ORLANDO – Pulmonary artery pressure monitoring using an implanted device was even more effective for controlling pulmonary artery pressures in 2,000 real-world U.S. heart failure patients than it was in the pivotal trial that led to the device’s regulatory approval.

Data from the first 2,000 U.S. heart failure patients to receive the CardioMEMS pulmonary artery (PA) pressure monitoring device and have at least 6 months of follow-up data since the device received Food and Drug Administration approval in 2014 showed that cumulative PA pressure reductions in these patients during the first 6 months of use averaged 434 mm Hg per patient when compared with their baseline PA pressure when they first received the device. This was nearly threefold better than the average 150–mm Hg cumulative reduction in PA pressure per patient during 6 months of use seen in the CHAMPION trial, Dr. William T. Abraham reported at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

Although this analysis of data from the registry maintained for U.S. patients who receive the CardioMEMS device does not yet include information on how these patients fared clinically, and specifically how often they required rehospitalization for heart failure, the strikingly high level of PA pressure control seen in the first 2,000 U.S. patients bodes well for what the clinical findings will show once they are available.

“In our experience with PA pressure monitoring, there is almost a linear relationship between reduced PA pressures and reduced numbers of events” in the form of rehospitalizations for heart failure, said Dr. Abraham, professor of medicine and director of cardiovascular medicine at Ohio State University in Columbus. Once data on outcomes are analyzed for the registry patients, “I think they will be even better than they were in the trial,” he said in an interview.

The PA pressure data in these initial patients “are very important because they tell us that in general use, clinicians – many of whom are at community hospitals – are very capable of using the CardioMEMS data to control patient pressures, and in CHAMPION we showed that there is a relationship between controlled pressures and improved outcomes,” he said. The findings also help allay a key concern about the potential benefit from implanting a device to monitor PA pressure, which is that clinicians must respond to the information and tweak a patient’s diuretic and vasodilator treatments in order for pressure monitoring to have an effect on heart failure outcomes.

“These data clearly refute that concern,” Dr. Abraham said.

He expressed some surprise that PA pressure control with monitoring was so much more effective in real-world use than in the CHAMPION pivotal trial. “In the trial, it was a paradigm shift to manage heart failure patients based on their PA pressures and not according to their symptoms,” he said. With CardioMEMS pressure monitoring, clinicians are supposed to treat high PA pressure with dose adjustments even if the patient feels okay. The new data suggest that clinicians now using the device “have gotten the message that if you don’t do something with the data the patients won’t improve.”

The registry patients came from 47 states and 427 unique physicians who worked in a range of settings including large and small centers, and academic and nonacademic community centers. The patients averaged 70 years, 40% were women, a third had a left ventricular ejection fraction at or above 40%, and their average PA pressure at the time they had their device implanted was 34.9 mm Hg. This pressure was notably higher than the average 31.6 mm Hg pressure among patients enrolled in CHAMPION, a fact that also helps explain why the registry patients received a larger pressure-reduction benefit: They started from a higher level than the trial patients, and during follow-up, their achieved pressures were always compared back to their high baseline pressures.

The registry patients were also substantially older than the trial patients, who had averaged 62 years, and the registry included substantially more women and more patients with higher ejection fractions. Dr. Abraham did not report data on their New York Heart Association class at entry, but labeling for CardioMEMS specifies that patients should have class III heart failure as well as a recent heart failure hospitalization.

Dr. Abraham’s analysis also showed that the greatest degree of PA pressure control occurred in the patients who began device-based treatment with the highest PA pressures. Nearly half the 2,000 registry patients had an entry PA pressure at or above 35 mm Hg, and over a period of 6 months, they averaged a cumulative 876–mm Hg reduction in their PA pressure relative to their baseline level. The third of patients who began with a PA pressure of 25-34 mm Hg had an average 169–mm Hg cumulative pressure reduction over the 6 month period, and the 18% of patients who began with a PA pressure of less than 25 mm Hg actually had an average cumulative increase in the PA pressure of 163 mm Hg. Target PA pressures are usually in the normal range of 18-25 mm Hg.

The analyses also showed that the impact of PA pressure monitoring on pressure was roughly similar regardless of the left ventricular ejection fraction patients had at baseline, and regardless of their sex.

The registry data were collected by St. Jude, the company that markets the CardioMEMS device. Dr. Abraham is a consultant to St. Jude and was lead investigator for the CHAMPION pivotal trial.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Pulmonary artery pressure monitoring using an implanted device was even more effective for controlling pulmonary artery pressures in 2,000 real-world U.S. heart failure patients than it was in the pivotal trial that led to the device’s regulatory approval.

Data from the first 2,000 U.S. heart failure patients to receive the CardioMEMS pulmonary artery (PA) pressure monitoring device and have at least 6 months of follow-up data since the device received Food and Drug Administration approval in 2014 showed that cumulative PA pressure reductions in these patients during the first 6 months of use averaged 434 mm Hg per patient when compared with their baseline PA pressure when they first received the device. This was nearly threefold better than the average 150–mm Hg cumulative reduction in PA pressure per patient during 6 months of use seen in the CHAMPION trial, Dr. William T. Abraham reported at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

Although this analysis of data from the registry maintained for U.S. patients who receive the CardioMEMS device does not yet include information on how these patients fared clinically, and specifically how often they required rehospitalization for heart failure, the strikingly high level of PA pressure control seen in the first 2,000 U.S. patients bodes well for what the clinical findings will show once they are available.

“In our experience with PA pressure monitoring, there is almost a linear relationship between reduced PA pressures and reduced numbers of events” in the form of rehospitalizations for heart failure, said Dr. Abraham, professor of medicine and director of cardiovascular medicine at Ohio State University in Columbus. Once data on outcomes are analyzed for the registry patients, “I think they will be even better than they were in the trial,” he said in an interview.

The PA pressure data in these initial patients “are very important because they tell us that in general use, clinicians – many of whom are at community hospitals – are very capable of using the CardioMEMS data to control patient pressures, and in CHAMPION we showed that there is a relationship between controlled pressures and improved outcomes,” he said. The findings also help allay a key concern about the potential benefit from implanting a device to monitor PA pressure, which is that clinicians must respond to the information and tweak a patient’s diuretic and vasodilator treatments in order for pressure monitoring to have an effect on heart failure outcomes.

“These data clearly refute that concern,” Dr. Abraham said.

He expressed some surprise that PA pressure control with monitoring was so much more effective in real-world use than in the CHAMPION pivotal trial. “In the trial, it was a paradigm shift to manage heart failure patients based on their PA pressures and not according to their symptoms,” he said. With CardioMEMS pressure monitoring, clinicians are supposed to treat high PA pressure with dose adjustments even if the patient feels okay. The new data suggest that clinicians now using the device “have gotten the message that if you don’t do something with the data the patients won’t improve.”

The registry patients came from 47 states and 427 unique physicians who worked in a range of settings including large and small centers, and academic and nonacademic community centers. The patients averaged 70 years, 40% were women, a third had a left ventricular ejection fraction at or above 40%, and their average PA pressure at the time they had their device implanted was 34.9 mm Hg. This pressure was notably higher than the average 31.6 mm Hg pressure among patients enrolled in CHAMPION, a fact that also helps explain why the registry patients received a larger pressure-reduction benefit: They started from a higher level than the trial patients, and during follow-up, their achieved pressures were always compared back to their high baseline pressures.

The registry patients were also substantially older than the trial patients, who had averaged 62 years, and the registry included substantially more women and more patients with higher ejection fractions. Dr. Abraham did not report data on their New York Heart Association class at entry, but labeling for CardioMEMS specifies that patients should have class III heart failure as well as a recent heart failure hospitalization.

Dr. Abraham’s analysis also showed that the greatest degree of PA pressure control occurred in the patients who began device-based treatment with the highest PA pressures. Nearly half the 2,000 registry patients had an entry PA pressure at or above 35 mm Hg, and over a period of 6 months, they averaged a cumulative 876–mm Hg reduction in their PA pressure relative to their baseline level. The third of patients who began with a PA pressure of 25-34 mm Hg had an average 169–mm Hg cumulative pressure reduction over the 6 month period, and the 18% of patients who began with a PA pressure of less than 25 mm Hg actually had an average cumulative increase in the PA pressure of 163 mm Hg. Target PA pressures are usually in the normal range of 18-25 mm Hg.

The analyses also showed that the impact of PA pressure monitoring on pressure was roughly similar regardless of the left ventricular ejection fraction patients had at baseline, and regardless of their sex.

The registry data were collected by St. Jude, the company that markets the CardioMEMS device. Dr. Abraham is a consultant to St. Jude and was lead investigator for the CHAMPION pivotal trial.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Pulmonary artery pressure monitoring using an implanted device was even more effective for controlling pulmonary artery pressures in 2,000 real-world U.S. heart failure patients than it was in the pivotal trial that led to the device’s regulatory approval.

Data from the first 2,000 U.S. heart failure patients to receive the CardioMEMS pulmonary artery (PA) pressure monitoring device and have at least 6 months of follow-up data since the device received Food and Drug Administration approval in 2014 showed that cumulative PA pressure reductions in these patients during the first 6 months of use averaged 434 mm Hg per patient when compared with their baseline PA pressure when they first received the device. This was nearly threefold better than the average 150–mm Hg cumulative reduction in PA pressure per patient during 6 months of use seen in the CHAMPION trial, Dr. William T. Abraham reported at the annual scientific meeting of the Heart Failure Society of America.

Mitchel L. Zoler/Frontline Medical News

Although this analysis of data from the registry maintained for U.S. patients who receive the CardioMEMS device does not yet include information on how these patients fared clinically, and specifically how often they required rehospitalization for heart failure, the strikingly high level of PA pressure control seen in the first 2,000 U.S. patients bodes well for what the clinical findings will show once they are available.

“In our experience with PA pressure monitoring, there is almost a linear relationship between reduced PA pressures and reduced numbers of events” in the form of rehospitalizations for heart failure, said Dr. Abraham, professor of medicine and director of cardiovascular medicine at Ohio State University in Columbus. Once data on outcomes are analyzed for the registry patients, “I think they will be even better than they were in the trial,” he said in an interview.

The PA pressure data in these initial patients “are very important because they tell us that in general use, clinicians – many of whom are at community hospitals – are very capable of using the CardioMEMS data to control patient pressures, and in CHAMPION we showed that there is a relationship between controlled pressures and improved outcomes,” he said. The findings also help allay a key concern about the potential benefit from implanting a device to monitor PA pressure, which is that clinicians must respond to the information and tweak a patient’s diuretic and vasodilator treatments in order for pressure monitoring to have an effect on heart failure outcomes.

“These data clearly refute that concern,” Dr. Abraham said.

He expressed some surprise that PA pressure control with monitoring was so much more effective in real-world use than in the CHAMPION pivotal trial. “In the trial, it was a paradigm shift to manage heart failure patients based on their PA pressures and not according to their symptoms,” he said. With CardioMEMS pressure monitoring, clinicians are supposed to treat high PA pressure with dose adjustments even if the patient feels okay. The new data suggest that clinicians now using the device “have gotten the message that if you don’t do something with the data the patients won’t improve.”

The registry patients came from 47 states and 427 unique physicians who worked in a range of settings including large and small centers, and academic and nonacademic community centers. The patients averaged 70 years, 40% were women, a third had a left ventricular ejection fraction at or above 40%, and their average PA pressure at the time they had their device implanted was 34.9 mm Hg. This pressure was notably higher than the average 31.6 mm Hg pressure among patients enrolled in CHAMPION, a fact that also helps explain why the registry patients received a larger pressure-reduction benefit: They started from a higher level than the trial patients, and during follow-up, their achieved pressures were always compared back to their high baseline pressures.

The registry patients were also substantially older than the trial patients, who had averaged 62 years, and the registry included substantially more women and more patients with higher ejection fractions. Dr. Abraham did not report data on their New York Heart Association class at entry, but labeling for CardioMEMS specifies that patients should have class III heart failure as well as a recent heart failure hospitalization.

Dr. Abraham’s analysis also showed that the greatest degree of PA pressure control occurred in the patients who began device-based treatment with the highest PA pressures. Nearly half the 2,000 registry patients had an entry PA pressure at or above 35 mm Hg, and over a period of 6 months, they averaged a cumulative 876–mm Hg reduction in their PA pressure relative to their baseline level. The third of patients who began with a PA pressure of 25-34 mm Hg had an average 169–mm Hg cumulative pressure reduction over the 6 month period, and the 18% of patients who began with a PA pressure of less than 25 mm Hg actually had an average cumulative increase in the PA pressure of 163 mm Hg. Target PA pressures are usually in the normal range of 18-25 mm Hg.

The analyses also showed that the impact of PA pressure monitoring on pressure was roughly similar regardless of the left ventricular ejection fraction patients had at baseline, and regardless of their sex.

The registry data were collected by St. Jude, the company that markets the CardioMEMS device. Dr. Abraham is a consultant to St. Jude and was lead investigator for the CHAMPION pivotal trial.

[email protected]

On Twitter @mitchelzoler

LONDON – A study comparing patient data with six definitions of the Asthma-COPD Overlap Syndrome (ACOS) found only one of the patients analyzed met all definitions. This provoked an animated discussion at the annual congress of the European Respiratory Society about the utility of ACOS as a clinical entity.

Of 864 patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma drawn from the Netherlands Epidemiology of Obesity cohort (a population-based study with 5,784 patients), 39.1% (338 patients) met at least one of the definitions of ACOS, while 0.1% (one patient) met the criteria for all six definitions.

When this finding was presented, the ERS audience first laughed and then applauded. At the end of the presentation, long lines formed at the microphones. Every comment made was hostile to the concept of ACOS.

“Let us bring ACOS to an honorable death,” said one audience member. His point, reiterated by all who commented subsequently, was that ACOS confuses efforts to treat the underlying respiratory symptoms. Even in those who have both asthma and COPD, the speaker, like other members of the audience, said he considered the diagnosis of ACOS unhelpful.

The six definitions in the study included the latest and just published consensus definition from the ERS (Eur Respir J. 2016;48[3]:664-73). According to the ERS definition, the key features of ACOS are age greater than 40 years, long-term history of asthma (since childhood or early adulthood), and significant exposure to cigarette or biomass smoke.

The other definitions analyzed included a medical history of both asthma and COPD, a self-reported history of both asthma and COPD, and a record of the proportion of a person’s vital capacity that he/she is able to expire in 1 second of forced expiration of less than 0.7 plus a record of fractionated nitric oxide concentration in exhaled breath of greater than or equal to 45 parts per billion.

Although attempted, a Venn diagram that would show overlapping subsets of patients that fell into these definitions “was not possible,” according to Tobias Bonten, MD, University of Leiden, the Netherlands.

Asthma duration was just over 10 years in those identified as having ACOS by medical history alone (registry-based definitions), just over 20 years in those with a medical history and objective evidence of impaired lung function, but about 40 years in those with a self-report of both asthma and COPD.

One area that all groups created by the ACOS definitions did have in common was demographic variables, such as median age, proportion of patients defined as overweight or obese by body mass index, and proportion who were current smokers.

Members of the audience acknowledged the importance of considering the coexistence of asthma and COPD, but expressed skepticism about the value of ACOS as a separate entity in the clinic.

“ACOS is something like the emperor’s new clothes,” one audience member said during the discussion. “It is important to identify asthma patients with obstruction because they have reduced lung function that should be treated more actively, but I find the definition [of ACOS] unnecessary,” he said.

A similar conclusion was drawn in a review article devoted to ACOS published last year (N Engl J Med. 2015;373[13]:1241-9). “It is premature to recommend the designation of ACOS as a disease entity,” the authors wrote.

This is a position widely shared by clinicians, judging from audience comments provoked by this demonstration.

For the sake of time, the moderators were forced to end the discussion with significant lines of clinicians at the microphone.

“It is quite clear that ACOS should die,” said one of the last speakers given a chance to voice an opinion. He suggested that the coexistence of asthma and COPD is something that “quite clearly can happen,” but he objected to definitions he said are unhelpful for clinical care.

Dr. Bonten reported no relevant financial relationships.

LONDON – A study comparing patient data with six definitions of the Asthma-COPD Overlap Syndrome (ACOS) found only one of the patients analyzed met all definitions. This provoked an animated discussion at the annual congress of the European Respiratory Society about the utility of ACOS as a clinical entity.

Of 864 patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma drawn from the Netherlands Epidemiology of Obesity cohort (a population-based study with 5,784 patients), 39.1% (338 patients) met at least one of the definitions of ACOS, while 0.1% (one patient) met the criteria for all six definitions.

When this finding was presented, the ERS audience first laughed and then applauded. At the end of the presentation, long lines formed at the microphones. Every comment made was hostile to the concept of ACOS.

“Let us bring ACOS to an honorable death,” said one audience member. His point, reiterated by all who commented subsequently, was that ACOS confuses efforts to treat the underlying respiratory symptoms. Even in those who have both asthma and COPD, the speaker, like other members of the audience, said he considered the diagnosis of ACOS unhelpful.

The six definitions in the study included the latest and just published consensus definition from the ERS (Eur Respir J. 2016;48[3]:664-73). According to the ERS definition, the key features of ACOS are age greater than 40 years, long-term history of asthma (since childhood or early adulthood), and significant exposure to cigarette or biomass smoke.

The other definitions analyzed included a medical history of both asthma and COPD, a self-reported history of both asthma and COPD, and a record of the proportion of a person’s vital capacity that he/she is able to expire in 1 second of forced expiration of less than 0.7 plus a record of fractionated nitric oxide concentration in exhaled breath of greater than or equal to 45 parts per billion.

Although attempted, a Venn diagram that would show overlapping subsets of patients that fell into these definitions “was not possible,” according to Tobias Bonten, MD, University of Leiden, the Netherlands.

Asthma duration was just over 10 years in those identified as having ACOS by medical history alone (registry-based definitions), just over 20 years in those with a medical history and objective evidence of impaired lung function, but about 40 years in those with a self-report of both asthma and COPD.

One area that all groups created by the ACOS definitions did have in common was demographic variables, such as median age, proportion of patients defined as overweight or obese by body mass index, and proportion who were current smokers.

Members of the audience acknowledged the importance of considering the coexistence of asthma and COPD, but expressed skepticism about the value of ACOS as a separate entity in the clinic.

“ACOS is something like the emperor’s new clothes,” one audience member said during the discussion. “It is important to identify asthma patients with obstruction because they have reduced lung function that should be treated more actively, but I find the definition [of ACOS] unnecessary,” he said.

A similar conclusion was drawn in a review article devoted to ACOS published last year (N Engl J Med. 2015;373[13]:1241-9). “It is premature to recommend the designation of ACOS as a disease entity,” the authors wrote.

This is a position widely shared by clinicians, judging from audience comments provoked by this demonstration.

For the sake of time, the moderators were forced to end the discussion with significant lines of clinicians at the microphone.

“It is quite clear that ACOS should die,” said one of the last speakers given a chance to voice an opinion. He suggested that the coexistence of asthma and COPD is something that “quite clearly can happen,” but he objected to definitions he said are unhelpful for clinical care.

Dr. Bonten reported no relevant financial relationships.

LONDON – A study comparing patient data with six definitions of the Asthma-COPD Overlap Syndrome (ACOS) found only one of the patients analyzed met all definitions. This provoked an animated discussion at the annual congress of the European Respiratory Society about the utility of ACOS as a clinical entity.

Of 864 patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma drawn from the Netherlands Epidemiology of Obesity cohort (a population-based study with 5,784 patients), 39.1% (338 patients) met at least one of the definitions of ACOS, while 0.1% (one patient) met the criteria for all six definitions.

When this finding was presented, the ERS audience first laughed and then applauded. At the end of the presentation, long lines formed at the microphones. Every comment made was hostile to the concept of ACOS.

“Let us bring ACOS to an honorable death,” said one audience member. His point, reiterated by all who commented subsequently, was that ACOS confuses efforts to treat the underlying respiratory symptoms. Even in those who have both asthma and COPD, the speaker, like other members of the audience, said he considered the diagnosis of ACOS unhelpful.

The six definitions in the study included the latest and just published consensus definition from the ERS (Eur Respir J. 2016;48[3]:664-73). According to the ERS definition, the key features of ACOS are age greater than 40 years, long-term history of asthma (since childhood or early adulthood), and significant exposure to cigarette or biomass smoke.

The other definitions analyzed included a medical history of both asthma and COPD, a self-reported history of both asthma and COPD, and a record of the proportion of a person’s vital capacity that he/she is able to expire in 1 second of forced expiration of less than 0.7 plus a record of fractionated nitric oxide concentration in exhaled breath of greater than or equal to 45 parts per billion.

Although attempted, a Venn diagram that would show overlapping subsets of patients that fell into these definitions “was not possible,” according to Tobias Bonten, MD, University of Leiden, the Netherlands.

Asthma duration was just over 10 years in those identified as having ACOS by medical history alone (registry-based definitions), just over 20 years in those with a medical history and objective evidence of impaired lung function, but about 40 years in those with a self-report of both asthma and COPD.

One area that all groups created by the ACOS definitions did have in common was demographic variables, such as median age, proportion of patients defined as overweight or obese by body mass index, and proportion who were current smokers.

Members of the audience acknowledged the importance of considering the coexistence of asthma and COPD, but expressed skepticism about the value of ACOS as a separate entity in the clinic.

“ACOS is something like the emperor’s new clothes,” one audience member said during the discussion. “It is important to identify asthma patients with obstruction because they have reduced lung function that should be treated more actively, but I find the definition [of ACOS] unnecessary,” he said.

A similar conclusion was drawn in a review article devoted to ACOS published last year (N Engl J Med. 2015;373[13]:1241-9). “It is premature to recommend the designation of ACOS as a disease entity,” the authors wrote.

This is a position widely shared by clinicians, judging from audience comments provoked by this demonstration.

For the sake of time, the moderators were forced to end the discussion with significant lines of clinicians at the microphone.

“It is quite clear that ACOS should die,” said one of the last speakers given a chance to voice an opinion. He suggested that the coexistence of asthma and COPD is something that “quite clearly can happen,” but he objected to definitions he said are unhelpful for clinical care.

Dr. Bonten reported no relevant financial relationships.

PD-1 antibodies are being touted as a promising immunotherapeutic approach for treating malignant melanoma among other cancers. The antibodies target proteins that promote programmed cell death and activate the immune system to attack tumors.              

Related: BRAF Inhibitor Resistance Reprograms Metabolic and Survival Pathways to Sensitize Melanoma Cells to Arginine Deprivation              

To find out more about the efficacy and safety of PD-1 antibody treatment, researchers from Xiamen University, Chinese Academy of Medical Sciences, and Peking Union Medical College, China, reviewed data from 5 multicenter, randomized clinical trials involving 2,828 patients. In 2 trials, patients were previously untreated; in the other 3, patients had progression after anti-CTLA-4 treatment or had received no more than 1 previous systemic therapy. Patients in the experimental groups received nivolumab or pembrolizumab; patients in the control groups received ipilimumab or chemotherapy.

In all 5 trials, the researchers noted significant differences between the anti-PD-1 groups and the control groups. The PD-1 antibody treatment was associated with a significantly better overall response rate (ORR): 40.0% in patients on nivolumab 3 mg/kg IV every 2 weeks as front-line therapy and 31.6% in those who received nivolumab at the same dosage after progression from anti-CTLA-4 treatment. Response was improved whether the drug was used as first-line treatment or for refractory/relapsed melanoma.     

Related: Nivolumab Approved for Expanded Indication     

Patients in the PD-1 groups also had a significantly greater rate of progression-free survival (PFS) compared with those who received other treatments, such as chemotherapy and ipilimumab. The median PFS was > 4.7 months in the nivolumab group and > 3.7 months in the pembrolizumab group. In 2 trials, the ORR among patients receiving pembrolizumab was between 23.3% and 33.2%; different dosages improved the overall response rate in both untreated and relapsed/refractory patients.

The most common adverse events (AEs) were fatigue, diarrhea, pruritus, rash, and nausea. Patients treated with nivolumab reported significantly fewer AEs. Although a high dosage or short intermission of pembrolizumab extended the median PFS, a subgroup analysis of different doses revealed a significant dose-dependent increase in AEs.

Source:

Lin Z, Chen X, Li Z, et al. PLoS One. 2016;11(8):e0160485.
doi: 10.1371/journal.pone.0160485.

PD-1 antibodies are being touted as a promising immunotherapeutic approach for treating malignant melanoma among other cancers. The antibodies target proteins that promote programmed cell death and activate the immune system to attack tumors.              

Related: BRAF Inhibitor Resistance Reprograms Metabolic and Survival Pathways to Sensitize Melanoma Cells to Arginine Deprivation              

To find out more about the efficacy and safety of PD-1 antibody treatment, researchers from Xiamen University, Chinese Academy of Medical Sciences, and Peking Union Medical College, China, reviewed data from 5 multicenter, randomized clinical trials involving 2,828 patients. In 2 trials, patients were previously untreated; in the other 3, patients had progression after anti-CTLA-4 treatment or had received no more than 1 previous systemic therapy. Patients in the experimental groups received nivolumab or pembrolizumab; patients in the control groups received ipilimumab or chemotherapy.

In all 5 trials, the researchers noted significant differences between the anti-PD-1 groups and the control groups. The PD-1 antibody treatment was associated with a significantly better overall response rate (ORR): 40.0% in patients on nivolumab 3 mg/kg IV every 2 weeks as front-line therapy and 31.6% in those who received nivolumab at the same dosage after progression from anti-CTLA-4 treatment. Response was improved whether the drug was used as first-line treatment or for refractory/relapsed melanoma.     

Related: Nivolumab Approved for Expanded Indication     

Patients in the PD-1 groups also had a significantly greater rate of progression-free survival (PFS) compared with those who received other treatments, such as chemotherapy and ipilimumab. The median PFS was > 4.7 months in the nivolumab group and > 3.7 months in the pembrolizumab group. In 2 trials, the ORR among patients receiving pembrolizumab was between 23.3% and 33.2%; different dosages improved the overall response rate in both untreated and relapsed/refractory patients.

The most common adverse events (AEs) were fatigue, diarrhea, pruritus, rash, and nausea. Patients treated with nivolumab reported significantly fewer AEs. Although a high dosage or short intermission of pembrolizumab extended the median PFS, a subgroup analysis of different doses revealed a significant dose-dependent increase in AEs.

Source:

Lin Z, Chen X, Li Z, et al. PLoS One. 2016;11(8):e0160485.
doi: 10.1371/journal.pone.0160485.

PD-1 antibodies are being touted as a promising immunotherapeutic approach for treating malignant melanoma among other cancers. The antibodies target proteins that promote programmed cell death and activate the immune system to attack tumors.              

Related: BRAF Inhibitor Resistance Reprograms Metabolic and Survival Pathways to Sensitize Melanoma Cells to Arginine Deprivation              

To find out more about the efficacy and safety of PD-1 antibody treatment, researchers from Xiamen University, Chinese Academy of Medical Sciences, and Peking Union Medical College, China, reviewed data from 5 multicenter, randomized clinical trials involving 2,828 patients. In 2 trials, patients were previously untreated; in the other 3, patients had progression after anti-CTLA-4 treatment or had received no more than 1 previous systemic therapy. Patients in the experimental groups received nivolumab or pembrolizumab; patients in the control groups received ipilimumab or chemotherapy.

In all 5 trials, the researchers noted significant differences between the anti-PD-1 groups and the control groups. The PD-1 antibody treatment was associated with a significantly better overall response rate (ORR): 40.0% in patients on nivolumab 3 mg/kg IV every 2 weeks as front-line therapy and 31.6% in those who received nivolumab at the same dosage after progression from anti-CTLA-4 treatment. Response was improved whether the drug was used as first-line treatment or for refractory/relapsed melanoma.     

Related: Nivolumab Approved for Expanded Indication     

Patients in the PD-1 groups also had a significantly greater rate of progression-free survival (PFS) compared with those who received other treatments, such as chemotherapy and ipilimumab. The median PFS was > 4.7 months in the nivolumab group and > 3.7 months in the pembrolizumab group. In 2 trials, the ORR among patients receiving pembrolizumab was between 23.3% and 33.2%; different dosages improved the overall response rate in both untreated and relapsed/refractory patients.

The most common adverse events (AEs) were fatigue, diarrhea, pruritus, rash, and nausea. Patients treated with nivolumab reported significantly fewer AEs. Although a high dosage or short intermission of pembrolizumab extended the median PFS, a subgroup analysis of different doses revealed a significant dose-dependent increase in AEs.

Source:

Lin Z, Chen X, Li Z, et al. PLoS One. 2016;11(8):e0160485.
doi: 10.1371/journal.pone.0160485.

In a rare turn, the Senate Veterans Affairs Committee recently focused on what the VA is doing right. “We are changing culture and doing so by celebrating the people who have dedicated their careers to serving veterans,” testified Carolyn Clancy, MD, deputy under secretary for health for organizational excellence. “We are breaking down cultural barriers, like competition, by creating systematic incentives to share what has worked with others in the system.”

Dr. Clancy outlined some of the successes from the VA’s newly developed Diffusion of Excellence Initiative. The goal of the initiative has been to “identify clinical and administrative best practices, disseminate these practices to other sites of care, and encourage standardization of practices that deliver positive outcomes for veterans and their families,” Dr. Clancy reported. So far the initiative has generated more than 260 ongoing innovations at 70 facilities.

According to Dr. Clancy, the Diffusion of Excellence Initiative uses an internal VA social media platform to identify promising practices that align with strategic priorities, offer efficient resource use, can be implemented in diverse care environments, and can be implemented within 6 to 12 months. The initiative also sought to identify local champions or early adopters who can begin to implement the best practice locally. Once it is proven practice, the initiative seeks to find additional locations to further test the practice in a different setting. Best practices are chosen for national standardization if they have had relative success with an initial implementation and similar outcomes when replicated elsewhere.

So far 50 best practices have been replicated and are ready for widespread dissemination. “Identifying and spreading best practices can be a major driver of consistent, high-quality health care for veterans,” Dr. Clancy told the Senate panel. “This is restoring trust in the system. It offers a model for other health systems.”

Examples of best practices include the following:

Improving Same-Day Access Using Registered Nurse (RN) Care Manager “Chair” Visits: At the Boise VAMC in Idaho, the primary care team created a process where same-day appointment requests are triaged and scribed by RN Care Managers, saving primary care providers’ time when they see patients between appointments to assess and confirm the care plan.

Access Data Dashboard to Improve Clinic Management: The data analysis team at Harry S. Truman Memorial Veterans’ Hospital (Columbia, Missouri) implemented a dashboard for clinic access metrics (no-shows, completed appointment wait times, clinic utilization, etc). These metrics are posted monthly on an accessible dashboard that can be used by staff to solve problems and make key decisions that help veterans get timely access to care.

Planning for Future Medical Decision via Group Visits: This initiative presents advance care directives and other care planning for future medical decisions in interactive and patient-centered group visits.

Increasing Access to Primary Care With Pharmacists: The William S. Middleton Memorial Veterans’ Hospital (Madison, Wisconsin) matched clinical pharmacy specialists with multiple patient aligned care teams to conduct new patient intake calls 1 week before a new patient has his or her first appointment with a provider, collecting medications, noting any formulary conversions, and orienting the patient to VA.

eScreening: The eScreening Program is a mobile technology developed to facilitate the screening process and improve care coordination and measurement-based care for veterans. It offers veteran-directed screening, real-time scoring, individualized patient feedback, instantaneous medical record clinical documentation, immediate alerts to clinicians for evaluation and triage, and monitoring of treatment outcomes.

Regional Liver Tumor Board: The hepatology team at the Philadelphia VAMC combined a regional telehealth-supported liver cancer tumor board model, a web-based submission process, and a consolidated database to manage and track communications for patients with liver cancer. This practice has shortened the time for veterans with liver cancer to receive their evaluation and first treatment as well as reduced unnecessary biopsies—easing the minds and experiences of patients and their families in an incredibly stressful time.

In a rare turn, the Senate Veterans Affairs Committee recently focused on what the VA is doing right. “We are changing culture and doing so by celebrating the people who have dedicated their careers to serving veterans,” testified Carolyn Clancy, MD, deputy under secretary for health for organizational excellence. “We are breaking down cultural barriers, like competition, by creating systematic incentives to share what has worked with others in the system.”

Dr. Clancy outlined some of the successes from the VA’s newly developed Diffusion of Excellence Initiative. The goal of the initiative has been to “identify clinical and administrative best practices, disseminate these practices to other sites of care, and encourage standardization of practices that deliver positive outcomes for veterans and their families,” Dr. Clancy reported. So far the initiative has generated more than 260 ongoing innovations at 70 facilities.

According to Dr. Clancy, the Diffusion of Excellence Initiative uses an internal VA social media platform to identify promising practices that align with strategic priorities, offer efficient resource use, can be implemented in diverse care environments, and can be implemented within 6 to 12 months. The initiative also sought to identify local champions or early adopters who can begin to implement the best practice locally. Once it is proven practice, the initiative seeks to find additional locations to further test the practice in a different setting. Best practices are chosen for national standardization if they have had relative success with an initial implementation and similar outcomes when replicated elsewhere.

So far 50 best practices have been replicated and are ready for widespread dissemination. “Identifying and spreading best practices can be a major driver of consistent, high-quality health care for veterans,” Dr. Clancy told the Senate panel. “This is restoring trust in the system. It offers a model for other health systems.”

Examples of best practices include the following:

Improving Same-Day Access Using Registered Nurse (RN) Care Manager “Chair” Visits: At the Boise VAMC in Idaho, the primary care team created a process where same-day appointment requests are triaged and scribed by RN Care Managers, saving primary care providers’ time when they see patients between appointments to assess and confirm the care plan.

Access Data Dashboard to Improve Clinic Management: The data analysis team at Harry S. Truman Memorial Veterans’ Hospital (Columbia, Missouri) implemented a dashboard for clinic access metrics (no-shows, completed appointment wait times, clinic utilization, etc). These metrics are posted monthly on an accessible dashboard that can be used by staff to solve problems and make key decisions that help veterans get timely access to care.

Planning for Future Medical Decision via Group Visits: This initiative presents advance care directives and other care planning for future medical decisions in interactive and patient-centered group visits.

Increasing Access to Primary Care With Pharmacists: The William S. Middleton Memorial Veterans’ Hospital (Madison, Wisconsin) matched clinical pharmacy specialists with multiple patient aligned care teams to conduct new patient intake calls 1 week before a new patient has his or her first appointment with a provider, collecting medications, noting any formulary conversions, and orienting the patient to VA.

eScreening: The eScreening Program is a mobile technology developed to facilitate the screening process and improve care coordination and measurement-based care for veterans. It offers veteran-directed screening, real-time scoring, individualized patient feedback, instantaneous medical record clinical documentation, immediate alerts to clinicians for evaluation and triage, and monitoring of treatment outcomes.

Regional Liver Tumor Board: The hepatology team at the Philadelphia VAMC combined a regional telehealth-supported liver cancer tumor board model, a web-based submission process, and a consolidated database to manage and track communications for patients with liver cancer. This practice has shortened the time for veterans with liver cancer to receive their evaluation and first treatment as well as reduced unnecessary biopsies—easing the minds and experiences of patients and their families in an incredibly stressful time.

In a rare turn, the Senate Veterans Affairs Committee recently focused on what the VA is doing right. “We are changing culture and doing so by celebrating the people who have dedicated their careers to serving veterans,” testified Carolyn Clancy, MD, deputy under secretary for health for organizational excellence. “We are breaking down cultural barriers, like competition, by creating systematic incentives to share what has worked with others in the system.”

Dr. Clancy outlined some of the successes from the VA’s newly developed Diffusion of Excellence Initiative. The goal of the initiative has been to “identify clinical and administrative best practices, disseminate these practices to other sites of care, and encourage standardization of practices that deliver positive outcomes for veterans and their families,” Dr. Clancy reported. So far the initiative has generated more than 260 ongoing innovations at 70 facilities.

According to Dr. Clancy, the Diffusion of Excellence Initiative uses an internal VA social media platform to identify promising practices that align with strategic priorities, offer efficient resource use, can be implemented in diverse care environments, and can be implemented within 6 to 12 months. The initiative also sought to identify local champions or early adopters who can begin to implement the best practice locally. Once it is proven practice, the initiative seeks to find additional locations to further test the practice in a different setting. Best practices are chosen for national standardization if they have had relative success with an initial implementation and similar outcomes when replicated elsewhere.

So far 50 best practices have been replicated and are ready for widespread dissemination. “Identifying and spreading best practices can be a major driver of consistent, high-quality health care for veterans,” Dr. Clancy told the Senate panel. “This is restoring trust in the system. It offers a model for other health systems.”

Examples of best practices include the following:

Improving Same-Day Access Using Registered Nurse (RN) Care Manager “Chair” Visits: At the Boise VAMC in Idaho, the primary care team created a process where same-day appointment requests are triaged and scribed by RN Care Managers, saving primary care providers’ time when they see patients between appointments to assess and confirm the care plan.

Access Data Dashboard to Improve Clinic Management: The data analysis team at Harry S. Truman Memorial Veterans’ Hospital (Columbia, Missouri) implemented a dashboard for clinic access metrics (no-shows, completed appointment wait times, clinic utilization, etc). These metrics are posted monthly on an accessible dashboard that can be used by staff to solve problems and make key decisions that help veterans get timely access to care.

Planning for Future Medical Decision via Group Visits: This initiative presents advance care directives and other care planning for future medical decisions in interactive and patient-centered group visits.

Increasing Access to Primary Care With Pharmacists: The William S. Middleton Memorial Veterans’ Hospital (Madison, Wisconsin) matched clinical pharmacy specialists with multiple patient aligned care teams to conduct new patient intake calls 1 week before a new patient has his or her first appointment with a provider, collecting medications, noting any formulary conversions, and orienting the patient to VA.

eScreening: The eScreening Program is a mobile technology developed to facilitate the screening process and improve care coordination and measurement-based care for veterans. It offers veteran-directed screening, real-time scoring, individualized patient feedback, instantaneous medical record clinical documentation, immediate alerts to clinicians for evaluation and triage, and monitoring of treatment outcomes.

Regional Liver Tumor Board: The hepatology team at the Philadelphia VAMC combined a regional telehealth-supported liver cancer tumor board model, a web-based submission process, and a consolidated database to manage and track communications for patients with liver cancer. This practice has shortened the time for veterans with liver cancer to receive their evaluation and first treatment as well as reduced unnecessary biopsies—easing the minds and experiences of patients and their families in an incredibly stressful time.

NEW YORK – Sitting amid assorted curios scattered throughout the windowless, paper-strewn office where for the past 2 decades he taught and conducted research at Columbia University and the New York State Psychiatric Institute, Joshua A. Gordon, MD, PhD, reflected on his next career move.

“I’m nervous. Excited. I am going in with an open mind,” said Dr. Gordon, who in mid-September became the new director of the National Institute of Mental Health.

Some are hoping such an “open mind” will result in a change of priorities from those favored by Dr. Gordon’s predecessor, Thomas Insel, MD.

Whitney McKnight/Frontline Medical News

“I’d like to say how welcome it is to have a new perspective at the helm of the NIMH,” said Roberto Lewis-Fernandez, MD, a Columbia University psychiatry professor, and director of the New York State Center of Excellence for Cultural Competence at the New York State Psychiatric Institute, both in New York City.

After 13 years as director, Dr. Insel left the NIMH at the end of 2015 to take a job with a former Google division now called Verily Life Sciences, an Alphabet company. A psychiatrist also trained as a neuroscientist, Dr. Insel often was a flash point over concerns that during his tenure – the longest in NIMH history – neuroscience eclipsed other important areas, such as patient support, basic clinical observation, and the biopsychosocial model of mental illness.

“There is absolutely nothing wrong with neuroscience research. It is entirely indispensable to the discovery of new treatments for mental illness,” said Dr. Lewis-Fernandez. “The critique is about the proportion of the portfolio that should be devoted to this work.”

Future vs. now

Emphasizing too much “gee whiz” science at the expense of research into psychosocial services has meant the NIMH has failed to fully use its immense power to address disparities in access to care, create strategies for cost-efficient, scalable interventions, and clarify best practices in sorely needed suicide prevention, according to an editorial written by Dr. Lewis-Fernandez and 19 other current and former members of the NIMH National Advisory Mental Health Council (Br J Psychiatry. Jun 2016;208[6]507-9). In the piece, the writers took issue with what they called the NIMH’s overemphasis on basic and translational neuroscience research, citing how since 2012, the institute has spent less than 15% of its roughly $1.5 billion annual budget on non-HIV/AIDS services and interventions.

Dr. Insel often responded to such criticism in his widely read blog, where he acknowledged the tension between meeting patients’ current needs and investing in future discoveries, but also said the gap between what is known about the brain and about mental illness versus what is unknown was “unconscionable.” In an effort to help right this wrong, Dr. Insel announced that the NIMH essentially would drop use of the Diagnostic and Statistical Manual of Mental Disorders in favor of the Research Domain Criteria (RDoC) project, a new classification system of mental illness incorporating genetics, imaging, cognitive science, and other fields. He also made frequent media appearances to explain the institute’s participation in the 20-year, cross-disciplinary $4.5 billion Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. In addition, he championed the Human Connectome Project to map neurocircuitry.

‘Return to its roots’

Others believe that neuroscience notwithstanding, the institution, founded in 1949, is not hewing to its intended purpose, which is to “transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure,” according to its mission statement.

“The NIMH needs to return to its roots: studying, taking care of, and hopefully curing seriously mentally ill patients. That should be the most important piece of its agenda,” said practicing psychiatrist David Pickar, MD. Between 1977 and 1999, Dr. Pickar held a variety of NIMH intramural research division posts, including section chief for clinical neuroscience studies and chief of experimental therapeutics. Currently, he is an adjunct professor of psychiatry at Johns Hopkins University, Baltimore.

Dr. Gordon said such clinical research can be achieved through grants to external investigators. “We have limited resources at the NIMH when you consider how much money is spent overall on mental health care,” Dr. Gordon said. Four NIMH divisions are dedicated to overseeing extramural research, compared with one intramural research division.

In a breakdown of NIMH spending between 2005 and 2014, Dr. Insel wrote that, when adjusted for biomedical inflation, the institute’s overall budget remained virtually flat since 2003. And while the scientific scope of grants funded has not changed much, “from molecular neuroscience to strategies of community care,” what has changed is the proportion of spending on certain areas as “scientific opportunities have evolved,” Dr. Insel wrote.

This has meant a 28% increase in spending for the neuroscience and basic behavioral science division, up from 2% in 2005. That number reflects spending on the BRAIN initiative and on genomics. An additional 25% is spent on translational research, and only 10% – a reduction of about 17% since 2011 – on traditional services research and clinical trials, reflecting a preference for “experimental medicine trials that will be more informative of disease mechanisms,” Dr. Insel wrote. From 2011 to 2014, external spending on clinical trials dropped, from $110.3 million to $75.3 million. Monies spent on services research remained virtually steady at about $67 million annually.

Clinical experience matters

Although Dr. Gordon is celebrated for his neuroscientific work in optogenetics – an emerging technology not yet tested in humans that, if feasible, will allow scientists to turn on or off neurocircuits implicated in a range of mental diseases, including schizophrenia – he has maintained a clinical psychiatric practice for most of his career, whereas Dr. Insel has not.

This is seen by many as a sign Dr. Gordon might be the man to bridge the divide among proponents of less neuroscience and more services or clinical research.

“We trust that Dr. Gordon’s clinical training and exposure to day-to-day challenges of people living with mental illness will impress upon him the need to balance the NIMH’s research portfolio,” said Dr. Lewis-Fernandez, also director of the Hispanic Treatment Program at the New York State Psychiatric Institute.

Having one foot each in clinical practice and bench science might even have enhanced his candidacy for the directorship.

“While it is not necessary to have a neuropsychiatry background to be a visionary, Dr. Gordon’s background enables him to have an exceptionally broad vision of the field of mental health that spans cutting-edge science to clinical care,” Dr. Gordon’s new boss, National Institutes of Health director, Francis Collins, MD, PhD, said in an interview..

Firmly stating his commitment to neuroscience’s “tremendous potential” to improve patient care, Dr. Gordon said he believes most clinicians do not struggle to recognize various states of mental illness, but that they do run into fragmented care, which hurts their practice. “The biggest impact [the NIMH] would have during or immediately after my term would be figuring out how to get therapies that we know already work implemented either better or more uniformly.”

He cited as an example, the Recovery After an Initial Schizophrenia Episode (RAISE) program, an early intervention strategy that involves integrated care in an outpatient setting aimed at reducing the duration between first-episode psychosis and treatment. Widely considered an NIMH success story when compared with treatment as usual, both in terms of actual outcome data and patient satisfaction, Dr. Gordon said he believes it demonstrates how the NIMH can help mend fragmentation of mental health services. Using RAISE as a model “can have an impact in relatively targeted spheres,” he said.

Neither such systems engineering, nor Dr. Insel’s “experimental medicine,” should be the NIMH’s primary activity, according to Dr. Pickar. “Early intervention in the outpatient setting is lovely, but it’s not going to help research too terribly much. If you work directly with patients, you will be forced in the right direction,” he said.

As many as 40 patient beds per day were dedicated to clinical observation and treatment of patients with serious mental illness during his tenure, according to Dr. Pickar. In the past year, NIMH patient beds have totaled 24 with an average daily census of 92%, 8 of which are for pediatric-focused research. Often, beds are shared with other institutions such as the National Institute on Alcohol Abuse and Alcoholism, according to an NIMH spokesperson.

The combined reduction in both intra- and extramural clinical research does not bode well for patients, Dr. Pickar said. “Every advance in understanding the biology of serious mental illness starts with the clinical phenomena. That has gotten lost.”

Part of a bigger plan

Decisions over the NIMH’s priorities are not made in a vacuum, however. When asked about what aspects of clinical practice he expects to be the focus during Dr. Gordon’s tenure, Dr. Collins pointed to the presidential directive for precision medicine, saying he believes that eventually mental health diagnoses will “incorporate all of the information coming out of genetics, neuroscience, and behavioral science ... following the model of what is becoming the standard for cancer and heart disease.”

Research into the prevention of comorbid medical disorders in mental illness, and into ketamine as a rapidly acting, novel depression treatment, are important to the NIMH’s short-term focus, Dr. Collins said. But he also stressed that the quality of psychosocial treatments is “another very important area,” as is expanding access to treatment and reducing mental health disparities.

To wit, just days after Dr. Gordon assumed NIMH leadership, “Psychosocial Research at NIMH: A Primer” appeared on the institute’s website. Written by numerous staffers from across the NIMH, and overseen by interim director Bruce Cuthbert, PhD, the “primer” reiterates a commitment to neuroscience and the RDoC, while detailing how it is focused on patients’ needs now. There is a particular emphasis on expanded use of digital technologies to screen for and treat a variety of mental illnesses, and on the measurement of behavior, cognitive/affective processes, and patient self-reports as conducted by the NIMH’s cross-disciplinary mental health council. The document was created in response to pressure from researchers and clinicians alike who asked the institute for clarification and reassurance about the NIMH’s attention to psychosocial concerns, according to an NIMH spokesperson.

This kind of dialogue over roadblocks to care will characterize his leadership, particularly at the start, Dr. Gordon said. He encourages clinicians to communicate directly with him, particularly around where they think money should be spent in the short term. “I would love to hear that from them,” he said.

Although Dr. Gordon said that Dr. Insel hasn’t specifically told him what to do, he has offered his counsel. “I [have spoken] with Tom several times. He has given me wonderful advice, and the best piece was to take the first 6 months to a year and just listen. That’s what I intend on doing.”

[email protected]

On Twitter @whitneymcknight

NEW YORK – Sitting amid assorted curios scattered throughout the windowless, paper-strewn office where for the past 2 decades he taught and conducted research at Columbia University and the New York State Psychiatric Institute, Joshua A. Gordon, MD, PhD, reflected on his next career move.

“I’m nervous. Excited. I am going in with an open mind,” said Dr. Gordon, who in mid-September became the new director of the National Institute of Mental Health.

Some are hoping such an “open mind” will result in a change of priorities from those favored by Dr. Gordon’s predecessor, Thomas Insel, MD.

Whitney McKnight/Frontline Medical News

“I’d like to say how welcome it is to have a new perspective at the helm of the NIMH,” said Roberto Lewis-Fernandez, MD, a Columbia University psychiatry professor, and director of the New York State Center of Excellence for Cultural Competence at the New York State Psychiatric Institute, both in New York City.

After 13 years as director, Dr. Insel left the NIMH at the end of 2015 to take a job with a former Google division now called Verily Life Sciences, an Alphabet company. A psychiatrist also trained as a neuroscientist, Dr. Insel often was a flash point over concerns that during his tenure – the longest in NIMH history – neuroscience eclipsed other important areas, such as patient support, basic clinical observation, and the biopsychosocial model of mental illness.

“There is absolutely nothing wrong with neuroscience research. It is entirely indispensable to the discovery of new treatments for mental illness,” said Dr. Lewis-Fernandez. “The critique is about the proportion of the portfolio that should be devoted to this work.”

Future vs. now

Emphasizing too much “gee whiz” science at the expense of research into psychosocial services has meant the NIMH has failed to fully use its immense power to address disparities in access to care, create strategies for cost-efficient, scalable interventions, and clarify best practices in sorely needed suicide prevention, according to an editorial written by Dr. Lewis-Fernandez and 19 other current and former members of the NIMH National Advisory Mental Health Council (Br J Psychiatry. Jun 2016;208[6]507-9). In the piece, the writers took issue with what they called the NIMH’s overemphasis on basic and translational neuroscience research, citing how since 2012, the institute has spent less than 15% of its roughly $1.5 billion annual budget on non-HIV/AIDS services and interventions.

Dr. Insel often responded to such criticism in his widely read blog, where he acknowledged the tension between meeting patients’ current needs and investing in future discoveries, but also said the gap between what is known about the brain and about mental illness versus what is unknown was “unconscionable.” In an effort to help right this wrong, Dr. Insel announced that the NIMH essentially would drop use of the Diagnostic and Statistical Manual of Mental Disorders in favor of the Research Domain Criteria (RDoC) project, a new classification system of mental illness incorporating genetics, imaging, cognitive science, and other fields. He also made frequent media appearances to explain the institute’s participation in the 20-year, cross-disciplinary $4.5 billion Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. In addition, he championed the Human Connectome Project to map neurocircuitry.

‘Return to its roots’

Others believe that neuroscience notwithstanding, the institution, founded in 1949, is not hewing to its intended purpose, which is to “transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure,” according to its mission statement.

“The NIMH needs to return to its roots: studying, taking care of, and hopefully curing seriously mentally ill patients. That should be the most important piece of its agenda,” said practicing psychiatrist David Pickar, MD. Between 1977 and 1999, Dr. Pickar held a variety of NIMH intramural research division posts, including section chief for clinical neuroscience studies and chief of experimental therapeutics. Currently, he is an adjunct professor of psychiatry at Johns Hopkins University, Baltimore.

Dr. Gordon said such clinical research can be achieved through grants to external investigators. “We have limited resources at the NIMH when you consider how much money is spent overall on mental health care,” Dr. Gordon said. Four NIMH divisions are dedicated to overseeing extramural research, compared with one intramural research division.

In a breakdown of NIMH spending between 2005 and 2014, Dr. Insel wrote that, when adjusted for biomedical inflation, the institute’s overall budget remained virtually flat since 2003. And while the scientific scope of grants funded has not changed much, “from molecular neuroscience to strategies of community care,” what has changed is the proportion of spending on certain areas as “scientific opportunities have evolved,” Dr. Insel wrote.

This has meant a 28% increase in spending for the neuroscience and basic behavioral science division, up from 2% in 2005. That number reflects spending on the BRAIN initiative and on genomics. An additional 25% is spent on translational research, and only 10% – a reduction of about 17% since 2011 – on traditional services research and clinical trials, reflecting a preference for “experimental medicine trials that will be more informative of disease mechanisms,” Dr. Insel wrote. From 2011 to 2014, external spending on clinical trials dropped, from $110.3 million to $75.3 million. Monies spent on services research remained virtually steady at about $67 million annually.

Clinical experience matters

Although Dr. Gordon is celebrated for his neuroscientific work in optogenetics – an emerging technology not yet tested in humans that, if feasible, will allow scientists to turn on or off neurocircuits implicated in a range of mental diseases, including schizophrenia – he has maintained a clinical psychiatric practice for most of his career, whereas Dr. Insel has not.

This is seen by many as a sign Dr. Gordon might be the man to bridge the divide among proponents of less neuroscience and more services or clinical research.

“We trust that Dr. Gordon’s clinical training and exposure to day-to-day challenges of people living with mental illness will impress upon him the need to balance the NIMH’s research portfolio,” said Dr. Lewis-Fernandez, also director of the Hispanic Treatment Program at the New York State Psychiatric Institute.

Having one foot each in clinical practice and bench science might even have enhanced his candidacy for the directorship.

“While it is not necessary to have a neuropsychiatry background to be a visionary, Dr. Gordon’s background enables him to have an exceptionally broad vision of the field of mental health that spans cutting-edge science to clinical care,” Dr. Gordon’s new boss, National Institutes of Health director, Francis Collins, MD, PhD, said in an interview..

Firmly stating his commitment to neuroscience’s “tremendous potential” to improve patient care, Dr. Gordon said he believes most clinicians do not struggle to recognize various states of mental illness, but that they do run into fragmented care, which hurts their practice. “The biggest impact [the NIMH] would have during or immediately after my term would be figuring out how to get therapies that we know already work implemented either better or more uniformly.”

He cited as an example, the Recovery After an Initial Schizophrenia Episode (RAISE) program, an early intervention strategy that involves integrated care in an outpatient setting aimed at reducing the duration between first-episode psychosis and treatment. Widely considered an NIMH success story when compared with treatment as usual, both in terms of actual outcome data and patient satisfaction, Dr. Gordon said he believes it demonstrates how the NIMH can help mend fragmentation of mental health services. Using RAISE as a model “can have an impact in relatively targeted spheres,” he said.

Neither such systems engineering, nor Dr. Insel’s “experimental medicine,” should be the NIMH’s primary activity, according to Dr. Pickar. “Early intervention in the outpatient setting is lovely, but it’s not going to help research too terribly much. If you work directly with patients, you will be forced in the right direction,” he said.

As many as 40 patient beds per day were dedicated to clinical observation and treatment of patients with serious mental illness during his tenure, according to Dr. Pickar. In the past year, NIMH patient beds have totaled 24 with an average daily census of 92%, 8 of which are for pediatric-focused research. Often, beds are shared with other institutions such as the National Institute on Alcohol Abuse and Alcoholism, according to an NIMH spokesperson.

The combined reduction in both intra- and extramural clinical research does not bode well for patients, Dr. Pickar said. “Every advance in understanding the biology of serious mental illness starts with the clinical phenomena. That has gotten lost.”

Part of a bigger plan

Decisions over the NIMH’s priorities are not made in a vacuum, however. When asked about what aspects of clinical practice he expects to be the focus during Dr. Gordon’s tenure, Dr. Collins pointed to the presidential directive for precision medicine, saying he believes that eventually mental health diagnoses will “incorporate all of the information coming out of genetics, neuroscience, and behavioral science ... following the model of what is becoming the standard for cancer and heart disease.”

Research into the prevention of comorbid medical disorders in mental illness, and into ketamine as a rapidly acting, novel depression treatment, are important to the NIMH’s short-term focus, Dr. Collins said. But he also stressed that the quality of psychosocial treatments is “another very important area,” as is expanding access to treatment and reducing mental health disparities.

To wit, just days after Dr. Gordon assumed NIMH leadership, “Psychosocial Research at NIMH: A Primer” appeared on the institute’s website. Written by numerous staffers from across the NIMH, and overseen by interim director Bruce Cuthbert, PhD, the “primer” reiterates a commitment to neuroscience and the RDoC, while detailing how it is focused on patients’ needs now. There is a particular emphasis on expanded use of digital technologies to screen for and treat a variety of mental illnesses, and on the measurement of behavior, cognitive/affective processes, and patient self-reports as conducted by the NIMH’s cross-disciplinary mental health council. The document was created in response to pressure from researchers and clinicians alike who asked the institute for clarification and reassurance about the NIMH’s attention to psychosocial concerns, according to an NIMH spokesperson.

This kind of dialogue over roadblocks to care will characterize his leadership, particularly at the start, Dr. Gordon said. He encourages clinicians to communicate directly with him, particularly around where they think money should be spent in the short term. “I would love to hear that from them,” he said.

Although Dr. Gordon said that Dr. Insel hasn’t specifically told him what to do, he has offered his counsel. “I [have spoken] with Tom several times. He has given me wonderful advice, and the best piece was to take the first 6 months to a year and just listen. That’s what I intend on doing.”

[email protected]

On Twitter @whitneymcknight

NEW YORK – Sitting amid assorted curios scattered throughout the windowless, paper-strewn office where for the past 2 decades he taught and conducted research at Columbia University and the New York State Psychiatric Institute, Joshua A. Gordon, MD, PhD, reflected on his next career move.

“I’m nervous. Excited. I am going in with an open mind,” said Dr. Gordon, who in mid-September became the new director of the National Institute of Mental Health.

Some are hoping such an “open mind” will result in a change of priorities from those favored by Dr. Gordon’s predecessor, Thomas Insel, MD.

Whitney McKnight/Frontline Medical News

“I’d like to say how welcome it is to have a new perspective at the helm of the NIMH,” said Roberto Lewis-Fernandez, MD, a Columbia University psychiatry professor, and director of the New York State Center of Excellence for Cultural Competence at the New York State Psychiatric Institute, both in New York City.

After 13 years as director, Dr. Insel left the NIMH at the end of 2015 to take a job with a former Google division now called Verily Life Sciences, an Alphabet company. A psychiatrist also trained as a neuroscientist, Dr. Insel often was a flash point over concerns that during his tenure – the longest in NIMH history – neuroscience eclipsed other important areas, such as patient support, basic clinical observation, and the biopsychosocial model of mental illness.

“There is absolutely nothing wrong with neuroscience research. It is entirely indispensable to the discovery of new treatments for mental illness,” said Dr. Lewis-Fernandez. “The critique is about the proportion of the portfolio that should be devoted to this work.”

Future vs. now

Emphasizing too much “gee whiz” science at the expense of research into psychosocial services has meant the NIMH has failed to fully use its immense power to address disparities in access to care, create strategies for cost-efficient, scalable interventions, and clarify best practices in sorely needed suicide prevention, according to an editorial written by Dr. Lewis-Fernandez and 19 other current and former members of the NIMH National Advisory Mental Health Council (Br J Psychiatry. Jun 2016;208[6]507-9). In the piece, the writers took issue with what they called the NIMH’s overemphasis on basic and translational neuroscience research, citing how since 2012, the institute has spent less than 15% of its roughly $1.5 billion annual budget on non-HIV/AIDS services and interventions.

Dr. Insel often responded to such criticism in his widely read blog, where he acknowledged the tension between meeting patients’ current needs and investing in future discoveries, but also said the gap between what is known about the brain and about mental illness versus what is unknown was “unconscionable.” In an effort to help right this wrong, Dr. Insel announced that the NIMH essentially would drop use of the Diagnostic and Statistical Manual of Mental Disorders in favor of the Research Domain Criteria (RDoC) project, a new classification system of mental illness incorporating genetics, imaging, cognitive science, and other fields. He also made frequent media appearances to explain the institute’s participation in the 20-year, cross-disciplinary $4.5 billion Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. In addition, he championed the Human Connectome Project to map neurocircuitry.

‘Return to its roots’

Others believe that neuroscience notwithstanding, the institution, founded in 1949, is not hewing to its intended purpose, which is to “transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure,” according to its mission statement.

“The NIMH needs to return to its roots: studying, taking care of, and hopefully curing seriously mentally ill patients. That should be the most important piece of its agenda,” said practicing psychiatrist David Pickar, MD. Between 1977 and 1999, Dr. Pickar held a variety of NIMH intramural research division posts, including section chief for clinical neuroscience studies and chief of experimental therapeutics. Currently, he is an adjunct professor of psychiatry at Johns Hopkins University, Baltimore.

Dr. Gordon said such clinical research can be achieved through grants to external investigators. “We have limited resources at the NIMH when you consider how much money is spent overall on mental health care,” Dr. Gordon said. Four NIMH divisions are dedicated to overseeing extramural research, compared with one intramural research division.

In a breakdown of NIMH spending between 2005 and 2014, Dr. Insel wrote that, when adjusted for biomedical inflation, the institute’s overall budget remained virtually flat since 2003. And while the scientific scope of grants funded has not changed much, “from molecular neuroscience to strategies of community care,” what has changed is the proportion of spending on certain areas as “scientific opportunities have evolved,” Dr. Insel wrote.

This has meant a 28% increase in spending for the neuroscience and basic behavioral science division, up from 2% in 2005. That number reflects spending on the BRAIN initiative and on genomics. An additional 25% is spent on translational research, and only 10% – a reduction of about 17% since 2011 – on traditional services research and clinical trials, reflecting a preference for “experimental medicine trials that will be more informative of disease mechanisms,” Dr. Insel wrote. From 2011 to 2014, external spending on clinical trials dropped, from $110.3 million to $75.3 million. Monies spent on services research remained virtually steady at about $67 million annually.

Clinical experience matters

Although Dr. Gordon is celebrated for his neuroscientific work in optogenetics – an emerging technology not yet tested in humans that, if feasible, will allow scientists to turn on or off neurocircuits implicated in a range of mental diseases, including schizophrenia – he has maintained a clinical psychiatric practice for most of his career, whereas Dr. Insel has not.

This is seen by many as a sign Dr. Gordon might be the man to bridge the divide among proponents of less neuroscience and more services or clinical research.

“We trust that Dr. Gordon’s clinical training and exposure to day-to-day challenges of people living with mental illness will impress upon him the need to balance the NIMH’s research portfolio,” said Dr. Lewis-Fernandez, also director of the Hispanic Treatment Program at the New York State Psychiatric Institute.

Having one foot each in clinical practice and bench science might even have enhanced his candidacy for the directorship.

“While it is not necessary to have a neuropsychiatry background to be a visionary, Dr. Gordon’s background enables him to have an exceptionally broad vision of the field of mental health that spans cutting-edge science to clinical care,” Dr. Gordon’s new boss, National Institutes of Health director, Francis Collins, MD, PhD, said in an interview..

Firmly stating his commitment to neuroscience’s “tremendous potential” to improve patient care, Dr. Gordon said he believes most clinicians do not struggle to recognize various states of mental illness, but that they do run into fragmented care, which hurts their practice. “The biggest impact [the NIMH] would have during or immediately after my term would be figuring out how to get therapies that we know already work implemented either better or more uniformly.”

He cited as an example, the Recovery After an Initial Schizophrenia Episode (RAISE) program, an early intervention strategy that involves integrated care in an outpatient setting aimed at reducing the duration between first-episode psychosis and treatment. Widely considered an NIMH success story when compared with treatment as usual, both in terms of actual outcome data and patient satisfaction, Dr. Gordon said he believes it demonstrates how the NIMH can help mend fragmentation of mental health services. Using RAISE as a model “can have an impact in relatively targeted spheres,” he said.

Neither such systems engineering, nor Dr. Insel’s “experimental medicine,” should be the NIMH’s primary activity, according to Dr. Pickar. “Early intervention in the outpatient setting is lovely, but it’s not going to help research too terribly much. If you work directly with patients, you will be forced in the right direction,” he said.

As many as 40 patient beds per day were dedicated to clinical observation and treatment of patients with serious mental illness during his tenure, according to Dr. Pickar. In the past year, NIMH patient beds have totaled 24 with an average daily census of 92%, 8 of which are for pediatric-focused research. Often, beds are shared with other institutions such as the National Institute on Alcohol Abuse and Alcoholism, according to an NIMH spokesperson.

The combined reduction in both intra- and extramural clinical research does not bode well for patients, Dr. Pickar said. “Every advance in understanding the biology of serious mental illness starts with the clinical phenomena. That has gotten lost.”

Part of a bigger plan

Decisions over the NIMH’s priorities are not made in a vacuum, however. When asked about what aspects of clinical practice he expects to be the focus during Dr. Gordon’s tenure, Dr. Collins pointed to the presidential directive for precision medicine, saying he believes that eventually mental health diagnoses will “incorporate all of the information coming out of genetics, neuroscience, and behavioral science ... following the model of what is becoming the standard for cancer and heart disease.”

Research into the prevention of comorbid medical disorders in mental illness, and into ketamine as a rapidly acting, novel depression treatment, are important to the NIMH’s short-term focus, Dr. Collins said. But he also stressed that the quality of psychosocial treatments is “another very important area,” as is expanding access to treatment and reducing mental health disparities.

To wit, just days after Dr. Gordon assumed NIMH leadership, “Psychosocial Research at NIMH: A Primer” appeared on the institute’s website. Written by numerous staffers from across the NIMH, and overseen by interim director Bruce Cuthbert, PhD, the “primer” reiterates a commitment to neuroscience and the RDoC, while detailing how it is focused on patients’ needs now. There is a particular emphasis on expanded use of digital technologies to screen for and treat a variety of mental illnesses, and on the measurement of behavior, cognitive/affective processes, and patient self-reports as conducted by the NIMH’s cross-disciplinary mental health council. The document was created in response to pressure from researchers and clinicians alike who asked the institute for clarification and reassurance about the NIMH’s attention to psychosocial concerns, according to an NIMH spokesperson.

This kind of dialogue over roadblocks to care will characterize his leadership, particularly at the start, Dr. Gordon said. He encourages clinicians to communicate directly with him, particularly around where they think money should be spent in the short term. “I would love to hear that from them,” he said.

Although Dr. Gordon said that Dr. Insel hasn’t specifically told him what to do, he has offered his counsel. “I [have spoken] with Tom several times. He has given me wonderful advice, and the best piece was to take the first 6 months to a year and just listen. That’s what I intend on doing.”

[email protected]

On Twitter @whitneymcknight

ROME – Coronary artery bypass surgery reduces cardiovascular mortality in heart failure patients with ischemic cardiomyopathy to a consistent extent regardless of age at the time of surgery, according to a secondary analysis from the landmark STICH trial, Eric J. Velazquez, MD, reported at the annual congress of the European Society of Cardiology.

“Cardiologists and cardiac surgeons can confidently offer patients CABG in addition to optimal medical therapy with the knowledge that cardiovascular mortality is reduced by CABG to a similar extent across all age groups in this trial through 10 years of follow-up,” said Dr. Velazquez, professor of medicine at Duke University in Durham, N.C.

Bruce Jancin/Frontline Medical News

However, that’s only part of the story. Cardiovascular mortality was a secondary endpoint in STICH (Surgical Treatment for Ischemic Heart Failure). The primary endpoint was all-cause mortality. And CABG’s impact on all-cause mortality was diminished in older STICH participants because of their greater comorbidity burden and the competing risk of noncardiovascular death, he added.

The take-home message is that cardiologists and heart surgeons need to carefully assess competing mortality risks before pursuing CABG in older patients, according to Dr. Velazquez.

Session cochair Kim A. Williams, MD, professor and chief of cardiology at Rush University Medical Center in Chicago, posed a direct question: “Is there an age cutoff for your group for bypass surgery?”

No, Dr. Velazquez replied. He pointed out that cardiovascular mortality remained the No. 1 cause of mortality across all age groups.

“If the expectation is that the major cause of fatal events is going to be cardiovascular, and CABG plus medical therapy reduces that risk consistently regardless of age, we think that there really is no particular age cutoff. There is a point at which the noncardiovascular risk predominates, but in the population we studied we did not see that point,” Dr. Velazquez added.

STICH was a 22-nation trial in which 1,212 patients with a left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomized to CABG plus optimal medical therapy or optimal medical therapy alone and followed for a median of 9.8 years (JACC Heart Fail. 2013;1[5]:400-8). For purposes of this secondary analysis, participants were divided into quartiles according to baseline age: Quartile 1 patients were up to 54 years old; quartile 2 were ages 55-60; quartile 3 were ages 61-67; and quartile 4 were ages 68 and up.

Older subjects had more comorbidities. All-cause mortality was significantly higher in older than younger patients: for CABG, 68% vs. 48% in quartiles 4 and 1, respectively; for medical therapy, 79% vs. 60% in the same two quartiles. In contrast, cardiovascular mortality did not differ significantly by age: It was 39% in quartile 4 and 35% in quartile 1 in the CABG group, and 53%, compared with 49%, in medically managed patients in quartiles 4 and 1.

For the secondary composite endpoint of all-cause mortality or cardiovascular hospitalization, the benefit of CABG plus medical management over medical management alone was significantly greater in younger than in older patients.

The rate of noncardiovascular mortality was 5.8% in quartiles 1 and 2, then leapt to 14.7% in quartile 3 and 21.1% in quartile 4.

Although the main focus of Dr. Velazquez’s presentation was the impact of CABG with advancing age, he said he found an important lesson in the younger population as well.

“We saw roughly a 40% relative risk reduction in all-cause mortality with CABG in the youngest quartile, compared with the three older groups. My interpretation of that data is that it’s probably not appropriate to avoid CABG in favor of another strategy in a younger patient when you see this kind of mortality benefit,” the cardiologist said.

One limitation of the STICH analysis, said session cochair Stephan Achenbach, MD, is that the study population was relatively young overall. The oldest patients in STICH were roughly the same age as the average patients undergoing CABG for left ventricular systolic dysfunction today at most centers, according to Dr. Achenbach, professor of cardiology at the University of Erlangen-Nuremberg (Germany).

Dr. Velazquez agreed. “I can’t speak as to whether these trial results would apply to the very elderly, patients age 90 and above,” he said.

Simultaneously with the presentation , the new STICH analysis was published online (Circulation. 2016 Aug 29. doi: 10.1161/CIRCULATIONAHA.116.024800).

STICH was funded by the National Institutes of Health. Dr. Velazquez reported having no relevant financial conflicts.

[email protected]

ROME – Coronary artery bypass surgery reduces cardiovascular mortality in heart failure patients with ischemic cardiomyopathy to a consistent extent regardless of age at the time of surgery, according to a secondary analysis from the landmark STICH trial, Eric J. Velazquez, MD, reported at the annual congress of the European Society of Cardiology.

“Cardiologists and cardiac surgeons can confidently offer patients CABG in addition to optimal medical therapy with the knowledge that cardiovascular mortality is reduced by CABG to a similar extent across all age groups in this trial through 10 years of follow-up,” said Dr. Velazquez, professor of medicine at Duke University in Durham, N.C.

Bruce Jancin/Frontline Medical News

However, that’s only part of the story. Cardiovascular mortality was a secondary endpoint in STICH (Surgical Treatment for Ischemic Heart Failure). The primary endpoint was all-cause mortality. And CABG’s impact on all-cause mortality was diminished in older STICH participants because of their greater comorbidity burden and the competing risk of noncardiovascular death, he added.

The take-home message is that cardiologists and heart surgeons need to carefully assess competing mortality risks before pursuing CABG in older patients, according to Dr. Velazquez.

Session cochair Kim A. Williams, MD, professor and chief of cardiology at Rush University Medical Center in Chicago, posed a direct question: “Is there an age cutoff for your group for bypass surgery?”

No, Dr. Velazquez replied. He pointed out that cardiovascular mortality remained the No. 1 cause of mortality across all age groups.

“If the expectation is that the major cause of fatal events is going to be cardiovascular, and CABG plus medical therapy reduces that risk consistently regardless of age, we think that there really is no particular age cutoff. There is a point at which the noncardiovascular risk predominates, but in the population we studied we did not see that point,” Dr. Velazquez added.

STICH was a 22-nation trial in which 1,212 patients with a left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomized to CABG plus optimal medical therapy or optimal medical therapy alone and followed for a median of 9.8 years (JACC Heart Fail. 2013;1[5]:400-8). For purposes of this secondary analysis, participants were divided into quartiles according to baseline age: Quartile 1 patients were up to 54 years old; quartile 2 were ages 55-60; quartile 3 were ages 61-67; and quartile 4 were ages 68 and up.

Older subjects had more comorbidities. All-cause mortality was significantly higher in older than younger patients: for CABG, 68% vs. 48% in quartiles 4 and 1, respectively; for medical therapy, 79% vs. 60% in the same two quartiles. In contrast, cardiovascular mortality did not differ significantly by age: It was 39% in quartile 4 and 35% in quartile 1 in the CABG group, and 53%, compared with 49%, in medically managed patients in quartiles 4 and 1.

For the secondary composite endpoint of all-cause mortality or cardiovascular hospitalization, the benefit of CABG plus medical management over medical management alone was significantly greater in younger than in older patients.

The rate of noncardiovascular mortality was 5.8% in quartiles 1 and 2, then leapt to 14.7% in quartile 3 and 21.1% in quartile 4.

Although the main focus of Dr. Velazquez’s presentation was the impact of CABG with advancing age, he said he found an important lesson in the younger population as well.

“We saw roughly a 40% relative risk reduction in all-cause mortality with CABG in the youngest quartile, compared with the three older groups. My interpretation of that data is that it’s probably not appropriate to avoid CABG in favor of another strategy in a younger patient when you see this kind of mortality benefit,” the cardiologist said.

One limitation of the STICH analysis, said session cochair Stephan Achenbach, MD, is that the study population was relatively young overall. The oldest patients in STICH were roughly the same age as the average patients undergoing CABG for left ventricular systolic dysfunction today at most centers, according to Dr. Achenbach, professor of cardiology at the University of Erlangen-Nuremberg (Germany).

Dr. Velazquez agreed. “I can’t speak as to whether these trial results would apply to the very elderly, patients age 90 and above,” he said.

Simultaneously with the presentation , the new STICH analysis was published online (Circulation. 2016 Aug 29. doi: 10.1161/CIRCULATIONAHA.116.024800).

STICH was funded by the National Institutes of Health. Dr. Velazquez reported having no relevant financial conflicts.

[email protected]

ROME – Coronary artery bypass surgery reduces cardiovascular mortality in heart failure patients with ischemic cardiomyopathy to a consistent extent regardless of age at the time of surgery, according to a secondary analysis from the landmark STICH trial, Eric J. Velazquez, MD, reported at the annual congress of the European Society of Cardiology.

“Cardiologists and cardiac surgeons can confidently offer patients CABG in addition to optimal medical therapy with the knowledge that cardiovascular mortality is reduced by CABG to a similar extent across all age groups in this trial through 10 years of follow-up,” said Dr. Velazquez, professor of medicine at Duke University in Durham, N.C.

Bruce Jancin/Frontline Medical News

However, that’s only part of the story. Cardiovascular mortality was a secondary endpoint in STICH (Surgical Treatment for Ischemic Heart Failure). The primary endpoint was all-cause mortality. And CABG’s impact on all-cause mortality was diminished in older STICH participants because of their greater comorbidity burden and the competing risk of noncardiovascular death, he added.

The take-home message is that cardiologists and heart surgeons need to carefully assess competing mortality risks before pursuing CABG in older patients, according to Dr. Velazquez.

Session cochair Kim A. Williams, MD, professor and chief of cardiology at Rush University Medical Center in Chicago, posed a direct question: “Is there an age cutoff for your group for bypass surgery?”

No, Dr. Velazquez replied. He pointed out that cardiovascular mortality remained the No. 1 cause of mortality across all age groups.

“If the expectation is that the major cause of fatal events is going to be cardiovascular, and CABG plus medical therapy reduces that risk consistently regardless of age, we think that there really is no particular age cutoff. There is a point at which the noncardiovascular risk predominates, but in the population we studied we did not see that point,” Dr. Velazquez added.

STICH was a 22-nation trial in which 1,212 patients with a left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomized to CABG plus optimal medical therapy or optimal medical therapy alone and followed for a median of 9.8 years (JACC Heart Fail. 2013;1[5]:400-8). For purposes of this secondary analysis, participants were divided into quartiles according to baseline age: Quartile 1 patients were up to 54 years old; quartile 2 were ages 55-60; quartile 3 were ages 61-67; and quartile 4 were ages 68 and up.

Older subjects had more comorbidities. All-cause mortality was significantly higher in older than younger patients: for CABG, 68% vs. 48% in quartiles 4 and 1, respectively; for medical therapy, 79% vs. 60% in the same two quartiles. In contrast, cardiovascular mortality did not differ significantly by age: It was 39% in quartile 4 and 35% in quartile 1 in the CABG group, and 53%, compared with 49%, in medically managed patients in quartiles 4 and 1.

For the secondary composite endpoint of all-cause mortality or cardiovascular hospitalization, the benefit of CABG plus medical management over medical management alone was significantly greater in younger than in older patients.

The rate of noncardiovascular mortality was 5.8% in quartiles 1 and 2, then leapt to 14.7% in quartile 3 and 21.1% in quartile 4.

Although the main focus of Dr. Velazquez’s presentation was the impact of CABG with advancing age, he said he found an important lesson in the younger population as well.

“We saw roughly a 40% relative risk reduction in all-cause mortality with CABG in the youngest quartile, compared with the three older groups. My interpretation of that data is that it’s probably not appropriate to avoid CABG in favor of another strategy in a younger patient when you see this kind of mortality benefit,” the cardiologist said.

One limitation of the STICH analysis, said session cochair Stephan Achenbach, MD, is that the study population was relatively young overall. The oldest patients in STICH were roughly the same age as the average patients undergoing CABG for left ventricular systolic dysfunction today at most centers, according to Dr. Achenbach, professor of cardiology at the University of Erlangen-Nuremberg (Germany).

Dr. Velazquez agreed. “I can’t speak as to whether these trial results would apply to the very elderly, patients age 90 and above,” he said.

Simultaneously with the presentation , the new STICH analysis was published online (Circulation. 2016 Aug 29. doi: 10.1161/CIRCULATIONAHA.116.024800).

STICH was funded by the National Institutes of Health. Dr. Velazquez reported having no relevant financial conflicts.

[email protected]

The Food and Drug Administration has updated the labels on certain HIV drugs to include a contraindication for lurasidone (Latuda), an antipsychotic medication.

Lurasidone is used to treat depressive episodes in bipolar I disorder (bipolar depression) and schizophrenia in adults. The contraindication was added because of “the potential for serious and/or life-threatening reactions,” according to the FDA.

The labels on the following pharmaceutical products will be updated to reflect the change:

Aptivus (tipranavir)

Crixivan (indinavir)

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide)

Invirase (saquinavir)

Kaletra (lopinavir/ritonavir)

Lexiva (fosamprenavir): Lurasidone is contraindicated because of the potential for serious and/or life-threatening reactions if fosamprenavir is coadministered with ritonavir.

Norvir (ritonavir)

Prezista (darunavir)

Reyataz (atazanavir): Lurasidone is contraindicated because of the potential for serious and/or life-threatening reactions if atazanavir is coadministered with ritonavir.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate)

Viracept (nelfinavir)

Labels for Evotaz (atazanavir/cobicistat) and Prezcobix (darunavir/cobicistat) already include a contraindication for lurasidone, the FDA announcement noted.

[email protected]

On Twitter @richpizzi

The Food and Drug Administration has updated the labels on certain HIV drugs to include a contraindication for lurasidone (Latuda), an antipsychotic medication.

Lurasidone is used to treat depressive episodes in bipolar I disorder (bipolar depression) and schizophrenia in adults. The contraindication was added because of “the potential for serious and/or life-threatening reactions,” according to the FDA.

The labels on the following pharmaceutical products will be updated to reflect the change:

Aptivus (tipranavir)

Crixivan (indinavir)

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide)

Invirase (saquinavir)

Kaletra (lopinavir/ritonavir)

Lexiva (fosamprenavir): Lurasidone is contraindicated because of the potential for serious and/or life-threatening reactions if fosamprenavir is coadministered with ritonavir.

Norvir (ritonavir)

Prezista (darunavir)

Reyataz (atazanavir): Lurasidone is contraindicated because of the potential for serious and/or life-threatening reactions if atazanavir is coadministered with ritonavir.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate)

Viracept (nelfinavir)

Labels for Evotaz (atazanavir/cobicistat) and Prezcobix (darunavir/cobicistat) already include a contraindication for lurasidone, the FDA announcement noted.

[email protected]

On Twitter @richpizzi

The Food and Drug Administration has updated the labels on certain HIV drugs to include a contraindication for lurasidone (Latuda), an antipsychotic medication.

Lurasidone is used to treat depressive episodes in bipolar I disorder (bipolar depression) and schizophrenia in adults. The contraindication was added because of “the potential for serious and/or life-threatening reactions,” according to the FDA.

The labels on the following pharmaceutical products will be updated to reflect the change:

Aptivus (tipranavir)

Crixivan (indinavir)

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide)

Invirase (saquinavir)

Kaletra (lopinavir/ritonavir)

Lexiva (fosamprenavir): Lurasidone is contraindicated because of the potential for serious and/or life-threatening reactions if fosamprenavir is coadministered with ritonavir.

Norvir (ritonavir)

Prezista (darunavir)

Reyataz (atazanavir): Lurasidone is contraindicated because of the potential for serious and/or life-threatening reactions if atazanavir is coadministered with ritonavir.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate)

Viracept (nelfinavir)

Labels for Evotaz (atazanavir/cobicistat) and Prezcobix (darunavir/cobicistat) already include a contraindication for lurasidone, the FDA announcement noted.

[email protected]

On Twitter @richpizzi

SAN DIEGO – As the number of surgery patients over the age of 65 continues to burgeon, clinicians have a resource to help them provide optimal perioperative care to this patient population.

At the American College of Surgeons/National Surgical Quality Improvement Program National Conference, Ronnie A. Rosenthal, MD, discussed highlights from “Optimal Perioperative Management of the Geriatric Patient: A Best Practice Guideline from the ACS NSQIP/American Geriatrics Society,” which was published in January 2016.

Work on the guideline began in 2013, when a 28-member multidisciplinary panel began to conduct a structured search of Medline to identify systematic reviews, meta-analyses, practice guidelines, and clinical trials on the topic. The panel included experts from ACS, the ACS Geriatric Surgery Task Force, the American Society of Anesthesiologists, the American Geriatrics Society, and the AGS’ Geriatrics for Specialists Initiative. The 61-page document is divided into four categories: immediate preoperative period, intraoperative management, postoperative care, and care transitions.

Working with patients on goals

As noted in the guideline, a primary goal of the immediate preoperative period is to discuss with the patient his or her goals and expectations. Patient expectations are influenced by their treatment preferences. In fact, researchers have found that older patients are less likely to want a treatment – even if it results in cure – that may result in severe functional or cognitive impairment. For patients with existing advanced directives, organizations representing nurses, anesthesiologists, and surgeons all agree that there must be a “reconsideration” of these directives prior to surgery. A discussion that includes the new risks of the procedure must be conducted to ensure that the approach to potential life-threatening problems is consistent with the patient’s values.

Preoperative management of medications

Another recommendation for the preoperative period is to ensure that older patients have shorter fasts, have appropriate prophylactic antibiotics, continue medications with withdrawal potential, and discontinue medications that are not essential. The latter point is based on the Beers Criteria, a list of medications that are inappropriate or potentially inappropriate to use in older adults (J Am Geriatr Soc. 2015 Nov;63[11]:2227-46). “You want to discontinue as many inappropriate medications as possible, because one of the main side effects of their use is delirium, and you want to avoid that,” said Dr. Rosenthal, professor of surgery at the Yale University, New Haven, Conn., and one of the guideline authors.

©Thinkstockphotos.com

Anesthesia and pain management

Intraoperative management strategies contained in the guideline include establishing an anesthetic approach and a perioperative analgesia pain plan, preventing postoperative nausea and vomiting, assessing patient safety in the OR, preventing predictable complications, and optimizing fluid management. Physiologic effects of anesthesia medications include changes in systemic vascular resistance, cardiac preload, baroreceptor responses, lung mechanics, oxygen diffusion, neurotransmitter function, and end-organ blood flow, among others. “These physiologic changes of aging have significant clinical implications,” Dr. Rosenthal noted. “These are variable among individuals and variable among organ systems, and it’s important that we pay attention to that. Because of this variability, there is insufficient evidence to recommend a single ‘best’ anesthetic plan for all older adults.”

The guideline recommends that each patient have an individualized pain plan that consists of a directed pain history and physical exam and is appropriately titrated for increased sensitivity. “It should include a prophylactic bowel regimen for anybody who’s on an opioid in particular,” she said. “We should avoid inappropriate medications like benzodiazepines, and we should use a multimodal therapy with opioid-sparing and regional techniques.”

Pulmonary considerations for anesthesia include susceptibility to hypocarbia and hypoxemia, and susceptibility to residual anesthetic effects. “Because of physiologic changes, the anesthesia medications aren’t metabolized in the same way,” she said. “Older people may have lower drug requirements and may not recover as quickly from the effects of these drugs. This can lead to respiratory compromise and also can increase the risk of aspiration.” Strategies to prevent pulmonary complications include using regional anesthesia when possible and avoiding the use of intermediate- and long-acting neuromuscular blocking agents. Dr. Rosenthal said that there is insufficient evidence in the current medical literature to recommend a single “best” intraoperative fluid management plan for all older adults. “Part of the reason it’s so difficult is because of the cardiac physiologic changes [with aging],” she explained. “Older people are susceptible to volume overload. On the other hand, they also may have an exaggerated decline in cardiac function if you give them too little fluid and they have insufficient preload. It’s a very fine line and that’s why it’s hard to recommend a single best strategy.”

Be alert to postoperative delirium

Postoperatively, the guideline recommends that care plans include controlling perioperative acute pain; addressing delirium/cognitive issues; preventing functional decline, falls, pressure ulcers, and urinary track infections; maintaining adequate nutrition; and avoiding pulmonary complications. Dr. Rosenthal underscored the importance of using the four-question Short Confusion Assessment Method (Short CAM) to assess for delirium. “For it to be delirium, there has to be evidence of acute change in mental status from baseline; it has to be acute and fluctuating, and characterized by inattention,” she said. “The patient also has to have either disorganized thinking or an altered level of consciousness.”

Many of the precipitating factors of delirium can be prevented by treating pain, watching medications, preventing dehydration and undernutrition, removing catheters and other devices when possible, preventing constipation, and using minimally invasive techniques to reduce the physiologic stress of surgery. “Sometimes symptoms of delirium are a warning sign that something else is going on, such as an infection, hypoxemia, electrolyte imbalance, neurological events, and major organ dysfunction,” she said. The first-line therapy for treating delirium as recommended in the guideline is a multicomponent intervention that focuses on frequent reorientation with voice, calendars, and clocks; eliminating use of restraints; having familiar objects in the room; and ensuring the use of assistive devices. The second-line therapy is antipsychotic medications at the lowest effective dose. “The mantra is start low and go slow,” she said.

Preventing postoperative functional decline

Another postoperative strategy in the guideline involves targeted fall prevention, such as having an assistive device at the bedside if used as an outpatient and prescribing early physical therapy focused on maintaining mobility as the primary event. “Every day an older patient is immobilized it takes at least 3 days to regain the lost function,” Dr. Rosenthal said. “And for older surgical patients, one in four experiences a significant decline in function by hospital discharge and 60% experience some loss of independence.” (The latter statistic comes from a study published online July 13, 2016, in JAMA Surgery: doi:10.1001/jamasurg.2016.1689.) Interventions for preventing functional decline include promotion of family participation in care, early mobilization, early physical/occupational therapy referral, geriatric consultation, comprehensive discharge planning, and nutritional support. She pointed out that an estimated 40% of community-dwelling elders and two-thirds of nursing home residents are either malnourished or “at risk” of malnutrition.

Transition of care

The final category in the guideline, transition of care, recommends an assessment of social support/home health needs, complete medication review, predischarge geriatric assessment, formal written discharge instructions, and communication with the patient’s primary care physician. “Common models of transitional care involve good coordination with the primary care physician,” she said. “There’s good data to show that people who see their primary care physician within 2 weeks of discharge do better in terms of readmission.”

Dr. Rosenthal reported having no financial disclosures.

[email protected]

SAN DIEGO – As the number of surgery patients over the age of 65 continues to burgeon, clinicians have a resource to help them provide optimal perioperative care to this patient population.

At the American College of Surgeons/National Surgical Quality Improvement Program National Conference, Ronnie A. Rosenthal, MD, discussed highlights from “Optimal Perioperative Management of the Geriatric Patient: A Best Practice Guideline from the ACS NSQIP/American Geriatrics Society,” which was published in January 2016.

Work on the guideline began in 2013, when a 28-member multidisciplinary panel began to conduct a structured search of Medline to identify systematic reviews, meta-analyses, practice guidelines, and clinical trials on the topic. The panel included experts from ACS, the ACS Geriatric Surgery Task Force, the American Society of Anesthesiologists, the American Geriatrics Society, and the AGS’ Geriatrics for Specialists Initiative. The 61-page document is divided into four categories: immediate preoperative period, intraoperative management, postoperative care, and care transitions.

Working with patients on goals

As noted in the guideline, a primary goal of the immediate preoperative period is to discuss with the patient his or her goals and expectations. Patient expectations are influenced by their treatment preferences. In fact, researchers have found that older patients are less likely to want a treatment – even if it results in cure – that may result in severe functional or cognitive impairment. For patients with existing advanced directives, organizations representing nurses, anesthesiologists, and surgeons all agree that there must be a “reconsideration” of these directives prior to surgery. A discussion that includes the new risks of the procedure must be conducted to ensure that the approach to potential life-threatening problems is consistent with the patient’s values.

Preoperative management of medications

Another recommendation for the preoperative period is to ensure that older patients have shorter fasts, have appropriate prophylactic antibiotics, continue medications with withdrawal potential, and discontinue medications that are not essential. The latter point is based on the Beers Criteria, a list of medications that are inappropriate or potentially inappropriate to use in older adults (J Am Geriatr Soc. 2015 Nov;63[11]:2227-46). “You want to discontinue as many inappropriate medications as possible, because one of the main side effects of their use is delirium, and you want to avoid that,” said Dr. Rosenthal, professor of surgery at the Yale University, New Haven, Conn., and one of the guideline authors.

©Thinkstockphotos.com

Anesthesia and pain management

Intraoperative management strategies contained in the guideline include establishing an anesthetic approach and a perioperative analgesia pain plan, preventing postoperative nausea and vomiting, assessing patient safety in the OR, preventing predictable complications, and optimizing fluid management. Physiologic effects of anesthesia medications include changes in systemic vascular resistance, cardiac preload, baroreceptor responses, lung mechanics, oxygen diffusion, neurotransmitter function, and end-organ blood flow, among others. “These physiologic changes of aging have significant clinical implications,” Dr. Rosenthal noted. “These are variable among individuals and variable among organ systems, and it’s important that we pay attention to that. Because of this variability, there is insufficient evidence to recommend a single ‘best’ anesthetic plan for all older adults.”

The guideline recommends that each patient have an individualized pain plan that consists of a directed pain history and physical exam and is appropriately titrated for increased sensitivity. “It should include a prophylactic bowel regimen for anybody who’s on an opioid in particular,” she said. “We should avoid inappropriate medications like benzodiazepines, and we should use a multimodal therapy with opioid-sparing and regional techniques.”

Pulmonary considerations for anesthesia include susceptibility to hypocarbia and hypoxemia, and susceptibility to residual anesthetic effects. “Because of physiologic changes, the anesthesia medications aren’t metabolized in the same way,” she said. “Older people may have lower drug requirements and may not recover as quickly from the effects of these drugs. This can lead to respiratory compromise and also can increase the risk of aspiration.” Strategies to prevent pulmonary complications include using regional anesthesia when possible and avoiding the use of intermediate- and long-acting neuromuscular blocking agents. Dr. Rosenthal said that there is insufficient evidence in the current medical literature to recommend a single “best” intraoperative fluid management plan for all older adults. “Part of the reason it’s so difficult is because of the cardiac physiologic changes [with aging],” she explained. “Older people are susceptible to volume overload. On the other hand, they also may have an exaggerated decline in cardiac function if you give them too little fluid and they have insufficient preload. It’s a very fine line and that’s why it’s hard to recommend a single best strategy.”

Be alert to postoperative delirium

Postoperatively, the guideline recommends that care plans include controlling perioperative acute pain; addressing delirium/cognitive issues; preventing functional decline, falls, pressure ulcers, and urinary track infections; maintaining adequate nutrition; and avoiding pulmonary complications. Dr. Rosenthal underscored the importance of using the four-question Short Confusion Assessment Method (Short CAM) to assess for delirium. “For it to be delirium, there has to be evidence of acute change in mental status from baseline; it has to be acute and fluctuating, and characterized by inattention,” she said. “The patient also has to have either disorganized thinking or an altered level of consciousness.”

Many of the precipitating factors of delirium can be prevented by treating pain, watching medications, preventing dehydration and undernutrition, removing catheters and other devices when possible, preventing constipation, and using minimally invasive techniques to reduce the physiologic stress of surgery. “Sometimes symptoms of delirium are a warning sign that something else is going on, such as an infection, hypoxemia, electrolyte imbalance, neurological events, and major organ dysfunction,” she said. The first-line therapy for treating delirium as recommended in the guideline is a multicomponent intervention that focuses on frequent reorientation with voice, calendars, and clocks; eliminating use of restraints; having familiar objects in the room; and ensuring the use of assistive devices. The second-line therapy is antipsychotic medications at the lowest effective dose. “The mantra is start low and go slow,” she said.

Preventing postoperative functional decline

Another postoperative strategy in the guideline involves targeted fall prevention, such as having an assistive device at the bedside if used as an outpatient and prescribing early physical therapy focused on maintaining mobility as the primary event. “Every day an older patient is immobilized it takes at least 3 days to regain the lost function,” Dr. Rosenthal said. “And for older surgical patients, one in four experiences a significant decline in function by hospital discharge and 60% experience some loss of independence.” (The latter statistic comes from a study published online July 13, 2016, in JAMA Surgery: doi:10.1001/jamasurg.2016.1689.) Interventions for preventing functional decline include promotion of family participation in care, early mobilization, early physical/occupational therapy referral, geriatric consultation, comprehensive discharge planning, and nutritional support. She pointed out that an estimated 40% of community-dwelling elders and two-thirds of nursing home residents are either malnourished or “at risk” of malnutrition.

Transition of care

The final category in the guideline, transition of care, recommends an assessment of social support/home health needs, complete medication review, predischarge geriatric assessment, formal written discharge instructions, and communication with the patient’s primary care physician. “Common models of transitional care involve good coordination with the primary care physician,” she said. “There’s good data to show that people who see their primary care physician within 2 weeks of discharge do better in terms of readmission.”

Dr. Rosenthal reported having no financial disclosures.

[email protected]

SAN DIEGO – As the number of surgery patients over the age of 65 continues to burgeon, clinicians have a resource to help them provide optimal perioperative care to this patient population.

At the American College of Surgeons/National Surgical Quality Improvement Program National Conference, Ronnie A. Rosenthal, MD, discussed highlights from “Optimal Perioperative Management of the Geriatric Patient: A Best Practice Guideline from the ACS NSQIP/American Geriatrics Society,” which was published in January 2016.

Work on the guideline began in 2013, when a 28-member multidisciplinary panel began to conduct a structured search of Medline to identify systematic reviews, meta-analyses, practice guidelines, and clinical trials on the topic. The panel included experts from ACS, the ACS Geriatric Surgery Task Force, the American Society of Anesthesiologists, the American Geriatrics Society, and the AGS’ Geriatrics for Specialists Initiative. The 61-page document is divided into four categories: immediate preoperative period, intraoperative management, postoperative care, and care transitions.

Working with patients on goals

As noted in the guideline, a primary goal of the immediate preoperative period is to discuss with the patient his or her goals and expectations. Patient expectations are influenced by their treatment preferences. In fact, researchers have found that older patients are less likely to want a treatment – even if it results in cure – that may result in severe functional or cognitive impairment. For patients with existing advanced directives, organizations representing nurses, anesthesiologists, and surgeons all agree that there must be a “reconsideration” of these directives prior to surgery. A discussion that includes the new risks of the procedure must be conducted to ensure that the approach to potential life-threatening problems is consistent with the patient’s values.

Preoperative management of medications

Another recommendation for the preoperative period is to ensure that older patients have shorter fasts, have appropriate prophylactic antibiotics, continue medications with withdrawal potential, and discontinue medications that are not essential. The latter point is based on the Beers Criteria, a list of medications that are inappropriate or potentially inappropriate to use in older adults (J Am Geriatr Soc. 2015 Nov;63[11]:2227-46). “You want to discontinue as many inappropriate medications as possible, because one of the main side effects of their use is delirium, and you want to avoid that,” said Dr. Rosenthal, professor of surgery at the Yale University, New Haven, Conn., and one of the guideline authors.

©Thinkstockphotos.com

Anesthesia and pain management

Intraoperative management strategies contained in the guideline include establishing an anesthetic approach and a perioperative analgesia pain plan, preventing postoperative nausea and vomiting, assessing patient safety in the OR, preventing predictable complications, and optimizing fluid management. Physiologic effects of anesthesia medications include changes in systemic vascular resistance, cardiac preload, baroreceptor responses, lung mechanics, oxygen diffusion, neurotransmitter function, and end-organ blood flow, among others. “These physiologic changes of aging have significant clinical implications,” Dr. Rosenthal noted. “These are variable among individuals and variable among organ systems, and it’s important that we pay attention to that. Because of this variability, there is insufficient evidence to recommend a single ‘best’ anesthetic plan for all older adults.”

The guideline recommends that each patient have an individualized pain plan that consists of a directed pain history and physical exam and is appropriately titrated for increased sensitivity. “It should include a prophylactic bowel regimen for anybody who’s on an opioid in particular,” she said. “We should avoid inappropriate medications like benzodiazepines, and we should use a multimodal therapy with opioid-sparing and regional techniques.”

Pulmonary considerations for anesthesia include susceptibility to hypocarbia and hypoxemia, and susceptibility to residual anesthetic effects. “Because of physiologic changes, the anesthesia medications aren’t metabolized in the same way,” she said. “Older people may have lower drug requirements and may not recover as quickly from the effects of these drugs. This can lead to respiratory compromise and also can increase the risk of aspiration.” Strategies to prevent pulmonary complications include using regional anesthesia when possible and avoiding the use of intermediate- and long-acting neuromuscular blocking agents. Dr. Rosenthal said that there is insufficient evidence in the current medical literature to recommend a single “best” intraoperative fluid management plan for all older adults. “Part of the reason it’s so difficult is because of the cardiac physiologic changes [with aging],” she explained. “Older people are susceptible to volume overload. On the other hand, they also may have an exaggerated decline in cardiac function if you give them too little fluid and they have insufficient preload. It’s a very fine line and that’s why it’s hard to recommend a single best strategy.”

Be alert to postoperative delirium

Postoperatively, the guideline recommends that care plans include controlling perioperative acute pain; addressing delirium/cognitive issues; preventing functional decline, falls, pressure ulcers, and urinary track infections; maintaining adequate nutrition; and avoiding pulmonary complications. Dr. Rosenthal underscored the importance of using the four-question Short Confusion Assessment Method (Short CAM) to assess for delirium. “For it to be delirium, there has to be evidence of acute change in mental status from baseline; it has to be acute and fluctuating, and characterized by inattention,” she said. “The patient also has to have either disorganized thinking or an altered level of consciousness.”

Many of the precipitating factors of delirium can be prevented by treating pain, watching medications, preventing dehydration and undernutrition, removing catheters and other devices when possible, preventing constipation, and using minimally invasive techniques to reduce the physiologic stress of surgery. “Sometimes symptoms of delirium are a warning sign that something else is going on, such as an infection, hypoxemia, electrolyte imbalance, neurological events, and major organ dysfunction,” she said. The first-line therapy for treating delirium as recommended in the guideline is a multicomponent intervention that focuses on frequent reorientation with voice, calendars, and clocks; eliminating use of restraints; having familiar objects in the room; and ensuring the use of assistive devices. The second-line therapy is antipsychotic medications at the lowest effective dose. “The mantra is start low and go slow,” she said.

Preventing postoperative functional decline

Another postoperative strategy in the guideline involves targeted fall prevention, such as having an assistive device at the bedside if used as an outpatient and prescribing early physical therapy focused on maintaining mobility as the primary event. “Every day an older patient is immobilized it takes at least 3 days to regain the lost function,” Dr. Rosenthal said. “And for older surgical patients, one in four experiences a significant decline in function by hospital discharge and 60% experience some loss of independence.” (The latter statistic comes from a study published online July 13, 2016, in JAMA Surgery: doi:10.1001/jamasurg.2016.1689.) Interventions for preventing functional decline include promotion of family participation in care, early mobilization, early physical/occupational therapy referral, geriatric consultation, comprehensive discharge planning, and nutritional support. She pointed out that an estimated 40% of community-dwelling elders and two-thirds of nursing home residents are either malnourished or “at risk” of malnutrition.

Transition of care

The final category in the guideline, transition of care, recommends an assessment of social support/home health needs, complete medication review, predischarge geriatric assessment, formal written discharge instructions, and communication with the patient’s primary care physician. “Common models of transitional care involve good coordination with the primary care physician,” she said. “There’s good data to show that people who see their primary care physician within 2 weeks of discharge do better in terms of readmission.”

Dr. Rosenthal reported having no financial disclosures.

[email protected]

Risk-assessment tools can give surgeons a clinical framework to help inform decisions about palliative care surgery in patients with advanced malignancies, but cannot replace nuanced clinical judgment that incorporates patients’ priorities, according to results of a meta-analysis.

Ian W. Folkert, MD, and Robert E. Roses, MD, of the department of surgery at the Hospital of the University of Pennsylvania, Philadelphia, reviewed the available research on the indications for palliative surgery for patients with advanced disease and risk-assessment tools for patient selection. Emergent and palliative surgery in such situations require a careful consideration of many clinical factors such as overall prognosis and risk of a surgical approach, compared with nonsurgical interventions (J Surg Oncol. 2016;114:[3]311-15). But the investigators concluded that while an evidence-based approach to patient selection for palliative cancer surgery can offer some guidance on the potential for achieving clinical goals, ultimately the decision to proceed must prioritize patient values and orientation to treatment.

Tumor bleeding

Tumor-related complications often initiate the question of palliative surgical and nonsurgical interventions.

Studies of acute hemorrhage from malignancies indicate that bleeding originating from a tumor is rarely massive and usually can be managed endoscopically (Clin Endosc. 2015 Mar;48[2]:121-7; Aliment Pharmacol Ther. 2013;38:144-50; Mayo Clin Proc. 1994;69[8]:736-40). Transcatheter arterial embolization also is used successfully to manage tumor bleeding (J Vasc Interv Radiol. 2015 Sep;26[9]:1297-304; Indian J Cancer. 2014 Feb; 51[6]56-9). The investigators stated, “Although tumor rebleeding may be frequent, repeat endoscopy is often effective and is self-recommending given the high risk of major morbidity after a palliative foregut resection ... [and] all efforts should be made to avoid emergency gastrectomy or esophagectomy.”

Obstructing tumors

Patients with acute colonic obstruction because of colon cancer typically have been treated with a proximal diverting colostomy, but palliative self-expanding metallic stent placement (SEMS) has emerged as an option. Recent studies have shown both short- and long-term clinical success of SEMS, but rates of major morbidity and mortality for emergent surgery and SEMS were similar, as were rates of overall survival (Surg Endosc. 2015;29[6];1580-5; World J Gastroenterol. 2013 Sep 7;19[33]:5565-74). SEMS-related mortality was primarily because of perforation (Endoscopy. 2008 Mar;40[3]:184-91). Stenting for esophageal and gastroesophageal (GE) function obstruction is also emerging as a nonsurgical option. The investigators noted, “There is a very limited role for palliative surgery for esophageal and GE junction tumors.” Gastric outlet obstruction, proximal duodenal obstruction, and biliary tract obstruction are treated palliatively with stents, but “gastrojejunostomy and other bypass operations may provide effective palliation in carefully selected patients.”

Tumor perforation

Few nonsurgical treatment options are available for tumor perforation. Palliative surgical intervention often is undertaken in the context of neutropenia and abdominal pain, the investigators said. These patients are at high risk for morbidity and mortality. One study reviewed found that “prolonged neutropenia and severe sepsis were associated with poor outcomes in all patients, while surgical management was associated with improved survival (Ann Surg. 2008;248[1];104-9), but nonoperative management and comfort care were deemed appropriate for those patients with advanced disease and for those in whom surgery is high risk.

Patient selection for palliative surgery

The studies examined suggest that patient selection for palliative surgical intervention requires the weighing of clinical variables of frailty, morbidity, and mortality. The investigators reviewed a variety of risk-assessment tools developed to help surgeons with that decision (J Am Coll Surg. 2003;197[1];16-21; J Palliat Med. 2014;17:37-42; Ann Surg. 2011;254[2]:333-8). Among the factors considered are the amplified risks of mortality in these patients, the high cost of emergent operations, and most importantly, the chances of extending survival. The complexity of palliative and emergent surgical indications means that risk-assessment studies are “frequently too reductive to provide meaningful guidance” to the surgeon.

Dr. Folkert and Dr. Roses concluded that risk-assessment tools underscore the poor outcomes associated with operations in this setting, and, to some extent, guide decision making, but “they do not supplant clinical judgment, nor do they account for patient values and orientation toward treatment. It remains impossible to place a uniform value on length and quality of life, and patients’ values are paramount in informing treatment decisions.”

The authors had no conflicts to disclose.

Risk-assessment tools can give surgeons a clinical framework to help inform decisions about palliative care surgery in patients with advanced malignancies, but cannot replace nuanced clinical judgment that incorporates patients’ priorities, according to results of a meta-analysis.

Ian W. Folkert, MD, and Robert E. Roses, MD, of the department of surgery at the Hospital of the University of Pennsylvania, Philadelphia, reviewed the available research on the indications for palliative surgery for patients with advanced disease and risk-assessment tools for patient selection. Emergent and palliative surgery in such situations require a careful consideration of many clinical factors such as overall prognosis and risk of a surgical approach, compared with nonsurgical interventions (J Surg Oncol. 2016;114:[3]311-15). But the investigators concluded that while an evidence-based approach to patient selection for palliative cancer surgery can offer some guidance on the potential for achieving clinical goals, ultimately the decision to proceed must prioritize patient values and orientation to treatment.

Tumor bleeding

Tumor-related complications often initiate the question of palliative surgical and nonsurgical interventions.

Studies of acute hemorrhage from malignancies indicate that bleeding originating from a tumor is rarely massive and usually can be managed endoscopically (Clin Endosc. 2015 Mar;48[2]:121-7; Aliment Pharmacol Ther. 2013;38:144-50; Mayo Clin Proc. 1994;69[8]:736-40). Transcatheter arterial embolization also is used successfully to manage tumor bleeding (J Vasc Interv Radiol. 2015 Sep;26[9]:1297-304; Indian J Cancer. 2014 Feb; 51[6]56-9). The investigators stated, “Although tumor rebleeding may be frequent, repeat endoscopy is often effective and is self-recommending given the high risk of major morbidity after a palliative foregut resection ... [and] all efforts should be made to avoid emergency gastrectomy or esophagectomy.”

Obstructing tumors

Patients with acute colonic obstruction because of colon cancer typically have been treated with a proximal diverting colostomy, but palliative self-expanding metallic stent placement (SEMS) has emerged as an option. Recent studies have shown both short- and long-term clinical success of SEMS, but rates of major morbidity and mortality for emergent surgery and SEMS were similar, as were rates of overall survival (Surg Endosc. 2015;29[6];1580-5; World J Gastroenterol. 2013 Sep 7;19[33]:5565-74). SEMS-related mortality was primarily because of perforation (Endoscopy. 2008 Mar;40[3]:184-91). Stenting for esophageal and gastroesophageal (GE) function obstruction is also emerging as a nonsurgical option. The investigators noted, “There is a very limited role for palliative surgery for esophageal and GE junction tumors.” Gastric outlet obstruction, proximal duodenal obstruction, and biliary tract obstruction are treated palliatively with stents, but “gastrojejunostomy and other bypass operations may provide effective palliation in carefully selected patients.”

Tumor perforation

Few nonsurgical treatment options are available for tumor perforation. Palliative surgical intervention often is undertaken in the context of neutropenia and abdominal pain, the investigators said. These patients are at high risk for morbidity and mortality. One study reviewed found that “prolonged neutropenia and severe sepsis were associated with poor outcomes in all patients, while surgical management was associated with improved survival (Ann Surg. 2008;248[1];104-9), but nonoperative management and comfort care were deemed appropriate for those patients with advanced disease and for those in whom surgery is high risk.

Patient selection for palliative surgery

The studies examined suggest that patient selection for palliative surgical intervention requires the weighing of clinical variables of frailty, morbidity, and mortality. The investigators reviewed a variety of risk-assessment tools developed to help surgeons with that decision (J Am Coll Surg. 2003;197[1];16-21; J Palliat Med. 2014;17:37-42; Ann Surg. 2011;254[2]:333-8). Among the factors considered are the amplified risks of mortality in these patients, the high cost of emergent operations, and most importantly, the chances of extending survival. The complexity of palliative and emergent surgical indications means that risk-assessment studies are “frequently too reductive to provide meaningful guidance” to the surgeon.

Dr. Folkert and Dr. Roses concluded that risk-assessment tools underscore the poor outcomes associated with operations in this setting, and, to some extent, guide decision making, but “they do not supplant clinical judgment, nor do they account for patient values and orientation toward treatment. It remains impossible to place a uniform value on length and quality of life, and patients’ values are paramount in informing treatment decisions.”

The authors had no conflicts to disclose.

Risk-assessment tools can give surgeons a clinical framework to help inform decisions about palliative care surgery in patients with advanced malignancies, but cannot replace nuanced clinical judgment that incorporates patients’ priorities, according to results of a meta-analysis.

Ian W. Folkert, MD, and Robert E. Roses, MD, of the department of surgery at the Hospital of the University of Pennsylvania, Philadelphia, reviewed the available research on the indications for palliative surgery for patients with advanced disease and risk-assessment tools for patient selection. Emergent and palliative surgery in such situations require a careful consideration of many clinical factors such as overall prognosis and risk of a surgical approach, compared with nonsurgical interventions (J Surg Oncol. 2016;114:[3]311-15). But the investigators concluded that while an evidence-based approach to patient selection for palliative cancer surgery can offer some guidance on the potential for achieving clinical goals, ultimately the decision to proceed must prioritize patient values and orientation to treatment.

Tumor bleeding

Tumor-related complications often initiate the question of palliative surgical and nonsurgical interventions.

Studies of acute hemorrhage from malignancies indicate that bleeding originating from a tumor is rarely massive and usually can be managed endoscopically (Clin Endosc. 2015 Mar;48[2]:121-7; Aliment Pharmacol Ther. 2013;38:144-50; Mayo Clin Proc. 1994;69[8]:736-40). Transcatheter arterial embolization also is used successfully to manage tumor bleeding (J Vasc Interv Radiol. 2015 Sep;26[9]:1297-304; Indian J Cancer. 2014 Feb; 51[6]56-9). The investigators stated, “Although tumor rebleeding may be frequent, repeat endoscopy is often effective and is self-recommending given the high risk of major morbidity after a palliative foregut resection ... [and] all efforts should be made to avoid emergency gastrectomy or esophagectomy.”

Obstructing tumors

Patients with acute colonic obstruction because of colon cancer typically have been treated with a proximal diverting colostomy, but palliative self-expanding metallic stent placement (SEMS) has emerged as an option. Recent studies have shown both short- and long-term clinical success of SEMS, but rates of major morbidity and mortality for emergent surgery and SEMS were similar, as were rates of overall survival (Surg Endosc. 2015;29[6];1580-5; World J Gastroenterol. 2013 Sep 7;19[33]:5565-74). SEMS-related mortality was primarily because of perforation (Endoscopy. 2008 Mar;40[3]:184-91). Stenting for esophageal and gastroesophageal (GE) function obstruction is also emerging as a nonsurgical option. The investigators noted, “There is a very limited role for palliative surgery for esophageal and GE junction tumors.” Gastric outlet obstruction, proximal duodenal obstruction, and biliary tract obstruction are treated palliatively with stents, but “gastrojejunostomy and other bypass operations may provide effective palliation in carefully selected patients.”

Tumor perforation

Few nonsurgical treatment options are available for tumor perforation. Palliative surgical intervention often is undertaken in the context of neutropenia and abdominal pain, the investigators said. These patients are at high risk for morbidity and mortality. One study reviewed found that “prolonged neutropenia and severe sepsis were associated with poor outcomes in all patients, while surgical management was associated with improved survival (Ann Surg. 2008;248[1];104-9), but nonoperative management and comfort care were deemed appropriate for those patients with advanced disease and for those in whom surgery is high risk.

Patient selection for palliative surgery

The studies examined suggest that patient selection for palliative surgical intervention requires the weighing of clinical variables of frailty, morbidity, and mortality. The investigators reviewed a variety of risk-assessment tools developed to help surgeons with that decision (J Am Coll Surg. 2003;197[1];16-21; J Palliat Med. 2014;17:37-42; Ann Surg. 2011;254[2]:333-8). Among the factors considered are the amplified risks of mortality in these patients, the high cost of emergent operations, and most importantly, the chances of extending survival. The complexity of palliative and emergent surgical indications means that risk-assessment studies are “frequently too reductive to provide meaningful guidance” to the surgeon.

Dr. Folkert and Dr. Roses concluded that risk-assessment tools underscore the poor outcomes associated with operations in this setting, and, to some extent, guide decision making, but “they do not supplant clinical judgment, nor do they account for patient values and orientation toward treatment. It remains impossible to place a uniform value on length and quality of life, and patients’ values are paramount in informing treatment decisions.”

The authors had no conflicts to disclose.

The three main approaches for treating localized prostate cancer – surgery, radiotherapy, or active monitoring – yield similar efficacy outcomes but different quality-of-life outcomes, according to two reports published on the New England Journal of Medicine.

Both reports present the findings of the ongoing Protect (Prostate Testing for Cancer and Treatment) trial, a large prospective, randomized trial in the United Kingdom comparing mortality and other health outcomes in men with PSA-detected localized disease. The trial involved 82,429 men aged 50-69 years who had a PSA test between 1999 and 2009, of whom 2,664 were found to have localized prostate cancer. A total of 1,643 of these participants agreed to be randomly assigned to radical prostatectomy (553 men), radical radiotherapy (545 men), or active monitoring (545 men).

©Mark Kostich/Thinkstock

“Active monitoring” involved avoiding any immediate therapy and regularly monitoring disease progression so that radical treatment with curative intent could be given if the need arose. Patients were monitored every 3 months for the first year, then every 6-12 months thereafter. This differs from “watchful waiting,” which doesn’t involve any plan for curative radical treatment if disease progresses.

The first report focused on mortality and disease progression in these 1,643 participants at a median of 10 years of follow-up. The primary outcome measure, prostate cancer–specific survival, was 98.8% or greater across all three study groups, and there was no significant difference among them. Thus, all three approaches yielded the same efficacy: prostate cancer–specific mortality of approximately 1%, said Freddie C. Hamdy, MD, of the Nuffield Department of Surgical Sciences, University of Oxford, and his associates.

However, the rate of disease progression among men assigned to surgery (8.9/1,000 person-years) or to radiotherapy (9.0/1,000 person-years) was less than half the rate among men assigned to active monitoring (22.9/1,000 person-years). The rate of metastasis followed this same pattern (2.4, 3.0, and 6.3 per 1,000 person-years, respectively).

“These differences show the effectiveness of immediate radical therapy over active monitoring, but they have not translated into significant differences – nor have they ruled out equivalence – in disease-specific or all-cause mortality; thus, longer-term follow-up is necessary,” Dr. Hamdy and his associates said (N Engl J Med. 2016 Sep 14. doi: 10.1056/NEJMoa1606220).

The trade-off was that 44% of the men assigned to active monitoring were able to forgo both radical surgery and radical radiotherapy, avoiding the adverse effects of those treatments. These included nine thromboembolic or cardiovascular events, 14 transfusions, one rectal injury, and nine anastomotic problems requiring intervention, they noted.

It is important to remember that approximately one-fourth of the men assigned to active monitoring went on to undergo radical treatment within 3 years, and that more than half did so by the 10-year follow-up date, the investigators added.

The second report focused on patient-reported outcomes concerning urinary, bowel, sexual, and quality-of-life issues in the 1,643 participants at 6 years of follow-up. These differed markedly among the three study groups, said Jenny L. Donovan, PhD, of the School of Social and Community Medicine, University of Bristol, U.K., and her associates.

Prostatectomy had a clear negative effect on urinary continence and sexual function, particularly erectile function, compared with radiotherapy and active monitoring. This peaked at 6 months after surgery, and though some patients recovered some function over time, urinary incontinence remained worse in the prostatectomy group than in the other two groups throughout follow-up. The use of absorbent pads rose from 1% at baseline to 46% at 6 months in the prostatectomy group. In comparison, the 6-month rate in the radiotherapy group rose to only 5% and that in the active-monitoring group to only 4%.

Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding, and nocturia than did the other two treatment approaches. However, many patients eventually showed considerable recovery on most of these measures, except that they continued to have bloody stools more frequently than did men who had prostatectomy or active monitoring.

Men in the active-monitoring group had substantially less difficulty with urinary, sexual, and bowel function, as expected. However, this gradually worsened over time as increasing numbers of these men eventually underwent radical treatments, Dr. Donovan and her associates wrote (N Engl J Med. 2016 Sep 14. doi: 10.1056/NEJMoa1606221).

Quality-of-life measures generally reflected these differences among the three study groups, “with some evidence of accommodation to changes over time.” General mental and physical health, cancer-specific quality of life, and anxiety and depression all were similar across the three groups at 6 years.

“Follow-up for an additional 5-10 years is required to fully inform decisions involving the trade-off between the shorter-term effects of the management strategies shown here and the longer course of progression and treatment of prostate cancer in the context of other life-threatening conditions,” they said.

The Protect trial was supported by the U.K. National Institute for Health Research Health Technology Assessment Programme, the University of Oxford, University Hospitals Bristol, the Oxford NIHR Biomedical Research Centre, and the Cancer Research U.K. Oxford Centre. Dr. Hamdy and Dr. Donovan and their associates reported having no relevant financial disclosures.

The three main approaches for treating localized prostate cancer – surgery, radiotherapy, or active monitoring – yield similar efficacy outcomes but different quality-of-life outcomes, according to two reports published on the New England Journal of Medicine.

Both reports present the findings of the ongoing Protect (Prostate Testing for Cancer and Treatment) trial, a large prospective, randomized trial in the United Kingdom comparing mortality and other health outcomes in men with PSA-detected localized disease. The trial involved 82,429 men aged 50-69 years who had a PSA test between 1999 and 2009, of whom 2,664 were found to have localized prostate cancer. A total of 1,643 of these participants agreed to be randomly assigned to radical prostatectomy (553 men), radical radiotherapy (545 men), or active monitoring (545 men).

©Mark Kostich/Thinkstock

“Active monitoring” involved avoiding any immediate therapy and regularly monitoring disease progression so that radical treatment with curative intent could be given if the need arose. Patients were monitored every 3 months for the first year, then every 6-12 months thereafter. This differs from “watchful waiting,” which doesn’t involve any plan for curative radical treatment if disease progresses.

The first report focused on mortality and disease progression in these 1,643 participants at a median of 10 years of follow-up. The primary outcome measure, prostate cancer–specific survival, was 98.8% or greater across all three study groups, and there was no significant difference among them. Thus, all three approaches yielded the same efficacy: prostate cancer–specific mortality of approximately 1%, said Freddie C. Hamdy, MD, of the Nuffield Department of Surgical Sciences, University of Oxford, and his associates.

However, the rate of disease progression among men assigned to surgery (8.9/1,000 person-years) or to radiotherapy (9.0/1,000 person-years) was less than half the rate among men assigned to active monitoring (22.9/1,000 person-years). The rate of metastasis followed this same pattern (2.4, 3.0, and 6.3 per 1,000 person-years, respectively).

“These differences show the effectiveness of immediate radical therapy over active monitoring, but they have not translated into significant differences – nor have they ruled out equivalence – in disease-specific or all-cause mortality; thus, longer-term follow-up is necessary,” Dr. Hamdy and his associates said (N Engl J Med. 2016 Sep 14. doi: 10.1056/NEJMoa1606220).

The trade-off was that 44% of the men assigned to active monitoring were able to forgo both radical surgery and radical radiotherapy, avoiding the adverse effects of those treatments. These included nine thromboembolic or cardiovascular events, 14 transfusions, one rectal injury, and nine anastomotic problems requiring intervention, they noted.

It is important to remember that approximately one-fourth of the men assigned to active monitoring went on to undergo radical treatment within 3 years, and that more than half did so by the 10-year follow-up date, the investigators added.

The second report focused on patient-reported outcomes concerning urinary, bowel, sexual, and quality-of-life issues in the 1,643 participants at 6 years of follow-up. These differed markedly among the three study groups, said Jenny L. Donovan, PhD, of the School of Social and Community Medicine, University of Bristol, U.K., and her associates.

Prostatectomy had a clear negative effect on urinary continence and sexual function, particularly erectile function, compared with radiotherapy and active monitoring. This peaked at 6 months after surgery, and though some patients recovered some function over time, urinary incontinence remained worse in the prostatectomy group than in the other two groups throughout follow-up. The use of absorbent pads rose from 1% at baseline to 46% at 6 months in the prostatectomy group. In comparison, the 6-month rate in the radiotherapy group rose to only 5% and that in the active-monitoring group to only 4%.

Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding, and nocturia than did the other two treatment approaches. However, many patients eventually showed considerable recovery on most of these measures, except that they continued to have bloody stools more frequently than did men who had prostatectomy or active monitoring.

Men in the active-monitoring group had substantially less difficulty with urinary, sexual, and bowel function, as expected. However, this gradually worsened over time as increasing numbers of these men eventually underwent radical treatments, Dr. Donovan and her associates wrote (N Engl J Med. 2016 Sep 14. doi: 10.1056/NEJMoa1606221).

Quality-of-life measures generally reflected these differences among the three study groups, “with some evidence of accommodation to changes over time.” General mental and physical health, cancer-specific quality of life, and anxiety and depression all were similar across the three groups at 6 years.

“Follow-up for an additional 5-10 years is required to fully inform decisions involving the trade-off between the shorter-term effects of the management strategies shown here and the longer course of progression and treatment of prostate cancer in the context of other life-threatening conditions,” they said.

The Protect trial was supported by the U.K. National Institute for Health Research Health Technology Assessment Programme, the University of Oxford, University Hospitals Bristol, the Oxford NIHR Biomedical Research Centre, and the Cancer Research U.K. Oxford Centre. Dr. Hamdy and Dr. Donovan and their associates reported having no relevant financial disclosures.

The three main approaches for treating localized prostate cancer – surgery, radiotherapy, or active monitoring – yield similar efficacy outcomes but different quality-of-life outcomes, according to two reports published on the New England Journal of Medicine.

Both reports present the findings of the ongoing Protect (Prostate Testing for Cancer and Treatment) trial, a large prospective, randomized trial in the United Kingdom comparing mortality and other health outcomes in men with PSA-detected localized disease. The trial involved 82,429 men aged 50-69 years who had a PSA test between 1999 and 2009, of whom 2,664 were found to have localized prostate cancer. A total of 1,643 of these participants agreed to be randomly assigned to radical prostatectomy (553 men), radical radiotherapy (545 men), or active monitoring (545 men).

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“Active monitoring” involved avoiding any immediate therapy and regularly monitoring disease progression so that radical treatment with curative intent could be given if the need arose. Patients were monitored every 3 months for the first year, then every 6-12 months thereafter. This differs from “watchful waiting,” which doesn’t involve any plan for curative radical treatment if disease progresses.

The first report focused on mortality and disease progression in these 1,643 participants at a median of 10 years of follow-up. The primary outcome measure, prostate cancer–specific survival, was 98.8% or greater across all three study groups, and there was no significant difference among them. Thus, all three approaches yielded the same efficacy: prostate cancer–specific mortality of approximately 1%, said Freddie C. Hamdy, MD, of the Nuffield Department of Surgical Sciences, University of Oxford, and his associates.

However, the rate of disease progression among men assigned to surgery (8.9/1,000 person-years) or to radiotherapy (9.0/1,000 person-years) was less than half the rate among men assigned to active monitoring (22.9/1,000 person-years). The rate of metastasis followed this same pattern (2.4, 3.0, and 6.3 per 1,000 person-years, respectively).

“These differences show the effectiveness of immediate radical therapy over active monitoring, but they have not translated into significant differences – nor have they ruled out equivalence – in disease-specific or all-cause mortality; thus, longer-term follow-up is necessary,” Dr. Hamdy and his associates said (N Engl J Med. 2016 Sep 14. doi: 10.1056/NEJMoa1606220).

The trade-off was that 44% of the men assigned to active monitoring were able to forgo both radical surgery and radical radiotherapy, avoiding the adverse effects of those treatments. These included nine thromboembolic or cardiovascular events, 14 transfusions, one rectal injury, and nine anastomotic problems requiring intervention, they noted.

It is important to remember that approximately one-fourth of the men assigned to active monitoring went on to undergo radical treatment within 3 years, and that more than half did so by the 10-year follow-up date, the investigators added.

The second report focused on patient-reported outcomes concerning urinary, bowel, sexual, and quality-of-life issues in the 1,643 participants at 6 years of follow-up. These differed markedly among the three study groups, said Jenny L. Donovan, PhD, of the School of Social and Community Medicine, University of Bristol, U.K., and her associates.

Prostatectomy had a clear negative effect on urinary continence and sexual function, particularly erectile function, compared with radiotherapy and active monitoring. This peaked at 6 months after surgery, and though some patients recovered some function over time, urinary incontinence remained worse in the prostatectomy group than in the other two groups throughout follow-up. The use of absorbent pads rose from 1% at baseline to 46% at 6 months in the prostatectomy group. In comparison, the 6-month rate in the radiotherapy group rose to only 5% and that in the active-monitoring group to only 4%.

Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding, and nocturia than did the other two treatment approaches. However, many patients eventually showed considerable recovery on most of these measures, except that they continued to have bloody stools more frequently than did men who had prostatectomy or active monitoring.

Men in the active-monitoring group had substantially less difficulty with urinary, sexual, and bowel function, as expected. However, this gradually worsened over time as increasing numbers of these men eventually underwent radical treatments, Dr. Donovan and her associates wrote (N Engl J Med. 2016 Sep 14. doi: 10.1056/NEJMoa1606221).

Quality-of-life measures generally reflected these differences among the three study groups, “with some evidence of accommodation to changes over time.” General mental and physical health, cancer-specific quality of life, and anxiety and depression all were similar across the three groups at 6 years.

“Follow-up for an additional 5-10 years is required to fully inform decisions involving the trade-off between the shorter-term effects of the management strategies shown here and the longer course of progression and treatment of prostate cancer in the context of other life-threatening conditions,” they said.

The Protect trial was supported by the U.K. National Institute for Health Research Health Technology Assessment Programme, the University of Oxford, University Hospitals Bristol, the Oxford NIHR Biomedical Research Centre, and the Cancer Research U.K. Oxford Centre. Dr. Hamdy and Dr. Donovan and their associates reported having no relevant financial disclosures.