alone, with 89% of concussions identified.

In a statement issued by the AAN, Dr. Balcer of the departments of population health and neurology at New York University noted that "the visual pathways are commonly affected in concussion. [And] adding a vision based test to evaluate athletes on the sidelines may allow us to better detect more athletes with concussion more quickly. This is particularly important since not all athletes reliably report their symptoms of concussion."

The findings add to previous work by Dr. Balcer and her colleagues in a similarly sized cohort of athletes from the University of Pennsylvania varsity football, sprint football, and women’s and men’s soccer and basketball teams (J. Neurol. Sci. 2011;309:34-9), and lend further support for the use of the K-D test as a rapid screening tool to assess players’ concussion during sporting events.

Up to 3.8 million sports-related concussive injuries have been estimated to occur in the United States each year, with diagnosis based on a variety of symptoms and signs that may include headache, unsteadiness, confusion, or behavior that is out of character for the individual concerned. It is important to be able to assess head injuries quickly, as concussion may be a result of a more serious neurological injury that needs emergency hospital treatment.

Unlike other tests for concussion that ideally need to be administered by a medical professional, anyone can administer the K-D test. This, together with the fact it takes less than 1 minute to complete, makes it ideal to use on the sidelines as an objective means of whether a concussive injury warrants more urgent attention.

The K-D test was developed in 1976 and assesses saccade, or the quick, simultaneous movement of both eyes in the same direction, as well as subjects’ language and level of concentration. It involves subjects’ quickly reading aloud a series of single-digit numbers shown to them on three test cards of increasing complexity. Subjects read the test cards from left to right and a stopwatch is used to record the time it takes them to complete each one. A time score is then obtained as the sum of all three test card times.

For the present study, the University of Florida sports teams administered several tests for concussion at the beginning of their seasons and again if concussion was suspected during the season. Thirty athletes experienced a first concussion during their athletic season.

The researchers found that worsening symptom severity scores obtained using the Post-Concussion Scale correlated strongly with increasing time to complete the K-D test (P less than .001).

"Among specific symptoms, light and noise sensitivities were particularly well correlated with K-D worsening," Dr. Balcer and her colleagues wrote in their abstract.

Furthermore, athletes who took longer to complete the K-D test at baseline had worse baseline score for visual motor speed assessed using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scale, which was conducted as part of routine clinical practice for concussion management but not diagnoses.

"The implications are that adding a vision-based test to sideline concussion assessment enables us to have a group of tests – a composite – that, when used together, can potentially help identify athletes with concussion," Dr. Balcer commented in an interview.

"A group of tests also helps add to clinical diagnosis of concussion immediately post injury by testing the brain’s many pathways that can be affected, including vision, cognition, and balance," she said.

"While no one test or group of tests can substitute for the fact that concussion is a clinical diagnosis, based on the judgment of the health care provider, trainer, parent, or athlete, having quick sideline tools that can be easily administered by laypeople adds an important element to how we identify concussions among youth athletes," Dr. Balcer observed. Young athletes are a particular group for which athletic trainers and physicians are not usually available on the sidelines.

The K-D test is relevant to any sporting activity in which there is likely to be physical contact between players or there is a chance of head injury or collision. In addition to football, soccer, and lacrosse, its use has been tested in sports such as boxing (Neurology 2011;76:1456-62), basketball (J. Neurol. Sci. 2011;309:34-9), ice hockey (J. Neurol. Sci. 2013;328:28-31), and rugby (J. Neurol. Sci. 2013;326:59-63).

The study was partly supported by the National Institutes of Health. Dr. Balcer declared no relevant conflicts of interest.

Depressive symptoms significantly increased the risk of coronary heart disease in a long-term study of more than 10,000 patients, suggesting that depression may be a modifiable cardiovascular risk factor.

Data from the prospective cohort Whitehall II study showed a dose-dependent increase in CHD risk with repeated observation of depressive symptoms. The presence of depressive symptoms identified on one or two occasions using the 30-item General Health Questionnaire (GHQ-30) was associated with a significant 12% increase in CHD risk (hazard ratio, 1.12). However, if depressive symptoms were recorded at three or four assessment points, the risk of CHD risk doubled significantly (HR, 2.06).

Depression was also measured using the more specific Center for Epidemiologic Studies Depression Scale (CES-D), with a significant 81% increase in CHD risk if depressive symptoms were evident (HR, 1.81).

In contrast, significant positive associations between depression and the development of stroke seen in the first 5 years of follow-up in the study (HR, 1.6) were not sustained in the long term (HR, 0.94 at 5-10 years’ follow-up).

The Whitehall II study began in 1985 to look at the long-term importance of social class on health. A baseline survey and subsequent clinical examination resulted in 10,308 men and women aged 35-55 years being recruited from 1985 to 1988. Clinical examinations were undertaken every 5 years, with postal surveys undertaken in between, and included the completion of the GHQ-30. The 20-item CES-D was also completed during one assessment period, between 2003 and 2009.

The results from the GHQ-30 were validated against clinical interviews, with a score of 0 representing no change and higher scores reflecting an increase in depressive symptoms. GHQ-30 "caseness" was defined as a score of 5 or more. CES-D caseness was defined as a score of 16 or more out of a maximum of 60.

National databases and records were used to identify cases of fatal and nonfatal cardiovascular events, stroke, and associated mortality. The MONICA-Augsburg Stroke Symptom Questionnaire was used to capture clinical symptoms of stroke, in addition to self-reported events collected throughout the study.

The mean age of participants at the first GHQ-30 measurement was 44 years, and was 61 years by the fourth assessment in 2003-2004. The majority (90%) of participants described themselves as white, and 67% of the cohort was male.

"We investigated the possibility of reverse causation by examining the association between prevalent major CHD or prevalent stroke with subsequent incidence of GHQ-30 caseness," the Whitehall II investigators noted in the study, which was published online in the European Journal of Preventative Cardiology (doi:10.1177/2047487314520785).

Although they found weak evidence that CHD was significantly associated with subsequent GHQ-30 caseness (odds ratio, 1.32), they did find a significant association between prevalent stroke and depressive symptoms (OR, 2.01).

It is not clear why depressive symptoms might be causally linked to CHD but not stroke. One plausible explanation is that it could be linked to blood pressure – a particularly important risk factor for stroke, but only one of many for CHD. Depressive symptoms have been linked to low blood pressure, "and this inverse association would tend to confound the association with stroke to a greater extent than with CHD," the authors noted. Antihypertensive medications might also be causing depression or psychological distress, the authors suggested.

"European prevention guidelines refer to depression as a coronary risk factor," noted lead author Dr. Eric Brunner of University College London in a press release issued by the European Society of Cardiology. "In our study, repeated episodes of depressive symptoms accounted for 10% of all CHD events in the study population." That figure suggests the existence of a causal relationship between depression and heart disease.

"Whether or not the association is causal, supporting individuals to recover from chronic or repeated episodes of depression has merit, particularly if the individual is then better able to reduce any vascular risk – for example, by quitting smoking."

More research is needed to examine the uncertainties regarding depression as a causal factor in CHD and stroke, Dr. Brunner and his associates concluded.

The research was funded by grants from the British Medical Research Council, the British Heart Foundation, the British Health and Safety Executive, the British Department of Health, the British Stroke Association, the U.S. National Heart, Lung, and Blood Institute, and the U.S. National Institute on Aging. The investigators had no conflicts of interest to disclose.

Depressive symptoms significantly increased the risk of coronary heart disease in a long-term study of more than 10,000 patients, suggesting that depression may be a modifiable cardiovascular risk factor.

Data from the prospective cohort Whitehall II study showed a dose-dependent increase in CHD risk with repeated observation of depressive symptoms. The presence of depressive symptoms identified on one or two occasions using the 30-item General Health Questionnaire (GHQ-30) was associated with a significant 12% increase in CHD risk (hazard ratio, 1.12). However, if depressive symptoms were recorded at three or four assessment points, the risk of CHD risk doubled significantly (HR, 2.06).

Depression was also measured using the more specific Center for Epidemiologic Studies Depression Scale (CES-D), with a significant 81% increase in CHD risk if depressive symptoms were evident (HR, 1.81).

In contrast, significant positive associations between depression and the development of stroke seen in the first 5 years of follow-up in the study (HR, 1.6) were not sustained in the long term (HR, 0.94 at 5-10 years’ follow-up).

The Whitehall II study began in 1985 to look at the long-term importance of social class on health. A baseline survey and subsequent clinical examination resulted in 10,308 men and women aged 35-55 years being recruited from 1985 to 1988. Clinical examinations were undertaken every 5 years, with postal surveys undertaken in between, and included the completion of the GHQ-30. The 20-item CES-D was also completed during one assessment period, between 2003 and 2009.

The results from the GHQ-30 were validated against clinical interviews, with a score of 0 representing no change and higher scores reflecting an increase in depressive symptoms. GHQ-30 "caseness" was defined as a score of 5 or more. CES-D caseness was defined as a score of 16 or more out of a maximum of 60.

National databases and records were used to identify cases of fatal and nonfatal cardiovascular events, stroke, and associated mortality. The MONICA-Augsburg Stroke Symptom Questionnaire was used to capture clinical symptoms of stroke, in addition to self-reported events collected throughout the study.

The mean age of participants at the first GHQ-30 measurement was 44 years, and was 61 years by the fourth assessment in 2003-2004. The majority (90%) of participants described themselves as white, and 67% of the cohort was male.

"We investigated the possibility of reverse causation by examining the association between prevalent major CHD or prevalent stroke with subsequent incidence of GHQ-30 caseness," the Whitehall II investigators noted in the study, which was published online in the European Journal of Preventative Cardiology (doi:10.1177/2047487314520785).

Although they found weak evidence that CHD was significantly associated with subsequent GHQ-30 caseness (odds ratio, 1.32), they did find a significant association between prevalent stroke and depressive symptoms (OR, 2.01).

It is not clear why depressive symptoms might be causally linked to CHD but not stroke. One plausible explanation is that it could be linked to blood pressure – a particularly important risk factor for stroke, but only one of many for CHD. Depressive symptoms have been linked to low blood pressure, "and this inverse association would tend to confound the association with stroke to a greater extent than with CHD," the authors noted. Antihypertensive medications might also be causing depression or psychological distress, the authors suggested.

"European prevention guidelines refer to depression as a coronary risk factor," noted lead author Dr. Eric Brunner of University College London in a press release issued by the European Society of Cardiology. "In our study, repeated episodes of depressive symptoms accounted for 10% of all CHD events in the study population." That figure suggests the existence of a causal relationship between depression and heart disease.

"Whether or not the association is causal, supporting individuals to recover from chronic or repeated episodes of depression has merit, particularly if the individual is then better able to reduce any vascular risk – for example, by quitting smoking."

More research is needed to examine the uncertainties regarding depression as a causal factor in CHD and stroke, Dr. Brunner and his associates concluded.

The research was funded by grants from the British Medical Research Council, the British Heart Foundation, the British Health and Safety Executive, the British Department of Health, the British Stroke Association, the U.S. National Heart, Lung, and Blood Institute, and the U.S. National Institute on Aging. The investigators had no conflicts of interest to disclose.

Depressive symptoms significantly increased the risk of coronary heart disease in a long-term study of more than 10,000 patients, suggesting that depression may be a modifiable cardiovascular risk factor.

Data from the prospective cohort Whitehall II study showed a dose-dependent increase in CHD risk with repeated observation of depressive symptoms. The presence of depressive symptoms identified on one or two occasions using the 30-item General Health Questionnaire (GHQ-30) was associated with a significant 12% increase in CHD risk (hazard ratio, 1.12). However, if depressive symptoms were recorded at three or four assessment points, the risk of CHD risk doubled significantly (HR, 2.06).

Depression was also measured using the more specific Center for Epidemiologic Studies Depression Scale (CES-D), with a significant 81% increase in CHD risk if depressive symptoms were evident (HR, 1.81).

In contrast, significant positive associations between depression and the development of stroke seen in the first 5 years of follow-up in the study (HR, 1.6) were not sustained in the long term (HR, 0.94 at 5-10 years’ follow-up).

The Whitehall II study began in 1985 to look at the long-term importance of social class on health. A baseline survey and subsequent clinical examination resulted in 10,308 men and women aged 35-55 years being recruited from 1985 to 1988. Clinical examinations were undertaken every 5 years, with postal surveys undertaken in between, and included the completion of the GHQ-30. The 20-item CES-D was also completed during one assessment period, between 2003 and 2009.

The results from the GHQ-30 were validated against clinical interviews, with a score of 0 representing no change and higher scores reflecting an increase in depressive symptoms. GHQ-30 "caseness" was defined as a score of 5 or more. CES-D caseness was defined as a score of 16 or more out of a maximum of 60.

National databases and records were used to identify cases of fatal and nonfatal cardiovascular events, stroke, and associated mortality. The MONICA-Augsburg Stroke Symptom Questionnaire was used to capture clinical symptoms of stroke, in addition to self-reported events collected throughout the study.

The mean age of participants at the first GHQ-30 measurement was 44 years, and was 61 years by the fourth assessment in 2003-2004. The majority (90%) of participants described themselves as white, and 67% of the cohort was male.

"We investigated the possibility of reverse causation by examining the association between prevalent major CHD or prevalent stroke with subsequent incidence of GHQ-30 caseness," the Whitehall II investigators noted in the study, which was published online in the European Journal of Preventative Cardiology (doi:10.1177/2047487314520785).

Although they found weak evidence that CHD was significantly associated with subsequent GHQ-30 caseness (odds ratio, 1.32), they did find a significant association between prevalent stroke and depressive symptoms (OR, 2.01).

It is not clear why depressive symptoms might be causally linked to CHD but not stroke. One plausible explanation is that it could be linked to blood pressure – a particularly important risk factor for stroke, but only one of many for CHD. Depressive symptoms have been linked to low blood pressure, "and this inverse association would tend to confound the association with stroke to a greater extent than with CHD," the authors noted. Antihypertensive medications might also be causing depression or psychological distress, the authors suggested.

"European prevention guidelines refer to depression as a coronary risk factor," noted lead author Dr. Eric Brunner of University College London in a press release issued by the European Society of Cardiology. "In our study, repeated episodes of depressive symptoms accounted for 10% of all CHD events in the study population." That figure suggests the existence of a causal relationship between depression and heart disease.

"Whether or not the association is causal, supporting individuals to recover from chronic or repeated episodes of depression has merit, particularly if the individual is then better able to reduce any vascular risk – for example, by quitting smoking."

More research is needed to examine the uncertainties regarding depression as a causal factor in CHD and stroke, Dr. Brunner and his associates concluded.

The research was funded by grants from the British Medical Research Council, the British Heart Foundation, the British Health and Safety Executive, the British Department of Health, the British Stroke Association, the U.S. National Heart, Lung, and Blood Institute, and the U.S. National Institute on Aging. The investigators had no conflicts of interest to disclose.

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study, called TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis), demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo (P = .0001). A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction (P = .0183).

Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

"These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting multiple sclerosis and as an option for patients who are unable to tolerate other disease-modifying therapies," wrote the TOWER Trial Group investigators (Lancet Neurol. 2014 Jan. 23 [doi: 10.1016/S1474-4422(13)70308-9]).

First author Dr. Christian Confavreux of University Claude Bernard Lyon 1, France, and his associates commented that the findings add to those previously reported from the phase III TEMSO trial (N. Engl. J. Med. 2011;365:1293-303), which showed that teriflunomide 7 mg and 14 mg both reduced the annualized relapse rate by around 31% when compared with placebo. They are also supported by the results of a phase II extension study.

Teriflunomide was approved for the treatment of adults with relapsing-remitting MS in the United States (trade name Aubagio) in 2012 and in Europe in 2013. The drug is the principal active metabolite in leflunomide, which is licensed for the treatment of rheumatoid arthritis.

The TOWER trial involved a total of 1,169 patients with relapsing-remitting MS who were randomized to treatment: 408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38 years, with just over 80% being of white, 15% of Asian, and 2% of black ethnicity.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary endpoint was sustained accumulation of disability. This was defined as an increase of at least 1 point on the Expanded Disability Status Scale (EDSS) from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 (P = .0442) for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

"The safety and tolerability profile of teriflunomide, as characterized in this and previous studies, was similar for both the 7-mg and 14-mg doses, including long-term treatment observations," the investigators wrote. The most common side effects seen in patients treated with teriflunomide were hair thinning, headache, and increase in alanine aminotransferase concentrations.

Genzyme, a Sanofi company, sponsored the trial. The investigators disclosed financial relationships with Genzyme as well as other companies that manufacture drugs used to treat MS.

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study, called TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis), demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo (P = .0001). A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction (P = .0183).

Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

"These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting multiple sclerosis and as an option for patients who are unable to tolerate other disease-modifying therapies," wrote the TOWER Trial Group investigators (Lancet Neurol. 2014 Jan. 23 [doi: 10.1016/S1474-4422(13)70308-9]).

First author Dr. Christian Confavreux of University Claude Bernard Lyon 1, France, and his associates commented that the findings add to those previously reported from the phase III TEMSO trial (N. Engl. J. Med. 2011;365:1293-303), which showed that teriflunomide 7 mg and 14 mg both reduced the annualized relapse rate by around 31% when compared with placebo. They are also supported by the results of a phase II extension study.

Teriflunomide was approved for the treatment of adults with relapsing-remitting MS in the United States (trade name Aubagio) in 2012 and in Europe in 2013. The drug is the principal active metabolite in leflunomide, which is licensed for the treatment of rheumatoid arthritis.

The TOWER trial involved a total of 1,169 patients with relapsing-remitting MS who were randomized to treatment: 408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38 years, with just over 80% being of white, 15% of Asian, and 2% of black ethnicity.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary endpoint was sustained accumulation of disability. This was defined as an increase of at least 1 point on the Expanded Disability Status Scale (EDSS) from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 (P = .0442) for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

"The safety and tolerability profile of teriflunomide, as characterized in this and previous studies, was similar for both the 7-mg and 14-mg doses, including long-term treatment observations," the investigators wrote. The most common side effects seen in patients treated with teriflunomide were hair thinning, headache, and increase in alanine aminotransferase concentrations.

Genzyme, a Sanofi company, sponsored the trial. The investigators disclosed financial relationships with Genzyme as well as other companies that manufacture drugs used to treat MS.

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study, called TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis), demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo (P = .0001). A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction (P = .0183).

Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

"These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting multiple sclerosis and as an option for patients who are unable to tolerate other disease-modifying therapies," wrote the TOWER Trial Group investigators (Lancet Neurol. 2014 Jan. 23 [doi: 10.1016/S1474-4422(13)70308-9]).

First author Dr. Christian Confavreux of University Claude Bernard Lyon 1, France, and his associates commented that the findings add to those previously reported from the phase III TEMSO trial (N. Engl. J. Med. 2011;365:1293-303), which showed that teriflunomide 7 mg and 14 mg both reduced the annualized relapse rate by around 31% when compared with placebo. They are also supported by the results of a phase II extension study.

Teriflunomide was approved for the treatment of adults with relapsing-remitting MS in the United States (trade name Aubagio) in 2012 and in Europe in 2013. The drug is the principal active metabolite in leflunomide, which is licensed for the treatment of rheumatoid arthritis.

The TOWER trial involved a total of 1,169 patients with relapsing-remitting MS who were randomized to treatment: 408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38 years, with just over 80% being of white, 15% of Asian, and 2% of black ethnicity.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary endpoint was sustained accumulation of disability. This was defined as an increase of at least 1 point on the Expanded Disability Status Scale (EDSS) from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 (P = .0442) for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

"The safety and tolerability profile of teriflunomide, as characterized in this and previous studies, was similar for both the 7-mg and 14-mg doses, including long-term treatment observations," the investigators wrote. The most common side effects seen in patients treated with teriflunomide were hair thinning, headache, and increase in alanine aminotransferase concentrations.

Genzyme, a Sanofi company, sponsored the trial. The investigators disclosed financial relationships with Genzyme as well as other companies that manufacture drugs used to treat MS.

Fecal immunochemical tests have an overall diagnostic accuracy of 95% for the detection of colorectal cancer, according to the results of a meta-analysis just published in the Annals of Internal Medicine.

The tests, which have already begun to replace the fecal occult blood test (FOBT) in national screening programs in the United States, Europe, and Asia, were found to be 79% sensitive and 94% specific for CRC.

"This systematic review and meta-analysis suggests that FITs [fecal immunochemical tests] have high accuracy, high specificity, and moderately high sensitivity for detection of CRC," Dr. Douglas Corley of the Kaiser Permanente division of research in Oakland, Calif., and his associates wrote (Ann. Intern. Med. 2014;160:171-81).

FITs are more sensitive at detecting both CRC and adenomas than the FOBT, they maintained, and are also more practical for people to perform at home, requiring only one or two stool samples and no special dietary or medication restrictions.

Despite a greater potential ease of use for mass screening, reports on the diagnostic performance of FITs have been inconsistent, the investigators explained. They therefore performed the meta-analysis to determine the overall diagnostic accuracy and factors affecting the tests’ performance. Nineteen trials were included that involved more than 113,000 individuals and provided data on eight different FITs available for use in the United States.

In addition to the sensitivities and specificities of FITs, positive and negative likelihood ratios (LR) were calculated to assess the ability of the tests to respectively "rule in" or "rule out" a diagnosis of CRC. The threshold set for a positive LR was a value above 5 and for a negative LR was 0.2. Pooled data from the trials showed a positive LR of 13.10 and a negative LR of 0.23.

Increasing the number of FIT samples did not affect the pooled sensitivities, specificities, positive LRs, or negative LRs of FITs for CRC. There also was no great difference in performance between the FIT brands evaluated in the studies. Dr. Corley and his associates pointed out, however, that head-to-head comparisons were not included in most studies so this finding should be interpreted with caution.

Diagnostic performance was affected by the cutoff values used to define a positive test, which might influence which test health systems decide to use, the researchers said.

"Health systems wishing to optimize use of a quantitative FIT should consider the tradeoff between increasing sensitivity (by lowering the cutoff threshold for a positive test) and the resulting increase in the number of positive results," they wrote. The latter could significantly impact colonoscopy resources if more procedures were indicated by a positive test.

The researchers recommended that health systems also look at individual studies comparing single or repeat testing, as the current data do not provide a definitive answer on the effect of sample number on the performance of FITs.

The National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the research.

Fecal immunochemical tests have an overall diagnostic accuracy of 95% for the detection of colorectal cancer, according to the results of a meta-analysis just published in the Annals of Internal Medicine.

The tests, which have already begun to replace the fecal occult blood test (FOBT) in national screening programs in the United States, Europe, and Asia, were found to be 79% sensitive and 94% specific for CRC.

"This systematic review and meta-analysis suggests that FITs [fecal immunochemical tests] have high accuracy, high specificity, and moderately high sensitivity for detection of CRC," Dr. Douglas Corley of the Kaiser Permanente division of research in Oakland, Calif., and his associates wrote (Ann. Intern. Med. 2014;160:171-81).

FITs are more sensitive at detecting both CRC and adenomas than the FOBT, they maintained, and are also more practical for people to perform at home, requiring only one or two stool samples and no special dietary or medication restrictions.

Despite a greater potential ease of use for mass screening, reports on the diagnostic performance of FITs have been inconsistent, the investigators explained. They therefore performed the meta-analysis to determine the overall diagnostic accuracy and factors affecting the tests’ performance. Nineteen trials were included that involved more than 113,000 individuals and provided data on eight different FITs available for use in the United States.

In addition to the sensitivities and specificities of FITs, positive and negative likelihood ratios (LR) were calculated to assess the ability of the tests to respectively "rule in" or "rule out" a diagnosis of CRC. The threshold set for a positive LR was a value above 5 and for a negative LR was 0.2. Pooled data from the trials showed a positive LR of 13.10 and a negative LR of 0.23.

Increasing the number of FIT samples did not affect the pooled sensitivities, specificities, positive LRs, or negative LRs of FITs for CRC. There also was no great difference in performance between the FIT brands evaluated in the studies. Dr. Corley and his associates pointed out, however, that head-to-head comparisons were not included in most studies so this finding should be interpreted with caution.

Diagnostic performance was affected by the cutoff values used to define a positive test, which might influence which test health systems decide to use, the researchers said.

"Health systems wishing to optimize use of a quantitative FIT should consider the tradeoff between increasing sensitivity (by lowering the cutoff threshold for a positive test) and the resulting increase in the number of positive results," they wrote. The latter could significantly impact colonoscopy resources if more procedures were indicated by a positive test.

The researchers recommended that health systems also look at individual studies comparing single or repeat testing, as the current data do not provide a definitive answer on the effect of sample number on the performance of FITs.

The National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the research.

Fecal immunochemical tests have an overall diagnostic accuracy of 95% for the detection of colorectal cancer, according to the results of a meta-analysis just published in the Annals of Internal Medicine.

The tests, which have already begun to replace the fecal occult blood test (FOBT) in national screening programs in the United States, Europe, and Asia, were found to be 79% sensitive and 94% specific for CRC.

"This systematic review and meta-analysis suggests that FITs [fecal immunochemical tests] have high accuracy, high specificity, and moderately high sensitivity for detection of CRC," Dr. Douglas Corley of the Kaiser Permanente division of research in Oakland, Calif., and his associates wrote (Ann. Intern. Med. 2014;160:171-81).

FITs are more sensitive at detecting both CRC and adenomas than the FOBT, they maintained, and are also more practical for people to perform at home, requiring only one or two stool samples and no special dietary or medication restrictions.

Despite a greater potential ease of use for mass screening, reports on the diagnostic performance of FITs have been inconsistent, the investigators explained. They therefore performed the meta-analysis to determine the overall diagnostic accuracy and factors affecting the tests’ performance. Nineteen trials were included that involved more than 113,000 individuals and provided data on eight different FITs available for use in the United States.

In addition to the sensitivities and specificities of FITs, positive and negative likelihood ratios (LR) were calculated to assess the ability of the tests to respectively "rule in" or "rule out" a diagnosis of CRC. The threshold set for a positive LR was a value above 5 and for a negative LR was 0.2. Pooled data from the trials showed a positive LR of 13.10 and a negative LR of 0.23.

Increasing the number of FIT samples did not affect the pooled sensitivities, specificities, positive LRs, or negative LRs of FITs for CRC. There also was no great difference in performance between the FIT brands evaluated in the studies. Dr. Corley and his associates pointed out, however, that head-to-head comparisons were not included in most studies so this finding should be interpreted with caution.

Diagnostic performance was affected by the cutoff values used to define a positive test, which might influence which test health systems decide to use, the researchers said.

"Health systems wishing to optimize use of a quantitative FIT should consider the tradeoff between increasing sensitivity (by lowering the cutoff threshold for a positive test) and the resulting increase in the number of positive results," they wrote. The latter could significantly impact colonoscopy resources if more procedures were indicated by a positive test.

The researchers recommended that health systems also look at individual studies comparing single or repeat testing, as the current data do not provide a definitive answer on the effect of sample number on the performance of FITs.

The National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the research.

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

AMSTERDAM – Despite finding no overall survival benefit by adding bevacizumab to standard chemotherapy for newly diagnosed or platinum-resistant advanced ovarian cancer, the results of two phase III clinical trials remain "practice changing," according to a commentator Dr. Rebecca Kristeleit at the the multidisciplinary European cancer congresses.

Final overall survival results from the ICON7 trial showed that, in more than 1,500 women with newly diagnosed advanced ovarian cancer, there was a nonstatistical (P =.85) difference in overall survival of about 0.9 months using the restricted mean when all patients were considered.

Sara Freeman/IMNG Medical Media

In the AURELIA trial, conducted in 361 women with platinum-resistant disease, the hazard ratio for overall survival was 0.85, in favor of the addition of bevacizumab to chemotherapy, although this was not statistically significant (P = .174). The median overall survival was 16.6 months vs. 13.3 months in the control arm.

"The message I take from ICON7 is that there is a significant overall survival benefit in the high-risk group," said Dr. Kristeleit. "It’s an important clinical improvement, and it’s most important in the poor-prognosis patients, the ones who are inoperable, and the ones who are stage IV."

Regarding AURELIA, Dr. Kristeleit, a senior lecturer and consultant medical oncologist at University College London, said, "The study has shown a significant progression-free survival benefit, and we need to remember that it has doubled this in this really hard to treat group of ovarian cancer patients where there is significant clinical need."

ICON7: Bevacizumab in front-line treatment

The ICON7 (International Collaboration on Ovarian Neoplasms) study investigated the safety and efficacy of adding bevacizumab (7.5 mg/kg every 3 weeks) to standard chemotherapy in women with newly diagnosed ovarian cancer who were recruited and treated at 253 centers. The mean age of patients in the trial was 57 years.

The primary efficacy findings from the study were reported 3 years ago at the annual Congress of the European Society for Medical Oncology and published in the New England Journal of Medicine (2011;365:2484-96). These findings showed a clear benefit of adding the targeted agent to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m²) given every 3 weeks for six cycles vs. chemotherapy alone, with median progression-free survival times of 19.0 vs. 17.3 months (HR, 0.81; P = .0041), respectively.

Sara Freeman/IMNG Medical Media

Now, with a median follow-up of 49 months, "it’s reassuring to see the progression-free survival is essentially the same [19.9 vs. 17.5 months]," observed study investigator Dr. Amit Oza of the Princess Margaret Cancer Centre at the University of Toronto.

Dr. Oza noted that 502 (33%) women met prespecified criteria for having a "poor prognosis," including women with suboptimally debulked stage III disease, those with stage IV disease, and those who could not have surgery, potentially putting them at high risk of progression. In those women, bevacizumab improved progression-free survival by a median of 5.5 months (HR, 0.73, P =.001), or 4.1 months using the restricted mean as the data were found to be non-proportional.

Final overall survival in these high-risk women was improved by a median of 9.4 months by the additional use of bevacizumab (HR, 0.78, P = .03), or 4.8 months using the restricted mean, from 34.5 months with chemotherapy alone to 39.3 months by the addition of the targeted agent.

"The overall survival difference in the high-risk subgroup is clinically meaningful," Dr. Oza said.

AURELIA: Bevacizumab in platinum-resistant disease

AURELIA was an open-label, randomized trial involving women who had progressive ovarian cancer within 6 months of receiving platinum-based chemotherapy. Women were randomized to receive chemotherapy alone (n = 182) or to chemotherapy plus bevacizumab (n = 179). The choice of chemotherapy was at the investigators’ discretion from a choice of weekly paclitaxel (80 mg/m² on days 1, 8, 15, and 22), topotecan (4 mg/m² on days 1, 8, and 15), or pegylated liposomal doxorubicin (PLD, 40 mg/m² on day 1). Bevacizumab was given at a dose of 15 mg/kg every 3 weeks.

The primary endpoint was progression-free survival, with secondary endpoints of overall survival, quality of life, and, of course, safety and tolerability. The primary endpoint findings were presented last year at the annual meeting American Society of Clinical Oncology (J. Clin. Oncol. 2012;30 Suppl:LBA5002) and showed that the addition of bevacizumab almost doubled progression-free survival from 3.4 months with chemotherapy alone to 6.7 months when bevacizumab was added (HR, 0.48, P less than .001).

"The study was not powered to detect a significant difference in overall survival," said Dr. Petronella O. Witteveen, who was one of the AURELIA study investigators. Dr. Witteveen of the University Medical Center Utrecht in the Netherlands commented that overall survival was a key secondary endpoint for the trial and that interpretation of these data were complicated by the high percentage (40%) of patients in the chemotherapy arm that were allowed to crossover to additional treatment with bevacizumab.

Sara Freeman/IMNG Medical Media

Although no difference between the treatment arms could be seen in the final overall survival analysis, exploratory findings hinted that patients who received bevacizumab in combination with weekly paclitaxel might have had a survival advantage. The median overall survival in the cohort of patients who received bevacizumab in addition to weekly paclitaxel (n = 60) was 22.4 months vs. 13.2 months in the patients who received the chemotherapy alone (n = 55; HR, 0.65). Overall survival in the topotecan and PLD cohorts did not show any benefit of the addition of bevacizumab, with median overall survival times of just over 13-14 months whether or not bevacizumab was added to chemotherapy.

Updated safety findings showed no undue concerns or new side effects, with a higher percentage of patients experiencing hypertension if treated with bevacizumab rather than chemotherapy alone (7.8% vs. 1.1%). "There were strict instructions to try to reduce the number of gastrointestinal perforations," Dr. Witteveen noted. This resulted in a low rate (1.1% vs. 0%) of this adverse event, she observed

"Practice-changing trials"

"I think these are practice-changing trials," Dr. Kristeleit commented, stating that bevacizumab is clearly an active drug in advanced bulky ovarian cancer.

Based on the ICON7 findings, "first-line bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high risk ovarian cancer," she said.

Meanwhile AURELIA shows, "Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer."

Bevacizumab (Avastin) was recently approved for use in combination with chemotherapy in the first- and second-line treatment of advanced ovarian cancer in Europe. In the second-line setting, it is indicated in platinum-sensitive disease and not platinum-resistant disease as tested in the AURELIA trial. Bevacizumab is not currently licensed for ovarian cancer treatment in the United States.

Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GlaxoSmithKline, and Novartis. ICON-7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.

AMSTERDAM – Despite finding no overall survival benefit by adding bevacizumab to standard chemotherapy for newly diagnosed or platinum-resistant advanced ovarian cancer, the results of two phase III clinical trials remain "practice changing," according to a commentator Dr. Rebecca Kristeleit at the the multidisciplinary European cancer congresses.

Final overall survival results from the ICON7 trial showed that, in more than 1,500 women with newly diagnosed advanced ovarian cancer, there was a nonstatistical (P =.85) difference in overall survival of about 0.9 months using the restricted mean when all patients were considered.

Sara Freeman/IMNG Medical Media

In the AURELIA trial, conducted in 361 women with platinum-resistant disease, the hazard ratio for overall survival was 0.85, in favor of the addition of bevacizumab to chemotherapy, although this was not statistically significant (P = .174). The median overall survival was 16.6 months vs. 13.3 months in the control arm.

"The message I take from ICON7 is that there is a significant overall survival benefit in the high-risk group," said Dr. Kristeleit. "It’s an important clinical improvement, and it’s most important in the poor-prognosis patients, the ones who are inoperable, and the ones who are stage IV."

Regarding AURELIA, Dr. Kristeleit, a senior lecturer and consultant medical oncologist at University College London, said, "The study has shown a significant progression-free survival benefit, and we need to remember that it has doubled this in this really hard to treat group of ovarian cancer patients where there is significant clinical need."

ICON7: Bevacizumab in front-line treatment

The ICON7 (International Collaboration on Ovarian Neoplasms) study investigated the safety and efficacy of adding bevacizumab (7.5 mg/kg every 3 weeks) to standard chemotherapy in women with newly diagnosed ovarian cancer who were recruited and treated at 253 centers. The mean age of patients in the trial was 57 years.

The primary efficacy findings from the study were reported 3 years ago at the annual Congress of the European Society for Medical Oncology and published in the New England Journal of Medicine (2011;365:2484-96). These findings showed a clear benefit of adding the targeted agent to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m²) given every 3 weeks for six cycles vs. chemotherapy alone, with median progression-free survival times of 19.0 vs. 17.3 months (HR, 0.81; P = .0041), respectively.

Sara Freeman/IMNG Medical Media

Now, with a median follow-up of 49 months, "it’s reassuring to see the progression-free survival is essentially the same [19.9 vs. 17.5 months]," observed study investigator Dr. Amit Oza of the Princess Margaret Cancer Centre at the University of Toronto.

Dr. Oza noted that 502 (33%) women met prespecified criteria for having a "poor prognosis," including women with suboptimally debulked stage III disease, those with stage IV disease, and those who could not have surgery, potentially putting them at high risk of progression. In those women, bevacizumab improved progression-free survival by a median of 5.5 months (HR, 0.73, P =.001), or 4.1 months using the restricted mean as the data were found to be non-proportional.

Final overall survival in these high-risk women was improved by a median of 9.4 months by the additional use of bevacizumab (HR, 0.78, P = .03), or 4.8 months using the restricted mean, from 34.5 months with chemotherapy alone to 39.3 months by the addition of the targeted agent.

"The overall survival difference in the high-risk subgroup is clinically meaningful," Dr. Oza said.

AURELIA: Bevacizumab in platinum-resistant disease

AURELIA was an open-label, randomized trial involving women who had progressive ovarian cancer within 6 months of receiving platinum-based chemotherapy. Women were randomized to receive chemotherapy alone (n = 182) or to chemotherapy plus bevacizumab (n = 179). The choice of chemotherapy was at the investigators’ discretion from a choice of weekly paclitaxel (80 mg/m² on days 1, 8, 15, and 22), topotecan (4 mg/m² on days 1, 8, and 15), or pegylated liposomal doxorubicin (PLD, 40 mg/m² on day 1). Bevacizumab was given at a dose of 15 mg/kg every 3 weeks.

The primary endpoint was progression-free survival, with secondary endpoints of overall survival, quality of life, and, of course, safety and tolerability. The primary endpoint findings were presented last year at the annual meeting American Society of Clinical Oncology (J. Clin. Oncol. 2012;30 Suppl:LBA5002) and showed that the addition of bevacizumab almost doubled progression-free survival from 3.4 months with chemotherapy alone to 6.7 months when bevacizumab was added (HR, 0.48, P less than .001).

"The study was not powered to detect a significant difference in overall survival," said Dr. Petronella O. Witteveen, who was one of the AURELIA study investigators. Dr. Witteveen of the University Medical Center Utrecht in the Netherlands commented that overall survival was a key secondary endpoint for the trial and that interpretation of these data were complicated by the high percentage (40%) of patients in the chemotherapy arm that were allowed to crossover to additional treatment with bevacizumab.

Sara Freeman/IMNG Medical Media

Although no difference between the treatment arms could be seen in the final overall survival analysis, exploratory findings hinted that patients who received bevacizumab in combination with weekly paclitaxel might have had a survival advantage. The median overall survival in the cohort of patients who received bevacizumab in addition to weekly paclitaxel (n = 60) was 22.4 months vs. 13.2 months in the patients who received the chemotherapy alone (n = 55; HR, 0.65). Overall survival in the topotecan and PLD cohorts did not show any benefit of the addition of bevacizumab, with median overall survival times of just over 13-14 months whether or not bevacizumab was added to chemotherapy.

Updated safety findings showed no undue concerns or new side effects, with a higher percentage of patients experiencing hypertension if treated with bevacizumab rather than chemotherapy alone (7.8% vs. 1.1%). "There were strict instructions to try to reduce the number of gastrointestinal perforations," Dr. Witteveen noted. This resulted in a low rate (1.1% vs. 0%) of this adverse event, she observed

"Practice-changing trials"

"I think these are practice-changing trials," Dr. Kristeleit commented, stating that bevacizumab is clearly an active drug in advanced bulky ovarian cancer.

Based on the ICON7 findings, "first-line bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high risk ovarian cancer," she said.

Meanwhile AURELIA shows, "Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer."

Bevacizumab (Avastin) was recently approved for use in combination with chemotherapy in the first- and second-line treatment of advanced ovarian cancer in Europe. In the second-line setting, it is indicated in platinum-sensitive disease and not platinum-resistant disease as tested in the AURELIA trial. Bevacizumab is not currently licensed for ovarian cancer treatment in the United States.

Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GlaxoSmithKline, and Novartis. ICON-7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.

AMSTERDAM – Despite finding no overall survival benefit by adding bevacizumab to standard chemotherapy for newly diagnosed or platinum-resistant advanced ovarian cancer, the results of two phase III clinical trials remain "practice changing," according to a commentator Dr. Rebecca Kristeleit at the the multidisciplinary European cancer congresses.

Final overall survival results from the ICON7 trial showed that, in more than 1,500 women with newly diagnosed advanced ovarian cancer, there was a nonstatistical (P =.85) difference in overall survival of about 0.9 months using the restricted mean when all patients were considered.

Sara Freeman/IMNG Medical Media

In the AURELIA trial, conducted in 361 women with platinum-resistant disease, the hazard ratio for overall survival was 0.85, in favor of the addition of bevacizumab to chemotherapy, although this was not statistically significant (P = .174). The median overall survival was 16.6 months vs. 13.3 months in the control arm.

"The message I take from ICON7 is that there is a significant overall survival benefit in the high-risk group," said Dr. Kristeleit. "It’s an important clinical improvement, and it’s most important in the poor-prognosis patients, the ones who are inoperable, and the ones who are stage IV."

Regarding AURELIA, Dr. Kristeleit, a senior lecturer and consultant medical oncologist at University College London, said, "The study has shown a significant progression-free survival benefit, and we need to remember that it has doubled this in this really hard to treat group of ovarian cancer patients where there is significant clinical need."

ICON7: Bevacizumab in front-line treatment

The ICON7 (International Collaboration on Ovarian Neoplasms) study investigated the safety and efficacy of adding bevacizumab (7.5 mg/kg every 3 weeks) to standard chemotherapy in women with newly diagnosed ovarian cancer who were recruited and treated at 253 centers. The mean age of patients in the trial was 57 years.

The primary efficacy findings from the study were reported 3 years ago at the annual Congress of the European Society for Medical Oncology and published in the New England Journal of Medicine (2011;365:2484-96). These findings showed a clear benefit of adding the targeted agent to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m²) given every 3 weeks for six cycles vs. chemotherapy alone, with median progression-free survival times of 19.0 vs. 17.3 months (HR, 0.81; P = .0041), respectively.

Sara Freeman/IMNG Medical Media

Now, with a median follow-up of 49 months, "it’s reassuring to see the progression-free survival is essentially the same [19.9 vs. 17.5 months]," observed study investigator Dr. Amit Oza of the Princess Margaret Cancer Centre at the University of Toronto.

Dr. Oza noted that 502 (33%) women met prespecified criteria for having a "poor prognosis," including women with suboptimally debulked stage III disease, those with stage IV disease, and those who could not have surgery, potentially putting them at high risk of progression. In those women, bevacizumab improved progression-free survival by a median of 5.5 months (HR, 0.73, P =.001), or 4.1 months using the restricted mean as the data were found to be non-proportional.

Final overall survival in these high-risk women was improved by a median of 9.4 months by the additional use of bevacizumab (HR, 0.78, P = .03), or 4.8 months using the restricted mean, from 34.5 months with chemotherapy alone to 39.3 months by the addition of the targeted agent.

"The overall survival difference in the high-risk subgroup is clinically meaningful," Dr. Oza said.

AURELIA: Bevacizumab in platinum-resistant disease

AURELIA was an open-label, randomized trial involving women who had progressive ovarian cancer within 6 months of receiving platinum-based chemotherapy. Women were randomized to receive chemotherapy alone (n = 182) or to chemotherapy plus bevacizumab (n = 179). The choice of chemotherapy was at the investigators’ discretion from a choice of weekly paclitaxel (80 mg/m² on days 1, 8, 15, and 22), topotecan (4 mg/m² on days 1, 8, and 15), or pegylated liposomal doxorubicin (PLD, 40 mg/m² on day 1). Bevacizumab was given at a dose of 15 mg/kg every 3 weeks.

The primary endpoint was progression-free survival, with secondary endpoints of overall survival, quality of life, and, of course, safety and tolerability. The primary endpoint findings were presented last year at the annual meeting American Society of Clinical Oncology (J. Clin. Oncol. 2012;30 Suppl:LBA5002) and showed that the addition of bevacizumab almost doubled progression-free survival from 3.4 months with chemotherapy alone to 6.7 months when bevacizumab was added (HR, 0.48, P less than .001).

"The study was not powered to detect a significant difference in overall survival," said Dr. Petronella O. Witteveen, who was one of the AURELIA study investigators. Dr. Witteveen of the University Medical Center Utrecht in the Netherlands commented that overall survival was a key secondary endpoint for the trial and that interpretation of these data were complicated by the high percentage (40%) of patients in the chemotherapy arm that were allowed to crossover to additional treatment with bevacizumab.

Sara Freeman/IMNG Medical Media

Although no difference between the treatment arms could be seen in the final overall survival analysis, exploratory findings hinted that patients who received bevacizumab in combination with weekly paclitaxel might have had a survival advantage. The median overall survival in the cohort of patients who received bevacizumab in addition to weekly paclitaxel (n = 60) was 22.4 months vs. 13.2 months in the patients who received the chemotherapy alone (n = 55; HR, 0.65). Overall survival in the topotecan and PLD cohorts did not show any benefit of the addition of bevacizumab, with median overall survival times of just over 13-14 months whether or not bevacizumab was added to chemotherapy.

Updated safety findings showed no undue concerns or new side effects, with a higher percentage of patients experiencing hypertension if treated with bevacizumab rather than chemotherapy alone (7.8% vs. 1.1%). "There were strict instructions to try to reduce the number of gastrointestinal perforations," Dr. Witteveen noted. This resulted in a low rate (1.1% vs. 0%) of this adverse event, she observed

"Practice-changing trials"

"I think these are practice-changing trials," Dr. Kristeleit commented, stating that bevacizumab is clearly an active drug in advanced bulky ovarian cancer.

Based on the ICON7 findings, "first-line bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high risk ovarian cancer," she said.

Meanwhile AURELIA shows, "Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer."

Bevacizumab (Avastin) was recently approved for use in combination with chemotherapy in the first- and second-line treatment of advanced ovarian cancer in Europe. In the second-line setting, it is indicated in platinum-sensitive disease and not platinum-resistant disease as tested in the AURELIA trial. Bevacizumab is not currently licensed for ovarian cancer treatment in the United States.

Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GlaxoSmithKline, and Novartis. ICON-7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.

Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A_1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA_1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA_1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA_1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.

Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A_1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA_1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA_1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA_1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.

Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A_1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA_1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA_1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA_1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.

Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A_1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA_1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA_1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA_1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.

Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A_1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA_1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA_1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA_1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.

Patients aged 65 years and older with type 2 diabetes who received intensive glucose-lowering therapy were at no greater risk of cardiovascular death than those who were given standard glucose-lowering therapy in the large ACCORD trial.

However, study participants who were under age 65 had a significantly higher risk of death from cardiovascular causes if they received intensive versus standard glucose-lowering treatment, with a hazard ratio of 1.71, compared with 0.97 for older patients.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD [cardiovascular disease] benefit," said Michael E. Miller, Ph.D., of Wake Forest University, Winston-Salem, N.C., and his associates (Diabetes Care 2013 Oct. 29, published online before print [doi: 10.2337/dc13-1545]).

Dr. Miller and his team performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study to determine if there was any difference in glucose control, tolerability, cardiovascular disease, or all-cause mortality according to patients’ age at randomization.

"The ACCORD results do not indicate that significant excess mortality occurred among intensively versus standard treatment older adults, [but] there is little evidence to suggest that older adults received a CVD benefit..."

ACCORD involved 10,251 patients (mean age, 62 years) with type 2 diabetes who had a median duration of diabetes of 10 years and a median hemoglobin A_1c level of 8.1% at enrollment. Patients were randomized to receive either intensive or standard glucose-lowering therapy, with target glycated HbA_1c levels of less than 6.0% or between 7.0% and 7.9%, respectively.

The main findings of the glucose-lowering component of the trial were published 5 years ago and showed that, rather than having a beneficial effect on cardiovascular or all-cause mortality as hypothesized, intensively lowering HbA_1c levels increased cardiovascular mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59). This led to the intensive-therapy arm being discontinued after a mean of 3.7 years’ follow-up.

Several analyses have since tried to determine why the excess mortality might have occurred, but there still appears to be no valid answer. For the current analysis, patients’ age at randomization was used to further examine the data. In total, there were 6,776 patients under age 65 and 3,475 who were at least 65 years old at randomization.

"Our analysis on the impact of baseline age on the effect of more intensive blood sugar lowering in the ACCORD trial indicates that, relative to standard glycemic treatment, intensive treatment resulted in similar metabolic and primary/secondary endpoint effects in older and younger participants," the researchers observed. Thus, patient age does not appear to influence whether HbA_1c targets can successfully be reached or not.

Hypoglycemia requiring medical assistance occurred in three times as many patients given intensive treatment as those given standard treatment, regardless of age. Rates were 15.3% versus 5.1% for older individuals, and 8.7% versus 3.0, respectively, for younger individuals.

Although the increased risk of hypoglycemia was similar for the two age groups, the absolute incidence of severe hypoglycemia was higher in older individuals, at 4.4% with intensive treatment and 1.4% with standard treatment, versus 2.5% and 0.8% for the younger patients.

The hypoglycemia findings "amplify prior findings in older patients," the researchers commented, highlighting "the need to individualize therapy in older adults with type 2 diabetes, as suggested by others."

Altogether, these new data from ACCORD can help to develop future trials in older individuals, the investigators concluded. "Exploratory analyses of the type we have performed can help to inform the design, implementation, and monitoring of future clinical trials that include older patients with type 2 diabetes and other chronic diseases."

ACCORD was supported by grants from the National Institutes of Health. Dr. Miller and several coauthors reported no conflicts of interest. Several authors disclosed ties with AstraZeneca, Bayer, and other companies.