The combination of nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine may be comparable in efficacy and safety to other chemotherapy combinations as first-line therapy for advanced or metastatic cholangiocarcinoma, but a phase 2 clinical trial failed to prove that hypothesis.

Among 74 patients with cholangiocarcinoma (CCA) treated with nab-paclitaxel and gemcitabine in a multicenter study, the 6-month progression-free survival (PFS) rate was 61%, which was lower than the 70% or higher rate required to confirm the trial’s primary endpoint, reported Vaibhav Sahai, MBBS, MS, of the University of Michigan in Ann Arbor, and his colleagues.

“Although the trial did not meet its primary efficacy endpoint, the PFS and OS [overall survival] were comparable to those of the gemcitabine plus cisplatin and gemcitabine plus oxaliplatin regimens in the ABC-02 and BINGO trials, respectively. As such, we conclude that combination nab-P and gemcitabine therapy is well tolerated and may be considered as an alternative regimen to current therapeutic approaches in advanced CCA,” they wrote. The report is in JAMA Oncology.

Recent evidence has suggested that nab-paclitaxel may potentiate the activity of gemcitabine by inhibiting cytidine deaminase, a gemcitabine-metabolizing enzyme, thereby allowing active metabolites of gemcitabine to accumulate in tumors, the author noted.

To see whether this observed synergy could translate into clinical benefit, they conducted a trial with 74 patients from 23 community and academic centers in the United States and Europe. The median patient age was 62 (range 36-87) years.

The patients received a median of six treatment cycles and were followed for a median of 10.2 months. Treatment consisted of intravenous nab-paclitaxel at a dose of 125mg/m², followed by gemcitabine 1,000 mg/m², on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.

The investigators explained the statistical design of the trial as follows:

“At completion, the trial required more than 43 of 67 evaluable patients to be alive and progression free at 6 months to conclude that the 6-month PFS rate was at least 70% (vs. a null hypothesis of 55%) based on historical data from the Advanced Biliary Cancer (ABC)–02 and BINGO (Gemcitabine and Oxaliplatin With or Without Cetuximab in Advanced Biliary-Tract Cancer) trials.”

As noted, the 6-month PFS rate in evaluable patients was 61%, which was not sufficient to either prove the alternative hypothesis or reject the null hypothesis.

Median PFS was 7.7 months, median time to progression was 7.7 months, and median overall survival was 12.4 months.

The confirmed best overall response rate was 30%, and the disease control rate was 66%.

In all, 72 of the 74 patients had a treatment-related adverse event, including fatigue in 52 patients, neutropenia in 50, and peripheral neuropathy in 41.

Grade 3 or greater adverse events occurred in 61 patients, with neutropenia in 32 patients as the most common treatment-related hematologic event, and grade 3 or greater fatigue in 10 patients as the most common nonhematologic event of grade 3 or greater.

“On the basis of the adverse event profile, nab-P plus gemcitabine treatment may be considered for patients who are not otherwise considered candidates for cisplatin-based therapy, specifically those with renal dysfunction,” the investigators wrote.

SOURCE: Sahai V et al. JAMA Oncol. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3277.

The combination of nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine may be comparable in efficacy and safety to other chemotherapy combinations as first-line therapy for advanced or metastatic cholangiocarcinoma, but a phase 2 clinical trial failed to prove that hypothesis.

Among 74 patients with cholangiocarcinoma (CCA) treated with nab-paclitaxel and gemcitabine in a multicenter study, the 6-month progression-free survival (PFS) rate was 61%, which was lower than the 70% or higher rate required to confirm the trial’s primary endpoint, reported Vaibhav Sahai, MBBS, MS, of the University of Michigan in Ann Arbor, and his colleagues.

“Although the trial did not meet its primary efficacy endpoint, the PFS and OS [overall survival] were comparable to those of the gemcitabine plus cisplatin and gemcitabine plus oxaliplatin regimens in the ABC-02 and BINGO trials, respectively. As such, we conclude that combination nab-P and gemcitabine therapy is well tolerated and may be considered as an alternative regimen to current therapeutic approaches in advanced CCA,” they wrote. The report is in JAMA Oncology.

Recent evidence has suggested that nab-paclitaxel may potentiate the activity of gemcitabine by inhibiting cytidine deaminase, a gemcitabine-metabolizing enzyme, thereby allowing active metabolites of gemcitabine to accumulate in tumors, the author noted.

To see whether this observed synergy could translate into clinical benefit, they conducted a trial with 74 patients from 23 community and academic centers in the United States and Europe. The median patient age was 62 (range 36-87) years.

The patients received a median of six treatment cycles and were followed for a median of 10.2 months. Treatment consisted of intravenous nab-paclitaxel at a dose of 125mg/m², followed by gemcitabine 1,000 mg/m², on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.

The investigators explained the statistical design of the trial as follows:

“At completion, the trial required more than 43 of 67 evaluable patients to be alive and progression free at 6 months to conclude that the 6-month PFS rate was at least 70% (vs. a null hypothesis of 55%) based on historical data from the Advanced Biliary Cancer (ABC)–02 and BINGO (Gemcitabine and Oxaliplatin With or Without Cetuximab in Advanced Biliary-Tract Cancer) trials.”

As noted, the 6-month PFS rate in evaluable patients was 61%, which was not sufficient to either prove the alternative hypothesis or reject the null hypothesis.

Median PFS was 7.7 months, median time to progression was 7.7 months, and median overall survival was 12.4 months.

The confirmed best overall response rate was 30%, and the disease control rate was 66%.

In all, 72 of the 74 patients had a treatment-related adverse event, including fatigue in 52 patients, neutropenia in 50, and peripheral neuropathy in 41.

Grade 3 or greater adverse events occurred in 61 patients, with neutropenia in 32 patients as the most common treatment-related hematologic event, and grade 3 or greater fatigue in 10 patients as the most common nonhematologic event of grade 3 or greater.

“On the basis of the adverse event profile, nab-P plus gemcitabine treatment may be considered for patients who are not otherwise considered candidates for cisplatin-based therapy, specifically those with renal dysfunction,” the investigators wrote.

SOURCE: Sahai V et al. JAMA Oncol. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3277.

The combination of nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine may be comparable in efficacy and safety to other chemotherapy combinations as first-line therapy for advanced or metastatic cholangiocarcinoma, but a phase 2 clinical trial failed to prove that hypothesis.

Among 74 patients with cholangiocarcinoma (CCA) treated with nab-paclitaxel and gemcitabine in a multicenter study, the 6-month progression-free survival (PFS) rate was 61%, which was lower than the 70% or higher rate required to confirm the trial’s primary endpoint, reported Vaibhav Sahai, MBBS, MS, of the University of Michigan in Ann Arbor, and his colleagues.

“Although the trial did not meet its primary efficacy endpoint, the PFS and OS [overall survival] were comparable to those of the gemcitabine plus cisplatin and gemcitabine plus oxaliplatin regimens in the ABC-02 and BINGO trials, respectively. As such, we conclude that combination nab-P and gemcitabine therapy is well tolerated and may be considered as an alternative regimen to current therapeutic approaches in advanced CCA,” they wrote. The report is in JAMA Oncology.

Recent evidence has suggested that nab-paclitaxel may potentiate the activity of gemcitabine by inhibiting cytidine deaminase, a gemcitabine-metabolizing enzyme, thereby allowing active metabolites of gemcitabine to accumulate in tumors, the author noted.

To see whether this observed synergy could translate into clinical benefit, they conducted a trial with 74 patients from 23 community and academic centers in the United States and Europe. The median patient age was 62 (range 36-87) years.

The patients received a median of six treatment cycles and were followed for a median of 10.2 months. Treatment consisted of intravenous nab-paclitaxel at a dose of 125mg/m², followed by gemcitabine 1,000 mg/m², on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.

The investigators explained the statistical design of the trial as follows:

“At completion, the trial required more than 43 of 67 evaluable patients to be alive and progression free at 6 months to conclude that the 6-month PFS rate was at least 70% (vs. a null hypothesis of 55%) based on historical data from the Advanced Biliary Cancer (ABC)–02 and BINGO (Gemcitabine and Oxaliplatin With or Without Cetuximab in Advanced Biliary-Tract Cancer) trials.”

As noted, the 6-month PFS rate in evaluable patients was 61%, which was not sufficient to either prove the alternative hypothesis or reject the null hypothesis.

Median PFS was 7.7 months, median time to progression was 7.7 months, and median overall survival was 12.4 months.

The confirmed best overall response rate was 30%, and the disease control rate was 66%.

In all, 72 of the 74 patients had a treatment-related adverse event, including fatigue in 52 patients, neutropenia in 50, and peripheral neuropathy in 41.

Grade 3 or greater adverse events occurred in 61 patients, with neutropenia in 32 patients as the most common treatment-related hematologic event, and grade 3 or greater fatigue in 10 patients as the most common nonhematologic event of grade 3 or greater.

“On the basis of the adverse event profile, nab-P plus gemcitabine treatment may be considered for patients who are not otherwise considered candidates for cisplatin-based therapy, specifically those with renal dysfunction,” the investigators wrote.

SOURCE: Sahai V et al. JAMA Oncol. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3277.

Young adults with autism – particularly those with no intellectual disability – are at a higher risk of depression than their counterparts without autism, according to results of a Swedish population-based study.

Furthermore, the study found that young adults with autism spectrum disorders (ASD) also are at an increased risk of depression than their nonautistic siblings, reported Dheeraj Rai, MRCPsych, PhD, and his coauthors on JAMA Network Open Psychiatry.

“Because of the likelihood of a substantial overrepresentation of depression among individuals with ASD, a greater focus on timely identification and management of depression is important considering that it is a potentially treatable cause of distress, disability, and suicidal behaviors,” wrote Dr. Rai of the Centre for Academic Mental Health at the University of Bristol (United Kingdom) and his coauthors.

Previously, the burden of depression was thought to be high among individuals with ASD, but this is only the second longitudinal study to demonstrate an increased depression risk in adults with ASD, compared with the general population, the investigators wrote.

The study, called the Stockholm Youth Cohort, included data on children and young people who lived in Stockholm County, Sweden, between 2001 and 2011. The cohort included a total of 223,842 individuals who were followed until they were aged at least 18 years, of whom 4,073 had a diagnosis of ASD (mean age, 21.5 years; 65.9% male).

A total of 19.8% of individuals with ASD received a depression diagnosis between the ages of 18 and 27, compared with 6% of individuals with no ASD diagnosis, investigators found.

Depression diagnosis was more likely in those who had ASD with no intellectual disability, with an adjusted risk ratio of 4.28 (95% confidence interval, 4.00-4.58), compared with 1.81 (95% CI, 1.51-2.17) for ASD with intellectual disability, they reported.

The investigators also identified siblings of individuals with ASD using data from a Swedish registry. Individuals with ASD had more than a twofold greater depression diagnosis risk, compared with nonautistic full siblings (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27).

“This association also seemed largely driven by an overrepresentation of depression in ASD without intellectual disability,” Dr. Rai and his coauthors wrote.

Those nonautistic siblings also had a somewhat higher risk of a depression diagnosis versus population controls, with adjusted risk ratios of 1.37 for full siblings and 1.42 for half siblings, they added.

Sibling comparisons in this study suggested “environmental pathways” in the association between autism and depression, according to authors.

“Studies identifying such pathways could assist in the development of preventive strategies or interventions,” they wrote.

Limitations of the study include the possibility of misclassification of depression diagnoses. Nevertheless, they said, the findings have implications for clinical practice and future research.

Dr. Rai reported receiving grants from The Baily Thomas Charitable Foundation, the National Institute for Health Research, and the Swedish Research Council for Health, Working Life and Welfare during the conduct of the study. His coauthors reported no other disclosures.

SOURCE: Rai D et al. JAMA Network Open. 2018 Aug 31. doi: 10.1001/jamanetworkopen.2018.1465.

Young adults with autism – particularly those with no intellectual disability – are at a higher risk of depression than their counterparts without autism, according to results of a Swedish population-based study.

Furthermore, the study found that young adults with autism spectrum disorders (ASD) also are at an increased risk of depression than their nonautistic siblings, reported Dheeraj Rai, MRCPsych, PhD, and his coauthors on JAMA Network Open Psychiatry.

“Because of the likelihood of a substantial overrepresentation of depression among individuals with ASD, a greater focus on timely identification and management of depression is important considering that it is a potentially treatable cause of distress, disability, and suicidal behaviors,” wrote Dr. Rai of the Centre for Academic Mental Health at the University of Bristol (United Kingdom) and his coauthors.

Previously, the burden of depression was thought to be high among individuals with ASD, but this is only the second longitudinal study to demonstrate an increased depression risk in adults with ASD, compared with the general population, the investigators wrote.

The study, called the Stockholm Youth Cohort, included data on children and young people who lived in Stockholm County, Sweden, between 2001 and 2011. The cohort included a total of 223,842 individuals who were followed until they were aged at least 18 years, of whom 4,073 had a diagnosis of ASD (mean age, 21.5 years; 65.9% male).

A total of 19.8% of individuals with ASD received a depression diagnosis between the ages of 18 and 27, compared with 6% of individuals with no ASD diagnosis, investigators found.

Depression diagnosis was more likely in those who had ASD with no intellectual disability, with an adjusted risk ratio of 4.28 (95% confidence interval, 4.00-4.58), compared with 1.81 (95% CI, 1.51-2.17) for ASD with intellectual disability, they reported.

The investigators also identified siblings of individuals with ASD using data from a Swedish registry. Individuals with ASD had more than a twofold greater depression diagnosis risk, compared with nonautistic full siblings (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27).

“This association also seemed largely driven by an overrepresentation of depression in ASD without intellectual disability,” Dr. Rai and his coauthors wrote.

Those nonautistic siblings also had a somewhat higher risk of a depression diagnosis versus population controls, with adjusted risk ratios of 1.37 for full siblings and 1.42 for half siblings, they added.

Sibling comparisons in this study suggested “environmental pathways” in the association between autism and depression, according to authors.

“Studies identifying such pathways could assist in the development of preventive strategies or interventions,” they wrote.

Limitations of the study include the possibility of misclassification of depression diagnoses. Nevertheless, they said, the findings have implications for clinical practice and future research.

Dr. Rai reported receiving grants from The Baily Thomas Charitable Foundation, the National Institute for Health Research, and the Swedish Research Council for Health, Working Life and Welfare during the conduct of the study. His coauthors reported no other disclosures.

SOURCE: Rai D et al. JAMA Network Open. 2018 Aug 31. doi: 10.1001/jamanetworkopen.2018.1465.

Young adults with autism – particularly those with no intellectual disability – are at a higher risk of depression than their counterparts without autism, according to results of a Swedish population-based study.

Furthermore, the study found that young adults with autism spectrum disorders (ASD) also are at an increased risk of depression than their nonautistic siblings, reported Dheeraj Rai, MRCPsych, PhD, and his coauthors on JAMA Network Open Psychiatry.

“Because of the likelihood of a substantial overrepresentation of depression among individuals with ASD, a greater focus on timely identification and management of depression is important considering that it is a potentially treatable cause of distress, disability, and suicidal behaviors,” wrote Dr. Rai of the Centre for Academic Mental Health at the University of Bristol (United Kingdom) and his coauthors.

Previously, the burden of depression was thought to be high among individuals with ASD, but this is only the second longitudinal study to demonstrate an increased depression risk in adults with ASD, compared with the general population, the investigators wrote.

The study, called the Stockholm Youth Cohort, included data on children and young people who lived in Stockholm County, Sweden, between 2001 and 2011. The cohort included a total of 223,842 individuals who were followed until they were aged at least 18 years, of whom 4,073 had a diagnosis of ASD (mean age, 21.5 years; 65.9% male).

A total of 19.8% of individuals with ASD received a depression diagnosis between the ages of 18 and 27, compared with 6% of individuals with no ASD diagnosis, investigators found.

Depression diagnosis was more likely in those who had ASD with no intellectual disability, with an adjusted risk ratio of 4.28 (95% confidence interval, 4.00-4.58), compared with 1.81 (95% CI, 1.51-2.17) for ASD with intellectual disability, they reported.

The investigators also identified siblings of individuals with ASD using data from a Swedish registry. Individuals with ASD had more than a twofold greater depression diagnosis risk, compared with nonautistic full siblings (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27).

“This association also seemed largely driven by an overrepresentation of depression in ASD without intellectual disability,” Dr. Rai and his coauthors wrote.

Those nonautistic siblings also had a somewhat higher risk of a depression diagnosis versus population controls, with adjusted risk ratios of 1.37 for full siblings and 1.42 for half siblings, they added.

Sibling comparisons in this study suggested “environmental pathways” in the association between autism and depression, according to authors.

“Studies identifying such pathways could assist in the development of preventive strategies or interventions,” they wrote.

Limitations of the study include the possibility of misclassification of depression diagnoses. Nevertheless, they said, the findings have implications for clinical practice and future research.

Dr. Rai reported receiving grants from The Baily Thomas Charitable Foundation, the National Institute for Health Research, and the Swedish Research Council for Health, Working Life and Welfare during the conduct of the study. His coauthors reported no other disclosures.

SOURCE: Rai D et al. JAMA Network Open. 2018 Aug 31. doi: 10.1001/jamanetworkopen.2018.1465.

CHICAGO—Lowering systolic blood pressure to a target of 120 mm Hg or less in people with cardiovascular risk factors reduces the risk of mild cognitive impairment (MCI) by 19% and reduces the risk of probable all-cause dementia by 17%, compared with achieving a less intensive target of lower than 140 mm Hg, according to research presented at AAIC 2018.

The class of antihypertensive did not affect the association. Generic drugs were as effective as branded drugs. Antihypertensive agents provided equal benefits to men, women, whites, blacks, and Hispanics. Furthermore, maintaining systolic blood pressure at 120 mm Hg or lower prevented MCI as well in patients older than 75 as it did in younger patients.

Jeff D. Williamson, MD, Chief of Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, presented the results of the four-year SPRINT MIND study. Strict blood pressure control (ie, a systolic target of 120 mm Hg or lower) for 3.2 years reduced the incidence of MCI to a greater extent than any amyloid-targeting investigational drug has done.

“This is the first disease-modifying strategy to reduce the risk of MCI,” said Dr. Williamson. Although the effect of strict blood pressure control on the primary end point (ie, a 17% risk reduction for probable all-cause dementia) was not statistically significant, “it is comforting to see that the benefit went in the same direction and was of the same magnitude,” said Dr. Williamson. “Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. Participants who underwent strict blood pressure control had 18% fewer white matter hyperintensities after four years of follow-up than other participants.

The results may represent a step forward in a field that has seen few of them recently. Generic antihypertensive agents can be inexpensive. They are widely available and confer benefits not only on cardiovascular health, but on kidney health as well, said Dr. Williamson.

“Hypertension is a highly prevalent condition…. The 19% overall risk reduction for MCI will have a huge impact,” he added.

“The most we can say right now is that we are able to reduce risk,” said Maria Carrillo, PhD, Chief Scientific Officer of the Alzheimer’s Association, in an interview. “Reducing the risk of MCI by 19% will have a huge impact on dementia overall. Slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, then I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

A Substudy of the SPRINT Trial

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target systolic blood pressure of less than 120 mm Hg, and the standard care strategy had a target of less than 140 mm Hg. SPRINT showed that intensive blood pressure control reduced the risk of cardiovascular events, stroke, and cardiovascular death by 30%. The study results helped inform the 2017 American Heart Association and American College of Cardiology clinical guidelines for treating high blood pressure.

The SPRINT MIND substudy examined whether intensive blood pressure management affected the risk of probable all-cause dementia or MCI or affected white matter lesion volume and brain volume.

The investigators examined data for 9,361 SPRINT subjects who were age 50 or older (mean age, 68) and had at least one cardiovascular risk factor. Approximately 30% of participants were black, and 10% were Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but were encouraged to use drugs with the strongest evidence of cardiovascular benefit. These drugs included thiazide-type diuretics, loop diuretics, and beta-adrenergic blockers. About 90% of the drugs used during the study were generic.

Subjects were seen monthly for the first three months. During this time, medications were adjusted to achieve the target blood pressure. After the third month, subjects were examined every three months. Medications could be adjusted monthly.

Results Favored Intensive Treatment

At one year, mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped early after a median follow-up of 3.26 years because of the observed cardiovascular disease benefit.

The SPRINT MIND study did not meet its primary end point. Incident probable all-cause dementia occurred in 175 people in the standard care group and 147 people in the intensive treatment group. The difference between groups in the rate of 17% risk reduction was not statistically significant.

The results for both secondary end points were significant, however. Incident MCI occurred in 348 participants in the standard treatment group and 285 participants in the intensive treatment group. The difference indicated a statistically significant 19% risk reduction associated with intensive treatment. Furthermore, intensive treatment significantly reduced the risk of the combined secondary end point of MCI and probable dementia by 15%. In all, 463 participants in the standard care group met this end point, compared with 398 in the intensive care group.

The imaging study included 454 subjects who had brain MRI at baseline and at four years after randomization. Total brain volume did not change, said Ilya Nasrallah, MD, Assistant Professor of Radiology at the University of Pennsylvania in Philadelphia. Patients in the intensively managed group, however, had 18% lower white matter lesion load than those in the standard care group.

White matter lesions often indicate small-vessel disease, which is associated with vascular dementia and, perhaps, Alzheimer’s disease. Most patients with Alzheimer’s disease have a mixed dementia that includes a vascular component, said Dr. Carrillo.

The Gravity of MCI

SPRINT MIND did not follow subjects for longer than four years or include follow-up for amyloid positivity or Alzheimer’s disease diagnosis. Nevertheless, preventing MCI is a significant achievement, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“There is nothing benign about MCI,” said Dr. Knopman. “It is the first sign of overt cognitive dysfunction, and although the rate at which MCI progresses to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think this study is going to change clinical practice for people in primary care, and the benefits at the population level are going to be substantial.”

Physicians may want to think about how the SPRINT MIND results might apply to younger patients with hypertension, whether they have other cardiovascular risk factors or not, said Dr. Williamson. “I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg and certainly start treating people in their 50s, and probably in their 40s,” he concluded.

—Michele G. Sullivan

Suggested Reading

SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.

CHICAGO—Lowering systolic blood pressure to a target of 120 mm Hg or less in people with cardiovascular risk factors reduces the risk of mild cognitive impairment (MCI) by 19% and reduces the risk of probable all-cause dementia by 17%, compared with achieving a less intensive target of lower than 140 mm Hg, according to research presented at AAIC 2018.

The class of antihypertensive did not affect the association. Generic drugs were as effective as branded drugs. Antihypertensive agents provided equal benefits to men, women, whites, blacks, and Hispanics. Furthermore, maintaining systolic blood pressure at 120 mm Hg or lower prevented MCI as well in patients older than 75 as it did in younger patients.

Jeff D. Williamson, MD, Chief of Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, presented the results of the four-year SPRINT MIND study. Strict blood pressure control (ie, a systolic target of 120 mm Hg or lower) for 3.2 years reduced the incidence of MCI to a greater extent than any amyloid-targeting investigational drug has done.

“This is the first disease-modifying strategy to reduce the risk of MCI,” said Dr. Williamson. Although the effect of strict blood pressure control on the primary end point (ie, a 17% risk reduction for probable all-cause dementia) was not statistically significant, “it is comforting to see that the benefit went in the same direction and was of the same magnitude,” said Dr. Williamson. “Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. Participants who underwent strict blood pressure control had 18% fewer white matter hyperintensities after four years of follow-up than other participants.

The results may represent a step forward in a field that has seen few of them recently. Generic antihypertensive agents can be inexpensive. They are widely available and confer benefits not only on cardiovascular health, but on kidney health as well, said Dr. Williamson.

“Hypertension is a highly prevalent condition…. The 19% overall risk reduction for MCI will have a huge impact,” he added.

“The most we can say right now is that we are able to reduce risk,” said Maria Carrillo, PhD, Chief Scientific Officer of the Alzheimer’s Association, in an interview. “Reducing the risk of MCI by 19% will have a huge impact on dementia overall. Slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, then I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

A Substudy of the SPRINT Trial

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target systolic blood pressure of less than 120 mm Hg, and the standard care strategy had a target of less than 140 mm Hg. SPRINT showed that intensive blood pressure control reduced the risk of cardiovascular events, stroke, and cardiovascular death by 30%. The study results helped inform the 2017 American Heart Association and American College of Cardiology clinical guidelines for treating high blood pressure.

The SPRINT MIND substudy examined whether intensive blood pressure management affected the risk of probable all-cause dementia or MCI or affected white matter lesion volume and brain volume.

The investigators examined data for 9,361 SPRINT subjects who were age 50 or older (mean age, 68) and had at least one cardiovascular risk factor. Approximately 30% of participants were black, and 10% were Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but were encouraged to use drugs with the strongest evidence of cardiovascular benefit. These drugs included thiazide-type diuretics, loop diuretics, and beta-adrenergic blockers. About 90% of the drugs used during the study were generic.

Subjects were seen monthly for the first three months. During this time, medications were adjusted to achieve the target blood pressure. After the third month, subjects were examined every three months. Medications could be adjusted monthly.

Results Favored Intensive Treatment

At one year, mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped early after a median follow-up of 3.26 years because of the observed cardiovascular disease benefit.

The SPRINT MIND study did not meet its primary end point. Incident probable all-cause dementia occurred in 175 people in the standard care group and 147 people in the intensive treatment group. The difference between groups in the rate of 17% risk reduction was not statistically significant.

The results for both secondary end points were significant, however. Incident MCI occurred in 348 participants in the standard treatment group and 285 participants in the intensive treatment group. The difference indicated a statistically significant 19% risk reduction associated with intensive treatment. Furthermore, intensive treatment significantly reduced the risk of the combined secondary end point of MCI and probable dementia by 15%. In all, 463 participants in the standard care group met this end point, compared with 398 in the intensive care group.

The imaging study included 454 subjects who had brain MRI at baseline and at four years after randomization. Total brain volume did not change, said Ilya Nasrallah, MD, Assistant Professor of Radiology at the University of Pennsylvania in Philadelphia. Patients in the intensively managed group, however, had 18% lower white matter lesion load than those in the standard care group.

White matter lesions often indicate small-vessel disease, which is associated with vascular dementia and, perhaps, Alzheimer’s disease. Most patients with Alzheimer’s disease have a mixed dementia that includes a vascular component, said Dr. Carrillo.

The Gravity of MCI

SPRINT MIND did not follow subjects for longer than four years or include follow-up for amyloid positivity or Alzheimer’s disease diagnosis. Nevertheless, preventing MCI is a significant achievement, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“There is nothing benign about MCI,” said Dr. Knopman. “It is the first sign of overt cognitive dysfunction, and although the rate at which MCI progresses to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think this study is going to change clinical practice for people in primary care, and the benefits at the population level are going to be substantial.”

Physicians may want to think about how the SPRINT MIND results might apply to younger patients with hypertension, whether they have other cardiovascular risk factors or not, said Dr. Williamson. “I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg and certainly start treating people in their 50s, and probably in their 40s,” he concluded.

—Michele G. Sullivan

Suggested Reading

SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.

CHICAGO—Lowering systolic blood pressure to a target of 120 mm Hg or less in people with cardiovascular risk factors reduces the risk of mild cognitive impairment (MCI) by 19% and reduces the risk of probable all-cause dementia by 17%, compared with achieving a less intensive target of lower than 140 mm Hg, according to research presented at AAIC 2018.

The class of antihypertensive did not affect the association. Generic drugs were as effective as branded drugs. Antihypertensive agents provided equal benefits to men, women, whites, blacks, and Hispanics. Furthermore, maintaining systolic blood pressure at 120 mm Hg or lower prevented MCI as well in patients older than 75 as it did in younger patients.

Jeff D. Williamson, MD, Chief of Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, presented the results of the four-year SPRINT MIND study. Strict blood pressure control (ie, a systolic target of 120 mm Hg or lower) for 3.2 years reduced the incidence of MCI to a greater extent than any amyloid-targeting investigational drug has done.

“This is the first disease-modifying strategy to reduce the risk of MCI,” said Dr. Williamson. Although the effect of strict blood pressure control on the primary end point (ie, a 17% risk reduction for probable all-cause dementia) was not statistically significant, “it is comforting to see that the benefit went in the same direction and was of the same magnitude,” said Dr. Williamson. “Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. Participants who underwent strict blood pressure control had 18% fewer white matter hyperintensities after four years of follow-up than other participants.

The results may represent a step forward in a field that has seen few of them recently. Generic antihypertensive agents can be inexpensive. They are widely available and confer benefits not only on cardiovascular health, but on kidney health as well, said Dr. Williamson.

“Hypertension is a highly prevalent condition…. The 19% overall risk reduction for MCI will have a huge impact,” he added.

“The most we can say right now is that we are able to reduce risk,” said Maria Carrillo, PhD, Chief Scientific Officer of the Alzheimer’s Association, in an interview. “Reducing the risk of MCI by 19% will have a huge impact on dementia overall. Slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, then I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

A Substudy of the SPRINT Trial

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target systolic blood pressure of less than 120 mm Hg, and the standard care strategy had a target of less than 140 mm Hg. SPRINT showed that intensive blood pressure control reduced the risk of cardiovascular events, stroke, and cardiovascular death by 30%. The study results helped inform the 2017 American Heart Association and American College of Cardiology clinical guidelines for treating high blood pressure.

The SPRINT MIND substudy examined whether intensive blood pressure management affected the risk of probable all-cause dementia or MCI or affected white matter lesion volume and brain volume.

The investigators examined data for 9,361 SPRINT subjects who were age 50 or older (mean age, 68) and had at least one cardiovascular risk factor. Approximately 30% of participants were black, and 10% were Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but were encouraged to use drugs with the strongest evidence of cardiovascular benefit. These drugs included thiazide-type diuretics, loop diuretics, and beta-adrenergic blockers. About 90% of the drugs used during the study were generic.

Subjects were seen monthly for the first three months. During this time, medications were adjusted to achieve the target blood pressure. After the third month, subjects were examined every three months. Medications could be adjusted monthly.

Results Favored Intensive Treatment

At one year, mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped early after a median follow-up of 3.26 years because of the observed cardiovascular disease benefit.

The SPRINT MIND study did not meet its primary end point. Incident probable all-cause dementia occurred in 175 people in the standard care group and 147 people in the intensive treatment group. The difference between groups in the rate of 17% risk reduction was not statistically significant.

The results for both secondary end points were significant, however. Incident MCI occurred in 348 participants in the standard treatment group and 285 participants in the intensive treatment group. The difference indicated a statistically significant 19% risk reduction associated with intensive treatment. Furthermore, intensive treatment significantly reduced the risk of the combined secondary end point of MCI and probable dementia by 15%. In all, 463 participants in the standard care group met this end point, compared with 398 in the intensive care group.

The imaging study included 454 subjects who had brain MRI at baseline and at four years after randomization. Total brain volume did not change, said Ilya Nasrallah, MD, Assistant Professor of Radiology at the University of Pennsylvania in Philadelphia. Patients in the intensively managed group, however, had 18% lower white matter lesion load than those in the standard care group.

White matter lesions often indicate small-vessel disease, which is associated with vascular dementia and, perhaps, Alzheimer’s disease. Most patients with Alzheimer’s disease have a mixed dementia that includes a vascular component, said Dr. Carrillo.

The Gravity of MCI

SPRINT MIND did not follow subjects for longer than four years or include follow-up for amyloid positivity or Alzheimer’s disease diagnosis. Nevertheless, preventing MCI is a significant achievement, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“There is nothing benign about MCI,” said Dr. Knopman. “It is the first sign of overt cognitive dysfunction, and although the rate at which MCI progresses to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think this study is going to change clinical practice for people in primary care, and the benefits at the population level are going to be substantial.”

Physicians may want to think about how the SPRINT MIND results might apply to younger patients with hypertension, whether they have other cardiovascular risk factors or not, said Dr. Williamson. “I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg and certainly start treating people in their 50s, and probably in their 40s,” he concluded.

—Michele G. Sullivan

Suggested Reading

SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.

Clinical question: Does prophylactic use of haloperidol increase survival in critically ill adults with high risk of delirium?

Background: Delirium is common and associated with high mortality. Studies evaluating prophylactic use of haloperidol have been inconclusive.

Study design: Randomized, double-blind, placebo-controlled, multicenter, investigator-driven study.

Setting: ICUs at university hospitals and teaching and nonteaching hospitals in the Netherlands.

Synopsis: 1,789 adults with mean age 66.6 years were randomized to receive either 1 or 2 mg of haloperidol or placebo. The 1-mg haloperidol group was prematurely stopped because of futility.

There was no difference in the primary outcome of survival days within a 28-day period between the 2-mg haloperidol group and the placebo group (hazard ratio, 1.003; 95% confidence interval, 0.78-1.30; P = .93).

Secondary outcome of survival was also the same at 90 days. No significant difference was seen in the delirium incidence, delirium- and coma-free days, and the delirium-related outcome measures.

Patients were already undergoing nonpharmacologic interventions for delirium prevention, and this likely attenuated the effects of haloperidol. The dose and duration of haloperidol used might have also been too low and short to have an effect on the outcomes considering the severity of patient illness.

Bottom line: Haloperidol has no role in prophylactic use to increase survival among critically ill patients with a high risk of delirium.

Citation: van den Boogaard M et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018 Feb 20;319(7):680-90.

Dr. Chikkanna is an assistant professor in the division of hospital medicine at the University of Kentucky, Lexington.

Clinical question: Does prophylactic use of haloperidol increase survival in critically ill adults with high risk of delirium?

Background: Delirium is common and associated with high mortality. Studies evaluating prophylactic use of haloperidol have been inconclusive.

Study design: Randomized, double-blind, placebo-controlled, multicenter, investigator-driven study.

Setting: ICUs at university hospitals and teaching and nonteaching hospitals in the Netherlands.

Synopsis: 1,789 adults with mean age 66.6 years were randomized to receive either 1 or 2 mg of haloperidol or placebo. The 1-mg haloperidol group was prematurely stopped because of futility.

There was no difference in the primary outcome of survival days within a 28-day period between the 2-mg haloperidol group and the placebo group (hazard ratio, 1.003; 95% confidence interval, 0.78-1.30; P = .93).

Secondary outcome of survival was also the same at 90 days. No significant difference was seen in the delirium incidence, delirium- and coma-free days, and the delirium-related outcome measures.

Patients were already undergoing nonpharmacologic interventions for delirium prevention, and this likely attenuated the effects of haloperidol. The dose and duration of haloperidol used might have also been too low and short to have an effect on the outcomes considering the severity of patient illness.

Bottom line: Haloperidol has no role in prophylactic use to increase survival among critically ill patients with a high risk of delirium.

Citation: van den Boogaard M et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018 Feb 20;319(7):680-90.

Dr. Chikkanna is an assistant professor in the division of hospital medicine at the University of Kentucky, Lexington.

Clinical question: Does prophylactic use of haloperidol increase survival in critically ill adults with high risk of delirium?

Background: Delirium is common and associated with high mortality. Studies evaluating prophylactic use of haloperidol have been inconclusive.

Study design: Randomized, double-blind, placebo-controlled, multicenter, investigator-driven study.

Setting: ICUs at university hospitals and teaching and nonteaching hospitals in the Netherlands.

Synopsis: 1,789 adults with mean age 66.6 years were randomized to receive either 1 or 2 mg of haloperidol or placebo. The 1-mg haloperidol group was prematurely stopped because of futility.

There was no difference in the primary outcome of survival days within a 28-day period between the 2-mg haloperidol group and the placebo group (hazard ratio, 1.003; 95% confidence interval, 0.78-1.30; P = .93).

Secondary outcome of survival was also the same at 90 days. No significant difference was seen in the delirium incidence, delirium- and coma-free days, and the delirium-related outcome measures.

Patients were already undergoing nonpharmacologic interventions for delirium prevention, and this likely attenuated the effects of haloperidol. The dose and duration of haloperidol used might have also been too low and short to have an effect on the outcomes considering the severity of patient illness.

Bottom line: Haloperidol has no role in prophylactic use to increase survival among critically ill patients with a high risk of delirium.

Citation: van den Boogaard M et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018 Feb 20;319(7):680-90.

Dr. Chikkanna is an assistant professor in the division of hospital medicine at the University of Kentucky, Lexington.

Both low-dose and full-dose rivaroxaban had superior benefit-risk profiles for extended VTE compared with aspirin. Also today, bone biopsy diagnostics for osteomyelitis vary widely, variation in bacterial drug susceptibility are tied to the risk of TB relapse, and CTA cuts MIs in patients with stable chest pain. Subscribe to the MDedge Daily News wherever you get your podcasts.
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Both low-dose and full-dose rivaroxaban had superior benefit-risk profiles for extended VTE compared with aspirin. Also today, bone biopsy diagnostics for osteomyelitis vary widely, variation in bacterial drug susceptibility are tied to the risk of TB relapse, and CTA cuts MIs in patients with stable chest pain. Subscribe to the MDedge Daily News wherever you get your podcasts.
Amazon Alexa
Apple Podcasts
Spotify

Both low-dose and full-dose rivaroxaban had superior benefit-risk profiles for extended VTE compared with aspirin. Also today, bone biopsy diagnostics for osteomyelitis vary widely, variation in bacterial drug susceptibility are tied to the risk of TB relapse, and CTA cuts MIs in patients with stable chest pain. Subscribe to the MDedge Daily News wherever you get your podcasts.
Amazon Alexa
Apple Podcasts
Spotify

The MDedge Cardiology team unpacks one of the world’s largest cardiology meetings from a Munich beer garden. Join MDedge reporters Bruce Jancin and Mitchel Zoler alongside MDedge Cardiology editor Catherine Hackett as they discuss practice changing data as well as what the world’s leading cardiologists are talking about.

The MDedge Cardiology team unpacks one of the world’s largest cardiology meetings from a Munich beer garden. Join MDedge reporters Bruce Jancin and Mitchel Zoler alongside MDedge Cardiology editor Catherine Hackett as they discuss practice changing data as well as what the world’s leading cardiologists are talking about.

The MDedge Cardiology team unpacks one of the world’s largest cardiology meetings from a Munich beer garden. Join MDedge reporters Bruce Jancin and Mitchel Zoler alongside MDedge Cardiology editor Catherine Hackett as they discuss practice changing data as well as what the world’s leading cardiologists are talking about.

Technical failures or adverse events complicated 4% of peroral endoscopic myotomies (POEMs) in a large single-center retrospective study.

Individual predictors of this composite negative outcome included case number, full-thickness myotomy, and procedure time, Zuqiang Liu, PhD, and his associates at Fudan University, Shanghai, China, wrote in the September issue of Clinical Gastroenterology and Hepatology.

After controlling for these risk factors, the composite rate of adverse events and technical failures dropped gradually after an endoscopist had performed his or her first 100 cases, according to the researchers. “Technical proficiency, demonstrated by plateauing of the procedure time, could be achieved after 70 cases,” they wrote. “The volume of cases required to manage challenging situations and prevent adverse events was thus higher than that needed for simple technical proficiency.” The experience of the training surgeon helped trainees gain technical proficiency faster, they added.

Peroral endoscopic myotomy (POEM) is minimally invasive and effectively treats spastic esophageal motility disorders. However, it is also a challenging procedure, and little is known about its learning curve. For the study, the researchers retrospectively reviewed technical failures and adverse events among 1,346 POEMs performed for achalasia at a single hospital in China between August 2010 and July 2015. They also assessed procedure time and a secondary composite outcome consisting of technical failure, adverse events, and clinical failure (further symptoms) for the first 192 cases performed by the original training surgeon.

There were 10 technical failures and 44 adverse events affecting a total of 54 patients (4%). Case number (P = .010), full-thickness myotomy (P = .002), and procedure time (P = .001) independently predicted this primary composite outcome. Adjusted cumulative sum analysis showed that the rate of this composite outcome decreased gradually after a surgeon had performed his or her first 100 cases. “The procedure time was high during the first few cases and decreased after endoscopists performed 70 cases,” indicating technical proficiency, the investigators wrote. The rate of the secondary composite outcome also fell gradually after the primary surgeon had performed between 90 and 100 cases.

For the first 192 cases performed by the lead surgeon, postprocedural follow-up time was typically 59 months, with a range of 3-71 months. Clinical failures occurred in 20 cases (10%). Rates of clinical failure were 6% at 1 year, 8% at 2 years, and 10% at 3 years.

This is the first study and the largest POEM database so far to assess the learning curve for this procedure by evaluating adverse events and clinical and technical failure, said the researchers. Previous studies consisted of small cases, usually of less than 100 patients each, they added. Such studies would inherently be biased because the smaller the caseload, the longer it might take for the learning curves of surgeons to plateau, they added.

Funders included the National Natural Science Foundation of China, the Major Project of Shanghai Municipal Science and Technology Committee, the Chen Guang Program of Shanghai Municipal Education Commission, and the Outstanding Young Doctor Training Project of Shanghai Municipal Commission of Health and Family Planning. The investigators reported having no relevant conflicts of interest.

SOURCE: Zuqiang L et al. Clin Gastroenterol Hepatol. 2017 Dec 5. doi: 10.1016/j.cgh.2017.11.048.

Technical failures or adverse events complicated 4% of peroral endoscopic myotomies (POEMs) in a large single-center retrospective study.

Individual predictors of this composite negative outcome included case number, full-thickness myotomy, and procedure time, Zuqiang Liu, PhD, and his associates at Fudan University, Shanghai, China, wrote in the September issue of Clinical Gastroenterology and Hepatology.

After controlling for these risk factors, the composite rate of adverse events and technical failures dropped gradually after an endoscopist had performed his or her first 100 cases, according to the researchers. “Technical proficiency, demonstrated by plateauing of the procedure time, could be achieved after 70 cases,” they wrote. “The volume of cases required to manage challenging situations and prevent adverse events was thus higher than that needed for simple technical proficiency.” The experience of the training surgeon helped trainees gain technical proficiency faster, they added.

Peroral endoscopic myotomy (POEM) is minimally invasive and effectively treats spastic esophageal motility disorders. However, it is also a challenging procedure, and little is known about its learning curve. For the study, the researchers retrospectively reviewed technical failures and adverse events among 1,346 POEMs performed for achalasia at a single hospital in China between August 2010 and July 2015. They also assessed procedure time and a secondary composite outcome consisting of technical failure, adverse events, and clinical failure (further symptoms) for the first 192 cases performed by the original training surgeon.

There were 10 technical failures and 44 adverse events affecting a total of 54 patients (4%). Case number (P = .010), full-thickness myotomy (P = .002), and procedure time (P = .001) independently predicted this primary composite outcome. Adjusted cumulative sum analysis showed that the rate of this composite outcome decreased gradually after a surgeon had performed his or her first 100 cases. “The procedure time was high during the first few cases and decreased after endoscopists performed 70 cases,” indicating technical proficiency, the investigators wrote. The rate of the secondary composite outcome also fell gradually after the primary surgeon had performed between 90 and 100 cases.

For the first 192 cases performed by the lead surgeon, postprocedural follow-up time was typically 59 months, with a range of 3-71 months. Clinical failures occurred in 20 cases (10%). Rates of clinical failure were 6% at 1 year, 8% at 2 years, and 10% at 3 years.

This is the first study and the largest POEM database so far to assess the learning curve for this procedure by evaluating adverse events and clinical and technical failure, said the researchers. Previous studies consisted of small cases, usually of less than 100 patients each, they added. Such studies would inherently be biased because the smaller the caseload, the longer it might take for the learning curves of surgeons to plateau, they added.

Funders included the National Natural Science Foundation of China, the Major Project of Shanghai Municipal Science and Technology Committee, the Chen Guang Program of Shanghai Municipal Education Commission, and the Outstanding Young Doctor Training Project of Shanghai Municipal Commission of Health and Family Planning. The investigators reported having no relevant conflicts of interest.

SOURCE: Zuqiang L et al. Clin Gastroenterol Hepatol. 2017 Dec 5. doi: 10.1016/j.cgh.2017.11.048.

Technical failures or adverse events complicated 4% of peroral endoscopic myotomies (POEMs) in a large single-center retrospective study.

Individual predictors of this composite negative outcome included case number, full-thickness myotomy, and procedure time, Zuqiang Liu, PhD, and his associates at Fudan University, Shanghai, China, wrote in the September issue of Clinical Gastroenterology and Hepatology.

After controlling for these risk factors, the composite rate of adverse events and technical failures dropped gradually after an endoscopist had performed his or her first 100 cases, according to the researchers. “Technical proficiency, demonstrated by plateauing of the procedure time, could be achieved after 70 cases,” they wrote. “The volume of cases required to manage challenging situations and prevent adverse events was thus higher than that needed for simple technical proficiency.” The experience of the training surgeon helped trainees gain technical proficiency faster, they added.

Peroral endoscopic myotomy (POEM) is minimally invasive and effectively treats spastic esophageal motility disorders. However, it is also a challenging procedure, and little is known about its learning curve. For the study, the researchers retrospectively reviewed technical failures and adverse events among 1,346 POEMs performed for achalasia at a single hospital in China between August 2010 and July 2015. They also assessed procedure time and a secondary composite outcome consisting of technical failure, adverse events, and clinical failure (further symptoms) for the first 192 cases performed by the original training surgeon.

There were 10 technical failures and 44 adverse events affecting a total of 54 patients (4%). Case number (P = .010), full-thickness myotomy (P = .002), and procedure time (P = .001) independently predicted this primary composite outcome. Adjusted cumulative sum analysis showed that the rate of this composite outcome decreased gradually after a surgeon had performed his or her first 100 cases. “The procedure time was high during the first few cases and decreased after endoscopists performed 70 cases,” indicating technical proficiency, the investigators wrote. The rate of the secondary composite outcome also fell gradually after the primary surgeon had performed between 90 and 100 cases.

For the first 192 cases performed by the lead surgeon, postprocedural follow-up time was typically 59 months, with a range of 3-71 months. Clinical failures occurred in 20 cases (10%). Rates of clinical failure were 6% at 1 year, 8% at 2 years, and 10% at 3 years.

This is the first study and the largest POEM database so far to assess the learning curve for this procedure by evaluating adverse events and clinical and technical failure, said the researchers. Previous studies consisted of small cases, usually of less than 100 patients each, they added. Such studies would inherently be biased because the smaller the caseload, the longer it might take for the learning curves of surgeons to plateau, they added.

Funders included the National Natural Science Foundation of China, the Major Project of Shanghai Municipal Science and Technology Committee, the Chen Guang Program of Shanghai Municipal Education Commission, and the Outstanding Young Doctor Training Project of Shanghai Municipal Commission of Health and Family Planning. The investigators reported having no relevant conflicts of interest.

SOURCE: Zuqiang L et al. Clin Gastroenterol Hepatol. 2017 Dec 5. doi: 10.1016/j.cgh.2017.11.048.

Patients with nonalcoholic fatty liver disease who consumed modest quantities of alcohol had significantly less improvement in steatosis and significantly lower odds of resolution of nonalcoholic steatohepatitis, compared with nondrinkers, according to the results of a longitudinal cohort study published in the Clinical Gastroenterology and Hepatology.

Kirby Hamilton/iStockphoto

Modest drinkers also had significantly less improvement in their AST levels, compared with nondrinkers, said Veeral Ajmera, MD, of the University of California, San Diego, and his associates. “Importantly, our results suggest that cessation of alcohol use may mitigate these changes,” they wrote. Clinicians should consider the spectrum of nonalcoholic fatty liver disease (NAFLD), and especially nonalcoholic steatohepatitis (NASH), when making recommendations about alcohol use. “More advanced NAFLD severity may warrant counseling against [even] modest alcohol use.”

More than one in three adults in the United States has NAFLD and about two-thirds drink alcohol, almost always in moderation, the researchers noted. Modest alcohol use has been linked to decreased cardiovascular risk, which is particularly relevant because patients with NAFLD tend to have risk factors for cardiovascular disease. Results from at least two cross-sectional studies also suggest modest drinkers with NAFLD have less severe histology, including less NASH and fibrosis. However, modest drinkers tend to be more physically active, with lower body mass indices, higher physical activity levels, and less obesity, which are potential confounders. To better understand the effects of modest alcohol consumption on NAFLD, the researchers studied adults with NAFLD who participated in studies conducted by the multicenter NASH Clinical Research Network.

The 285 participants were typically aged in their late 40s, female, white, and obese, with an average body mass index of 34.7 kg/m2. In all, 168 participants (59%) reported consuming up to two drinks per day, while 41% abstained from alcohol use. During an average of 47 months between biopsies (standard deviation, 26 months), nondrinkers averaged a 0.49 reduction in steatosis grade, significantly more than that of modest drinkers (reduction, 0.30; P = .04). Nondrinkers also had a greater decrease in mean AST level (7 U/L), compared with drinkers (2 U/L; P = .04).

A total of 64% of patients were classified as having definite NASH, 19% had NAFLD without NASH, and 17% had borderline NASH. At baseline, 23% of patients did not have fibrosis, 32% had stage 1 fibrosis, 21% had stage 2, 21% had stage 3, and 3% had stage 4. Modest drinkers were more likely to be white and were less likely to be diagnosed with definitive NASH at baseline. After controlling for these potential confounders, modest drinkers had significantly lower odds of NASH resolution, compared with nondrinkers (adjusted odds ratio, 0.32; 95% confidence interval, 0.11-0.92; P = .04).

“[The] presence of NASH has consistently been shown to predict increased risk for fibrosis progression, and therefore, our finding of less NASH resolution among consistent modest drinkers is clinically relevant,” the investigators wrote. “Although we were unable to assess the association between modest alcohol consumption and cardiovascular risk, we did not see any significant changes in measured metabolic risk factors with known associations with cardiovascular disease including low-density lipoprotein and high-density lipoprotein cholesterol and insulin resistance.”

Funders of the study included the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, the Advanced/Transplant Hepatology Fellowship, the American Association for the Study of Liver Diseases Foundation, and the Intramural Research Program of the National Institutes of Health.

SOURCE: Ajmera V et al. Clin Gastroenterol Hepatol. 2018 Mar 14. doi: 10.1016/j.cgh.2018.01.026.

Patients with nonalcoholic fatty liver disease who consumed modest quantities of alcohol had significantly less improvement in steatosis and significantly lower odds of resolution of nonalcoholic steatohepatitis, compared with nondrinkers, according to the results of a longitudinal cohort study published in the Clinical Gastroenterology and Hepatology.

Kirby Hamilton/iStockphoto

Modest drinkers also had significantly less improvement in their AST levels, compared with nondrinkers, said Veeral Ajmera, MD, of the University of California, San Diego, and his associates. “Importantly, our results suggest that cessation of alcohol use may mitigate these changes,” they wrote. Clinicians should consider the spectrum of nonalcoholic fatty liver disease (NAFLD), and especially nonalcoholic steatohepatitis (NASH), when making recommendations about alcohol use. “More advanced NAFLD severity may warrant counseling against [even] modest alcohol use.”

More than one in three adults in the United States has NAFLD and about two-thirds drink alcohol, almost always in moderation, the researchers noted. Modest alcohol use has been linked to decreased cardiovascular risk, which is particularly relevant because patients with NAFLD tend to have risk factors for cardiovascular disease. Results from at least two cross-sectional studies also suggest modest drinkers with NAFLD have less severe histology, including less NASH and fibrosis. However, modest drinkers tend to be more physically active, with lower body mass indices, higher physical activity levels, and less obesity, which are potential confounders. To better understand the effects of modest alcohol consumption on NAFLD, the researchers studied adults with NAFLD who participated in studies conducted by the multicenter NASH Clinical Research Network.

The 285 participants were typically aged in their late 40s, female, white, and obese, with an average body mass index of 34.7 kg/m2. In all, 168 participants (59%) reported consuming up to two drinks per day, while 41% abstained from alcohol use. During an average of 47 months between biopsies (standard deviation, 26 months), nondrinkers averaged a 0.49 reduction in steatosis grade, significantly more than that of modest drinkers (reduction, 0.30; P = .04). Nondrinkers also had a greater decrease in mean AST level (7 U/L), compared with drinkers (2 U/L; P = .04).

A total of 64% of patients were classified as having definite NASH, 19% had NAFLD without NASH, and 17% had borderline NASH. At baseline, 23% of patients did not have fibrosis, 32% had stage 1 fibrosis, 21% had stage 2, 21% had stage 3, and 3% had stage 4. Modest drinkers were more likely to be white and were less likely to be diagnosed with definitive NASH at baseline. After controlling for these potential confounders, modest drinkers had significantly lower odds of NASH resolution, compared with nondrinkers (adjusted odds ratio, 0.32; 95% confidence interval, 0.11-0.92; P = .04).

“[The] presence of NASH has consistently been shown to predict increased risk for fibrosis progression, and therefore, our finding of less NASH resolution among consistent modest drinkers is clinically relevant,” the investigators wrote. “Although we were unable to assess the association between modest alcohol consumption and cardiovascular risk, we did not see any significant changes in measured metabolic risk factors with known associations with cardiovascular disease including low-density lipoprotein and high-density lipoprotein cholesterol and insulin resistance.”

Funders of the study included the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, the Advanced/Transplant Hepatology Fellowship, the American Association for the Study of Liver Diseases Foundation, and the Intramural Research Program of the National Institutes of Health.

SOURCE: Ajmera V et al. Clin Gastroenterol Hepatol. 2018 Mar 14. doi: 10.1016/j.cgh.2018.01.026.

Patients with nonalcoholic fatty liver disease who consumed modest quantities of alcohol had significantly less improvement in steatosis and significantly lower odds of resolution of nonalcoholic steatohepatitis, compared with nondrinkers, according to the results of a longitudinal cohort study published in the Clinical Gastroenterology and Hepatology.

Kirby Hamilton/iStockphoto

Modest drinkers also had significantly less improvement in their AST levels, compared with nondrinkers, said Veeral Ajmera, MD, of the University of California, San Diego, and his associates. “Importantly, our results suggest that cessation of alcohol use may mitigate these changes,” they wrote. Clinicians should consider the spectrum of nonalcoholic fatty liver disease (NAFLD), and especially nonalcoholic steatohepatitis (NASH), when making recommendations about alcohol use. “More advanced NAFLD severity may warrant counseling against [even] modest alcohol use.”

More than one in three adults in the United States has NAFLD and about two-thirds drink alcohol, almost always in moderation, the researchers noted. Modest alcohol use has been linked to decreased cardiovascular risk, which is particularly relevant because patients with NAFLD tend to have risk factors for cardiovascular disease. Results from at least two cross-sectional studies also suggest modest drinkers with NAFLD have less severe histology, including less NASH and fibrosis. However, modest drinkers tend to be more physically active, with lower body mass indices, higher physical activity levels, and less obesity, which are potential confounders. To better understand the effects of modest alcohol consumption on NAFLD, the researchers studied adults with NAFLD who participated in studies conducted by the multicenter NASH Clinical Research Network.

The 285 participants were typically aged in their late 40s, female, white, and obese, with an average body mass index of 34.7 kg/m2. In all, 168 participants (59%) reported consuming up to two drinks per day, while 41% abstained from alcohol use. During an average of 47 months between biopsies (standard deviation, 26 months), nondrinkers averaged a 0.49 reduction in steatosis grade, significantly more than that of modest drinkers (reduction, 0.30; P = .04). Nondrinkers also had a greater decrease in mean AST level (7 U/L), compared with drinkers (2 U/L; P = .04).

A total of 64% of patients were classified as having definite NASH, 19% had NAFLD without NASH, and 17% had borderline NASH. At baseline, 23% of patients did not have fibrosis, 32% had stage 1 fibrosis, 21% had stage 2, 21% had stage 3, and 3% had stage 4. Modest drinkers were more likely to be white and were less likely to be diagnosed with definitive NASH at baseline. After controlling for these potential confounders, modest drinkers had significantly lower odds of NASH resolution, compared with nondrinkers (adjusted odds ratio, 0.32; 95% confidence interval, 0.11-0.92; P = .04).

“[The] presence of NASH has consistently been shown to predict increased risk for fibrosis progression, and therefore, our finding of less NASH resolution among consistent modest drinkers is clinically relevant,” the investigators wrote. “Although we were unable to assess the association between modest alcohol consumption and cardiovascular risk, we did not see any significant changes in measured metabolic risk factors with known associations with cardiovascular disease including low-density lipoprotein and high-density lipoprotein cholesterol and insulin resistance.”

Funders of the study included the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, the Advanced/Transplant Hepatology Fellowship, the American Association for the Study of Liver Diseases Foundation, and the Intramural Research Program of the National Institutes of Health.

SOURCE: Ajmera V et al. Clin Gastroenterol Hepatol. 2018 Mar 14. doi: 10.1016/j.cgh.2018.01.026.

Long-term pancreatic surveillance of high-risk patients identified cancers while they were still resectable, and 85% of such patients remained alive 3 years after diagnosis, researchers reported.

iStock/ThinkStock

“Among individuals undergoing pancreatic surveillance, specific detectable lesions with worrisome features predicted neoplastic progression. The short-term outcomes of patients with screening-detected PDACs [pancreatic ductal adenocarcinomas] improved,” wrote Marcia Irene Canto, MD, MHS, of the Johns Hopkins University, Baltimore, together with her associates in the September issue of Gastroenterology.

The lifetime risk of PDAC is about 1.5%, the researchers noted. Consequently, the U.S. Preventive Services Task Force does not recommend pancreatic surveillance at a population level. However, pancreatic screening is being evaluated for individuals who are at significantly elevated risk of PDAC, including those with at least two first-degree relatives with PDAC or who have germline mutations in BRCA1, BRCA2, PALB2, PRSS1 (hereditary pancreatitis), CDKN2A, MLH1, MSH2, MSH6, PMS2 (Lynch syndrome), or STK11 (Peutz-Jeghers syndrome).

For the study, Dr. Canto and her associates analyzed data from 354 such high-risk individuals enrolled in the CAPS (Cancer of the Pancreas Screening) cohort studies, which were conducted at tertiary care academic centers during 1998-2014. All participants underwent endoscopic ultrasound at baseline, followed by surveillance with endoscopic ultrasound, magnetic resonance imaging, computed tomography, or some combination of these modalities. Patients who developed pancreatic cancer or high-grade dysplasia were offered surgery.

In all, 68 patients (19%) developed pancreatic lesions with worrisome features, such as solid masses, multiple cysts, mural nodules, thickened or enhancing walls, cysts exceeding 3 cm in size or that grew more than 4 mm annually, a greater than 5-mm dilation of the main pancreatic duct, or an abrupt change in duct caliber. The lesions developed over a median of 13.1 months (interquartile range, 0.2-52 months).

A total of 7% of patients had neoplastic progression, including 14 cases of PDAC and 10 cases of high-grade dysplasia. Median times from baseline to detection of PDAC were 4.8 years overall (IQR, 1.6-6.9 years), 1.7 years (IQR, 0.5-4.4 years) among patients aged at least 60 years at baseline, and 5.2 years among younger patients (IQR, 0.4-8 years). Patients developed PDAC at a median of 67 years old.

Among 10 PDACs detected by surveillance, 9 were resectable. Three patients subsequently died of PDAC, while one patient died of complications of gastric cancer surgery. However, 85% of patients survived for at least 3 years after surgical resection of PDAC. The remaining four cases of PDAC were detected outside surveillance or after patients stopped surveillance.

The 10 cases of high-grade dysplasia consisted of intraductal papillary mucinous neoplasm with high-grade dysplasia or high-grade pancreatic intraepithelial neoplasia. Patients whose PDAC or high-grade dysplasia was detected by surveillance survived a median of 5.3 years, while patients whose surveillance was late or stopped and who subsequently developed neoplasia survived a median of only 1.4 years after diagnosis (P less than .0001).

Funders included the Pancreatic Cancer Action Network, Lustgarten Foundation for Pancreatic Cancer Research, the John and Peter Hooven Memorial Endowment, Hugh and Rachel Victor, and ChiRhoClin. Dr. Canto had no disclosures. Three coinvestigators disclosed royalties for licensing of PALB2 as a pancreatic cancer susceptibility gene.

SOURCE: Canto MI et al. Gastroenterology. 2018 May 24. doi: 10.1053/j.gastro.2018.05.035

Long-term pancreatic surveillance of high-risk patients identified cancers while they were still resectable, and 85% of such patients remained alive 3 years after diagnosis, researchers reported.

iStock/ThinkStock

“Among individuals undergoing pancreatic surveillance, specific detectable lesions with worrisome features predicted neoplastic progression. The short-term outcomes of patients with screening-detected PDACs [pancreatic ductal adenocarcinomas] improved,” wrote Marcia Irene Canto, MD, MHS, of the Johns Hopkins University, Baltimore, together with her associates in the September issue of Gastroenterology.

The lifetime risk of PDAC is about 1.5%, the researchers noted. Consequently, the U.S. Preventive Services Task Force does not recommend pancreatic surveillance at a population level. However, pancreatic screening is being evaluated for individuals who are at significantly elevated risk of PDAC, including those with at least two first-degree relatives with PDAC or who have germline mutations in BRCA1, BRCA2, PALB2, PRSS1 (hereditary pancreatitis), CDKN2A, MLH1, MSH2, MSH6, PMS2 (Lynch syndrome), or STK11 (Peutz-Jeghers syndrome).

For the study, Dr. Canto and her associates analyzed data from 354 such high-risk individuals enrolled in the CAPS (Cancer of the Pancreas Screening) cohort studies, which were conducted at tertiary care academic centers during 1998-2014. All participants underwent endoscopic ultrasound at baseline, followed by surveillance with endoscopic ultrasound, magnetic resonance imaging, computed tomography, or some combination of these modalities. Patients who developed pancreatic cancer or high-grade dysplasia were offered surgery.

In all, 68 patients (19%) developed pancreatic lesions with worrisome features, such as solid masses, multiple cysts, mural nodules, thickened or enhancing walls, cysts exceeding 3 cm in size or that grew more than 4 mm annually, a greater than 5-mm dilation of the main pancreatic duct, or an abrupt change in duct caliber. The lesions developed over a median of 13.1 months (interquartile range, 0.2-52 months).

A total of 7% of patients had neoplastic progression, including 14 cases of PDAC and 10 cases of high-grade dysplasia. Median times from baseline to detection of PDAC were 4.8 years overall (IQR, 1.6-6.9 years), 1.7 years (IQR, 0.5-4.4 years) among patients aged at least 60 years at baseline, and 5.2 years among younger patients (IQR, 0.4-8 years). Patients developed PDAC at a median of 67 years old.

Among 10 PDACs detected by surveillance, 9 were resectable. Three patients subsequently died of PDAC, while one patient died of complications of gastric cancer surgery. However, 85% of patients survived for at least 3 years after surgical resection of PDAC. The remaining four cases of PDAC were detected outside surveillance or after patients stopped surveillance.

The 10 cases of high-grade dysplasia consisted of intraductal papillary mucinous neoplasm with high-grade dysplasia or high-grade pancreatic intraepithelial neoplasia. Patients whose PDAC or high-grade dysplasia was detected by surveillance survived a median of 5.3 years, while patients whose surveillance was late or stopped and who subsequently developed neoplasia survived a median of only 1.4 years after diagnosis (P less than .0001).

Funders included the Pancreatic Cancer Action Network, Lustgarten Foundation for Pancreatic Cancer Research, the John and Peter Hooven Memorial Endowment, Hugh and Rachel Victor, and ChiRhoClin. Dr. Canto had no disclosures. Three coinvestigators disclosed royalties for licensing of PALB2 as a pancreatic cancer susceptibility gene.

SOURCE: Canto MI et al. Gastroenterology. 2018 May 24. doi: 10.1053/j.gastro.2018.05.035

Long-term pancreatic surveillance of high-risk patients identified cancers while they were still resectable, and 85% of such patients remained alive 3 years after diagnosis, researchers reported.

iStock/ThinkStock

“Among individuals undergoing pancreatic surveillance, specific detectable lesions with worrisome features predicted neoplastic progression. The short-term outcomes of patients with screening-detected PDACs [pancreatic ductal adenocarcinomas] improved,” wrote Marcia Irene Canto, MD, MHS, of the Johns Hopkins University, Baltimore, together with her associates in the September issue of Gastroenterology.

The lifetime risk of PDAC is about 1.5%, the researchers noted. Consequently, the U.S. Preventive Services Task Force does not recommend pancreatic surveillance at a population level. However, pancreatic screening is being evaluated for individuals who are at significantly elevated risk of PDAC, including those with at least two first-degree relatives with PDAC or who have germline mutations in BRCA1, BRCA2, PALB2, PRSS1 (hereditary pancreatitis), CDKN2A, MLH1, MSH2, MSH6, PMS2 (Lynch syndrome), or STK11 (Peutz-Jeghers syndrome).

For the study, Dr. Canto and her associates analyzed data from 354 such high-risk individuals enrolled in the CAPS (Cancer of the Pancreas Screening) cohort studies, which were conducted at tertiary care academic centers during 1998-2014. All participants underwent endoscopic ultrasound at baseline, followed by surveillance with endoscopic ultrasound, magnetic resonance imaging, computed tomography, or some combination of these modalities. Patients who developed pancreatic cancer or high-grade dysplasia were offered surgery.

In all, 68 patients (19%) developed pancreatic lesions with worrisome features, such as solid masses, multiple cysts, mural nodules, thickened or enhancing walls, cysts exceeding 3 cm in size or that grew more than 4 mm annually, a greater than 5-mm dilation of the main pancreatic duct, or an abrupt change in duct caliber. The lesions developed over a median of 13.1 months (interquartile range, 0.2-52 months).

A total of 7% of patients had neoplastic progression, including 14 cases of PDAC and 10 cases of high-grade dysplasia. Median times from baseline to detection of PDAC were 4.8 years overall (IQR, 1.6-6.9 years), 1.7 years (IQR, 0.5-4.4 years) among patients aged at least 60 years at baseline, and 5.2 years among younger patients (IQR, 0.4-8 years). Patients developed PDAC at a median of 67 years old.

Among 10 PDACs detected by surveillance, 9 were resectable. Three patients subsequently died of PDAC, while one patient died of complications of gastric cancer surgery. However, 85% of patients survived for at least 3 years after surgical resection of PDAC. The remaining four cases of PDAC were detected outside surveillance or after patients stopped surveillance.

The 10 cases of high-grade dysplasia consisted of intraductal papillary mucinous neoplasm with high-grade dysplasia or high-grade pancreatic intraepithelial neoplasia. Patients whose PDAC or high-grade dysplasia was detected by surveillance survived a median of 5.3 years, while patients whose surveillance was late or stopped and who subsequently developed neoplasia survived a median of only 1.4 years after diagnosis (P less than .0001).

Funders included the Pancreatic Cancer Action Network, Lustgarten Foundation for Pancreatic Cancer Research, the John and Peter Hooven Memorial Endowment, Hugh and Rachel Victor, and ChiRhoClin. Dr. Canto had no disclosures. Three coinvestigators disclosed royalties for licensing of PALB2 as a pancreatic cancer susceptibility gene.

SOURCE: Canto MI et al. Gastroenterology. 2018 May 24. doi: 10.1053/j.gastro.2018.05.035

To help, the National Center for Complementary and Integrative Health has turned its “Herbs at a Glance” webpage into an app: HerbList™. The app gives research-based information on safety, effectiveness, and side effects of kava, açai, ginkgo, turmeric, and > 50 other herbs and herbal supplements marketed for health purposes.

HerbList is available to download from Apple App Store and Google Play.

To help, the National Center for Complementary and Integrative Health has turned its “Herbs at a Glance” webpage into an app: HerbList™. The app gives research-based information on safety, effectiveness, and side effects of kava, açai, ginkgo, turmeric, and > 50 other herbs and herbal supplements marketed for health purposes.

HerbList is available to download from Apple App Store and Google Play.

To help, the National Center for Complementary and Integrative Health has turned its “Herbs at a Glance” webpage into an app: HerbList™. The app gives research-based information on safety, effectiveness, and side effects of kava, açai, ginkgo, turmeric, and > 50 other herbs and herbal supplements marketed for health purposes.

HerbList is available to download from Apple App Store and Google Play.