Pharmacology

Sodium-glucose cotransporter 2 inhibitors do not appear to increase the risk of urinary tract infections, compared with other antidiabetic medications, new research has found.

In a paper published in Annals of Internal Medicine, researchers reported the outcomes of a population-based, propensity-matched cohort study in which the analyzed data from 235,730 individuals newly prescribed sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase–4 (DPP-4) inhibitors, and glucagonlike peptide–1 receptor (GLP-1) agonists.

In the first cohort, comparing SGLT-2 inhibitors with DDP-4 inhibitors, there were no significant differences between the two groups in the incidence rate of severe urinary tract infections (UTIs) (adjusted hazard ratio, 0.98; 95% confidence interval, 0.68-1.41).

In the second cohort, which compared patients taking GLP-1 receptor agonists with those taking SGLT-2 inhibitors, researchers saw a slightly lower incidence of severe UTIs among individuals on SGLT-2 inhibitors (HR, 0.72; 95% CI, 0.53-0.99; P = .04).

The analysis also failed to find any evidence that SGLT-2 inhibitors were associated with an increase in the risk of hospitalization or outpatient treatment for a UTI.

Chintan V. Dave, PharmD – now at Rutgers University, New Brunswick, N.J. – and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote that the findings have significant clinical implications.

“Patients who may be good candidates to receive SGLT-2 inhibitors for diabetes control but who have a history of recurrent UTIs may be precluded from being prescribed these agents; because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death,” they wrote.

The researchers stressed that “other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes.”

The authors did note that their study was subject to the usual limitations of observational studies, such as susceptibility to confounding, and was also limited to people with health insurance.

An accompanying editorial by Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University, Montreal, commented that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.

However, they also stressed that the study excluded individuals at high risk or with a history of UTIs, and that these were subgroups who required further investigation.

The study was supported by the Harvard Medical School and the National Institute on Aging. Three authors reported support from private industry outside the submitted work.

SOURCE: Dave CV et al. Ann Intern Med. 2019 Jul 29. doi: 10.7326/M18-3136.

Sodium-glucose cotransporter 2 inhibitors do not appear to increase the risk of urinary tract infections, compared with other antidiabetic medications, new research has found.

In a paper published in Annals of Internal Medicine, researchers reported the outcomes of a population-based, propensity-matched cohort study in which the analyzed data from 235,730 individuals newly prescribed sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase–4 (DPP-4) inhibitors, and glucagonlike peptide–1 receptor (GLP-1) agonists.

In the first cohort, comparing SGLT-2 inhibitors with DDP-4 inhibitors, there were no significant differences between the two groups in the incidence rate of severe urinary tract infections (UTIs) (adjusted hazard ratio, 0.98; 95% confidence interval, 0.68-1.41).

In the second cohort, which compared patients taking GLP-1 receptor agonists with those taking SGLT-2 inhibitors, researchers saw a slightly lower incidence of severe UTIs among individuals on SGLT-2 inhibitors (HR, 0.72; 95% CI, 0.53-0.99; P = .04).

The analysis also failed to find any evidence that SGLT-2 inhibitors were associated with an increase in the risk of hospitalization or outpatient treatment for a UTI.

Chintan V. Dave, PharmD – now at Rutgers University, New Brunswick, N.J. – and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote that the findings have significant clinical implications.

“Patients who may be good candidates to receive SGLT-2 inhibitors for diabetes control but who have a history of recurrent UTIs may be precluded from being prescribed these agents; because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death,” they wrote.

The researchers stressed that “other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes.”

The authors did note that their study was subject to the usual limitations of observational studies, such as susceptibility to confounding, and was also limited to people with health insurance.

An accompanying editorial by Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University, Montreal, commented that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.

However, they also stressed that the study excluded individuals at high risk or with a history of UTIs, and that these were subgroups who required further investigation.

The study was supported by the Harvard Medical School and the National Institute on Aging. Three authors reported support from private industry outside the submitted work.

SOURCE: Dave CV et al. Ann Intern Med. 2019 Jul 29. doi: 10.7326/M18-3136.

Sodium-glucose cotransporter 2 inhibitors do not appear to increase the risk of urinary tract infections, compared with other antidiabetic medications, new research has found.

In a paper published in Annals of Internal Medicine, researchers reported the outcomes of a population-based, propensity-matched cohort study in which the analyzed data from 235,730 individuals newly prescribed sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase–4 (DPP-4) inhibitors, and glucagonlike peptide–1 receptor (GLP-1) agonists.

In the first cohort, comparing SGLT-2 inhibitors with DDP-4 inhibitors, there were no significant differences between the two groups in the incidence rate of severe urinary tract infections (UTIs) (adjusted hazard ratio, 0.98; 95% confidence interval, 0.68-1.41).

In the second cohort, which compared patients taking GLP-1 receptor agonists with those taking SGLT-2 inhibitors, researchers saw a slightly lower incidence of severe UTIs among individuals on SGLT-2 inhibitors (HR, 0.72; 95% CI, 0.53-0.99; P = .04).

The analysis also failed to find any evidence that SGLT-2 inhibitors were associated with an increase in the risk of hospitalization or outpatient treatment for a UTI.

Chintan V. Dave, PharmD – now at Rutgers University, New Brunswick, N.J. – and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote that the findings have significant clinical implications.

“Patients who may be good candidates to receive SGLT-2 inhibitors for diabetes control but who have a history of recurrent UTIs may be precluded from being prescribed these agents; because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death,” they wrote.

The researchers stressed that “other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes.”

The authors did note that their study was subject to the usual limitations of observational studies, such as susceptibility to confounding, and was also limited to people with health insurance.

An accompanying editorial by Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University, Montreal, commented that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.

However, they also stressed that the study excluded individuals at high risk or with a history of UTIs, and that these were subgroups who required further investigation.

The study was supported by the Harvard Medical School and the National Institute on Aging. Three authors reported support from private industry outside the submitted work.

SOURCE: Dave CV et al. Ann Intern Med. 2019 Jul 29. doi: 10.7326/M18-3136.

Real-world outcome data from patients with advanced non–small cell lung cancer (NSCLC) treated with immunotherapy are robust enough to use for regulatory and payer decisions, suggests an analysis of six data sets and more than 13,000 patients.

“Study of routinely collected health care data is increasingly important for various stakeholders who are interested in better understanding particular patient populations, evaluating drug safety in the postmarketing setting, measuring health care use and clinical outcomes, performing comparative effectiveness research, and optimizing drug pricing models,” noted lead investigator Mark Stewart, PhD, Friends of Cancer Research, Washington, and coinvestigators. “However, before [real-world data] finds widespread use as an adjunct to – or in unique settings, an alternative for – [randomized clinical trials], the validity of readily extractable clinical outcomes measures – real-world endpoints – must be established.”

The investigators undertook a retrospective cohort study using administrative claims and electronic health records for patients with advanced NSCLC treated with inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) between January 2011 and October 2017 in real-world settings. They analyzed six data sets having 269 to 6,924 patients each (13,639 patients total).

Results reported in JCO Clinical Cancer Informatics showed that the real-world intermediate endpoints of time to treatment discontinuation and time to next treatment were moderately to highly correlated with real-world overall survival (Spearman’s rank correlation coefficient, 0.36 to 0.89, with most values 0.60 or higher).

In real-world settings, the 1-year rate of overall survival after starting immunotherapy ranged from 40% to 57%. Real-world data and trial data were similar with respect to median overall survival (8.6-13.5 months vs. 9.2-12.7 months).

The data sources used for the study have been extensively used for research and are curated on an ongoing basis to ensure the data are accurate and as complete as possible, Dr. Stewart and coinvestigators noted.

“These findings demonstrate that real-world endpoints are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision-making,” they maintained. “Differences observed likely reflect true differences between real-world and protocol-driven practices.

“Additional studies are needed to further support the use of [real-world evidence] and inform the development of regulatory guidance,” the investigators concluded. “Standardizing definitions for real-world endpoints and determining appropriate analytic methodologies for [real-world data] will be critical for broader adoption of real-world studies and will provide greater confidence in associated findings. As more refined and standardized approaches are developed that incorporate deep clinical and bioinformatics expertise, the greater the utility of [real-world data] will be for detecting even small, but important, differences in treatment effects.”

Dr. Stewart disclosed no conflicts of interest. The study was supported in part by the National Cancer Institute and the Patient Centered Outcomes Research Institute.

SOURCE: Stewart M et al. JCO Clin Cancer Inform. 2019 July 23. doi: 10.1200/CCI.18.00155.

Real-world outcome data from patients with advanced non–small cell lung cancer (NSCLC) treated with immunotherapy are robust enough to use for regulatory and payer decisions, suggests an analysis of six data sets and more than 13,000 patients.

“Study of routinely collected health care data is increasingly important for various stakeholders who are interested in better understanding particular patient populations, evaluating drug safety in the postmarketing setting, measuring health care use and clinical outcomes, performing comparative effectiveness research, and optimizing drug pricing models,” noted lead investigator Mark Stewart, PhD, Friends of Cancer Research, Washington, and coinvestigators. “However, before [real-world data] finds widespread use as an adjunct to – or in unique settings, an alternative for – [randomized clinical trials], the validity of readily extractable clinical outcomes measures – real-world endpoints – must be established.”

The investigators undertook a retrospective cohort study using administrative claims and electronic health records for patients with advanced NSCLC treated with inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) between January 2011 and October 2017 in real-world settings. They analyzed six data sets having 269 to 6,924 patients each (13,639 patients total).

Results reported in JCO Clinical Cancer Informatics showed that the real-world intermediate endpoints of time to treatment discontinuation and time to next treatment were moderately to highly correlated with real-world overall survival (Spearman’s rank correlation coefficient, 0.36 to 0.89, with most values 0.60 or higher).

In real-world settings, the 1-year rate of overall survival after starting immunotherapy ranged from 40% to 57%. Real-world data and trial data were similar with respect to median overall survival (8.6-13.5 months vs. 9.2-12.7 months).

The data sources used for the study have been extensively used for research and are curated on an ongoing basis to ensure the data are accurate and as complete as possible, Dr. Stewart and coinvestigators noted.

“These findings demonstrate that real-world endpoints are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision-making,” they maintained. “Differences observed likely reflect true differences between real-world and protocol-driven practices.

“Additional studies are needed to further support the use of [real-world evidence] and inform the development of regulatory guidance,” the investigators concluded. “Standardizing definitions for real-world endpoints and determining appropriate analytic methodologies for [real-world data] will be critical for broader adoption of real-world studies and will provide greater confidence in associated findings. As more refined and standardized approaches are developed that incorporate deep clinical and bioinformatics expertise, the greater the utility of [real-world data] will be for detecting even small, but important, differences in treatment effects.”

Dr. Stewart disclosed no conflicts of interest. The study was supported in part by the National Cancer Institute and the Patient Centered Outcomes Research Institute.

SOURCE: Stewart M et al. JCO Clin Cancer Inform. 2019 July 23. doi: 10.1200/CCI.18.00155.

Real-world outcome data from patients with advanced non–small cell lung cancer (NSCLC) treated with immunotherapy are robust enough to use for regulatory and payer decisions, suggests an analysis of six data sets and more than 13,000 patients.

“Study of routinely collected health care data is increasingly important for various stakeholders who are interested in better understanding particular patient populations, evaluating drug safety in the postmarketing setting, measuring health care use and clinical outcomes, performing comparative effectiveness research, and optimizing drug pricing models,” noted lead investigator Mark Stewart, PhD, Friends of Cancer Research, Washington, and coinvestigators. “However, before [real-world data] finds widespread use as an adjunct to – or in unique settings, an alternative for – [randomized clinical trials], the validity of readily extractable clinical outcomes measures – real-world endpoints – must be established.”

The investigators undertook a retrospective cohort study using administrative claims and electronic health records for patients with advanced NSCLC treated with inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) between January 2011 and October 2017 in real-world settings. They analyzed six data sets having 269 to 6,924 patients each (13,639 patients total).

Results reported in JCO Clinical Cancer Informatics showed that the real-world intermediate endpoints of time to treatment discontinuation and time to next treatment were moderately to highly correlated with real-world overall survival (Spearman’s rank correlation coefficient, 0.36 to 0.89, with most values 0.60 or higher).

In real-world settings, the 1-year rate of overall survival after starting immunotherapy ranged from 40% to 57%. Real-world data and trial data were similar with respect to median overall survival (8.6-13.5 months vs. 9.2-12.7 months).

The data sources used for the study have been extensively used for research and are curated on an ongoing basis to ensure the data are accurate and as complete as possible, Dr. Stewart and coinvestigators noted.

“These findings demonstrate that real-world endpoints are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision-making,” they maintained. “Differences observed likely reflect true differences between real-world and protocol-driven practices.

“Additional studies are needed to further support the use of [real-world evidence] and inform the development of regulatory guidance,” the investigators concluded. “Standardizing definitions for real-world endpoints and determining appropriate analytic methodologies for [real-world data] will be critical for broader adoption of real-world studies and will provide greater confidence in associated findings. As more refined and standardized approaches are developed that incorporate deep clinical and bioinformatics expertise, the greater the utility of [real-world data] will be for detecting even small, but important, differences in treatment effects.”

Dr. Stewart disclosed no conflicts of interest. The study was supported in part by the National Cancer Institute and the Patient Centered Outcomes Research Institute.

SOURCE: Stewart M et al. JCO Clin Cancer Inform. 2019 July 23. doi: 10.1200/CCI.18.00155.

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

An implant that elutes an investigational antiretroviral agent provided drug release that should be sufficient for HIV prophylaxis for 12 months or more, according to results of a phase 1 clinical trial just presented here at the International AIDS Society Conference on HIV Science.

grandeduc/Thinkstock

The islatravir-eluting arm implant was safe and generally well tolerated, with drug concentrations that remained above the target level needed for protection throughout the randomized, placebo-controlled study, said investigator Randolph P. Matthews, MD, PhD, senior principal scientist at Merck, Kenilworth, N.J.

“Based on this study, the islatravir-eluting implant appears to be a potentially important option for preexposure prophylaxis (PrEP) as an agent that could be effective with yearly dosing,” Dr. Matthews said in an IAS press conference.

This drug-eluting implant, inserted subdermally in the skin of the upper arm, could represent a “meaningful option” for many individuals at high risk of HIV infection, particularly those who have adherence challenges, said Dr. Matthews.

“Many at-risk individuals face adherence challenges with the existing daily oral PrEP therapy,” he added. “A high degree of adherence is required for it to be effective, and daily adherence is challenging for many, particularly for women.”

Islatravir, formerly known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being evaluated in clinical trials not only for PrEP, but also for treatment of HIV-1 infection in combination with other antiretrovirals.

In preclinical trials, islatravir demonstrated high potency, a high barrier to resistance, and a long half-life, according to Dr. Matthews.

The phase 1, single-site, double-blind study included a total of 16 healthy adult volunteers who received implants of islatravir at one of two doses (54 mg and 62 mg) or placebo for 12 weeks.

Both active doses of islatravir led to concentrations above the target level at 12 weeks, and based on data modeling, the higher-dose implant would still be above the target level for at least a year, Dr. Matthews said in the press conference.

The projected duration above the target ranged from 12 to 16 months for the 62-mg dose of islatravir, and from 8 to 10 months for the 54-mg dose, according to the reported data.

All drug-related adverse events were mild or moderate in severity, and none of the volunteers discontinued the study because of an adverse event, Dr. Matthews said.

Taken together, these data support the continued progression of the implant clinical development program, said Dr. Matthews, who is an employee of Merck, which sponsored the study.

SOURCE: Matthews RP et al. IAS 2019, Abstract TUAC0401LB.

An implant that elutes an investigational antiretroviral agent provided drug release that should be sufficient for HIV prophylaxis for 12 months or more, according to results of a phase 1 clinical trial just presented here at the International AIDS Society Conference on HIV Science.

grandeduc/Thinkstock

The islatravir-eluting arm implant was safe and generally well tolerated, with drug concentrations that remained above the target level needed for protection throughout the randomized, placebo-controlled study, said investigator Randolph P. Matthews, MD, PhD, senior principal scientist at Merck, Kenilworth, N.J.

“Based on this study, the islatravir-eluting implant appears to be a potentially important option for preexposure prophylaxis (PrEP) as an agent that could be effective with yearly dosing,” Dr. Matthews said in an IAS press conference.

This drug-eluting implant, inserted subdermally in the skin of the upper arm, could represent a “meaningful option” for many individuals at high risk of HIV infection, particularly those who have adherence challenges, said Dr. Matthews.

“Many at-risk individuals face adherence challenges with the existing daily oral PrEP therapy,” he added. “A high degree of adherence is required for it to be effective, and daily adherence is challenging for many, particularly for women.”

Islatravir, formerly known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being evaluated in clinical trials not only for PrEP, but also for treatment of HIV-1 infection in combination with other antiretrovirals.

In preclinical trials, islatravir demonstrated high potency, a high barrier to resistance, and a long half-life, according to Dr. Matthews.

The phase 1, single-site, double-blind study included a total of 16 healthy adult volunteers who received implants of islatravir at one of two doses (54 mg and 62 mg) or placebo for 12 weeks.

Both active doses of islatravir led to concentrations above the target level at 12 weeks, and based on data modeling, the higher-dose implant would still be above the target level for at least a year, Dr. Matthews said in the press conference.

The projected duration above the target ranged from 12 to 16 months for the 62-mg dose of islatravir, and from 8 to 10 months for the 54-mg dose, according to the reported data.

All drug-related adverse events were mild or moderate in severity, and none of the volunteers discontinued the study because of an adverse event, Dr. Matthews said.

Taken together, these data support the continued progression of the implant clinical development program, said Dr. Matthews, who is an employee of Merck, which sponsored the study.

SOURCE: Matthews RP et al. IAS 2019, Abstract TUAC0401LB.

An implant that elutes an investigational antiretroviral agent provided drug release that should be sufficient for HIV prophylaxis for 12 months or more, according to results of a phase 1 clinical trial just presented here at the International AIDS Society Conference on HIV Science.

grandeduc/Thinkstock

The islatravir-eluting arm implant was safe and generally well tolerated, with drug concentrations that remained above the target level needed for protection throughout the randomized, placebo-controlled study, said investigator Randolph P. Matthews, MD, PhD, senior principal scientist at Merck, Kenilworth, N.J.

“Based on this study, the islatravir-eluting implant appears to be a potentially important option for preexposure prophylaxis (PrEP) as an agent that could be effective with yearly dosing,” Dr. Matthews said in an IAS press conference.

This drug-eluting implant, inserted subdermally in the skin of the upper arm, could represent a “meaningful option” for many individuals at high risk of HIV infection, particularly those who have adherence challenges, said Dr. Matthews.

“Many at-risk individuals face adherence challenges with the existing daily oral PrEP therapy,” he added. “A high degree of adherence is required for it to be effective, and daily adherence is challenging for many, particularly for women.”

Islatravir, formerly known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being evaluated in clinical trials not only for PrEP, but also for treatment of HIV-1 infection in combination with other antiretrovirals.

In preclinical trials, islatravir demonstrated high potency, a high barrier to resistance, and a long half-life, according to Dr. Matthews.

The phase 1, single-site, double-blind study included a total of 16 healthy adult volunteers who received implants of islatravir at one of two doses (54 mg and 62 mg) or placebo for 12 weeks.

Both active doses of islatravir led to concentrations above the target level at 12 weeks, and based on data modeling, the higher-dose implant would still be above the target level for at least a year, Dr. Matthews said in the press conference.

The projected duration above the target ranged from 12 to 16 months for the 62-mg dose of islatravir, and from 8 to 10 months for the 54-mg dose, according to the reported data.

All drug-related adverse events were mild or moderate in severity, and none of the volunteers discontinued the study because of an adverse event, Dr. Matthews said.

Taken together, these data support the continued progression of the implant clinical development program, said Dr. Matthews, who is an employee of Merck, which sponsored the study.

SOURCE: Matthews RP et al. IAS 2019, Abstract TUAC0401LB.

The Food and Drug Administration has approved Baqsimi nasal powder, the first glucagon therapy approved for the treatment of severe hypoglycemia that is administrable without an injection, in patients aged 4 years and older.

Olivier Le Moal/Getty Images

Injectable glucagon has been approved in the United States for several decades.

The safety and efficacy of the Baqsimi powder was assessed in two studies with adults with diabetes and one with pediatric patients. In all three studies, a single dose of Baqsimi was compared with a single dose of glucagon injection, and Baqsimi adequately raised blood sugar levels in response to insulin-induced hypoglycemia.

The most common adverse events associated with Baqsimi include nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. The safety profile is similar to that of injectable glucagon, with the addition of nasal- and eye-related symptoms because of the method of delivery.

“There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process. This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure. In those situations, we want the process to treat the suffering person to be as simple as possible,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved Baqsimi nasal powder, the first glucagon therapy approved for the treatment of severe hypoglycemia that is administrable without an injection, in patients aged 4 years and older.

Olivier Le Moal/Getty Images

Injectable glucagon has been approved in the United States for several decades.

The safety and efficacy of the Baqsimi powder was assessed in two studies with adults with diabetes and one with pediatric patients. In all three studies, a single dose of Baqsimi was compared with a single dose of glucagon injection, and Baqsimi adequately raised blood sugar levels in response to insulin-induced hypoglycemia.

The most common adverse events associated with Baqsimi include nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. The safety profile is similar to that of injectable glucagon, with the addition of nasal- and eye-related symptoms because of the method of delivery.

“There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process. This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure. In those situations, we want the process to treat the suffering person to be as simple as possible,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved Baqsimi nasal powder, the first glucagon therapy approved for the treatment of severe hypoglycemia that is administrable without an injection, in patients aged 4 years and older.

Olivier Le Moal/Getty Images

Injectable glucagon has been approved in the United States for several decades.

The safety and efficacy of the Baqsimi powder was assessed in two studies with adults with diabetes and one with pediatric patients. In all three studies, a single dose of Baqsimi was compared with a single dose of glucagon injection, and Baqsimi adequately raised blood sugar levels in response to insulin-induced hypoglycemia.

The most common adverse events associated with Baqsimi include nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. The safety profile is similar to that of injectable glucagon, with the addition of nasal- and eye-related symptoms because of the method of delivery.

“There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process. This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure. In those situations, we want the process to treat the suffering person to be as simple as possible,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

In patients with previously untreated achalasia, peroral endoscopic myotomy had a high procedural success rate as compared to pneumatic dilation, results of a randomized clinical trial show.

Peroral endoscopic myotomy (POEM) had a success rate exceeding 90%, versus just about 50% for standard balloon dilation in what investigators say is, to their knowledge, the first-ever randomized trial to evaluate POEM as a first-line modality for this esophageal motility disorder.

Reflux esophagitis was the major downside of POEM, according to investigators, who reported the complication in 41% of patients at a 2-year follow-up, as compared to just 7% of patients undergoing the standard balloon dilation.

Nevertheless, there were no serious adverse events among 63 POEM-treated patients, while one patient out of 63 undergoing pneumatic dilation had a perforation that required endoscopic closure and hospitalization, according to senior study author Albert J. Bredenoord, MD, PhD, of Amsterdam University Medical Center.

“These findings support consideration of POEM as an initial treatment option for patients with achalasia,” Dr. Bredenoord and coinvestigators said in a report on the study appearing in JAMA.

While endoscopic pneumatic dilation is the usual treatment for achalasia, POEM has become more commonly used following case series showing high rates of efficacy, according to the authors.

The POEM procedure also offers advantages over laparoscopic Heller myotomy, which is invasive and associated with severe complications, including a transmural perforation rate of 4%-10%, they said in their report.

Their randomized trial included 133 adults with newly diagnosed achalasia enrolled at one of six hospitals in Germany, Hong Kong, Italy, Netherlands, and the United States.

Patients were randomly assigned to undergo 1-2 pneumatic dilations performed by an endoscopist who had performed at least 20 such procedures in the past, or to a POEM procedure likewise performed by an expert who had already done more than 20 such procedures.

At baseline, patients’ Eckardt symptom scores ranged from 6 to 9 on a scale with 0 indicating the lowest severity, to 12 indicating the highest. The median Eckardt scores were 8 in the POEM group and 7 in the pneumatic dilation group.

Treatment success, defined as an Eckardt score under 3 and no severe complications or retreatment at 2 years, was achieved by 58 of 63 patients (92%) in the POEM group, compared with 34 of 63 patients (54%) in the pneumatic dilation group (P less than .001), investigators reported.

Reflux esophagitis was observed in 22 of 54 POEM-treated patients (41%) who underwent endoscopy at a 2-year evaluation, compared with only 2 of 29 patients (7%) who had received the balloon dilation procedure (P = .002). In line with that finding, both reflux symptoms and daily proton pump inhibitor use were more common in the POEM group, investigators said.

However, there were no differences between POEM and pneumatic dilation groups in quality of life and other secondary endpoints, including median barium column height and median integrated relaxation pressure, they reported.

Two serious adverse events related to treatment were seen, according to investigators, including one perforation requiring an endoscopic closure plus antibiotics and hospitalization for 13 days, and one hospital admission for a night because of severe chest pain with no signs of perforation.

“Although POEM is more invasive and requires more technical endoscopic skills, the risk of severe complications was not higher than with pneumatic dilation, especially when performed by experienced endoscopists,” Dr. Bredenoord and coauthors said in their report.

However, these results do not imply that the traditional dilation procedure should be abandoned, they said, as POEM is more invasive, more involved, and more likely to result in reflux esophagitis.

“It seems reasonable to offer both options to treatment-naive patients with achalasia and counsel them to select treatment based on the patient’s characteristics, personal preference, comorbidity, and disease subtype,” they said.

Funding for the study came from Fonds NutsOhra and the European Society of Gastrointestinal Endoscopy. Dr. Bredenoord reported disclosures related to Norgine, Laborie, Medtronic, Diversatek, Nutricia, Regeneron, Celgene, Bayer, and Dr. Falk Pharma.

SOURCE: Ponds FA et al. JAMA. 2019;322(2):134-44. doi: 10.1001/jama.2019.8859.

In patients with previously untreated achalasia, peroral endoscopic myotomy had a high procedural success rate as compared to pneumatic dilation, results of a randomized clinical trial show.

Peroral endoscopic myotomy (POEM) had a success rate exceeding 90%, versus just about 50% for standard balloon dilation in what investigators say is, to their knowledge, the first-ever randomized trial to evaluate POEM as a first-line modality for this esophageal motility disorder.

Reflux esophagitis was the major downside of POEM, according to investigators, who reported the complication in 41% of patients at a 2-year follow-up, as compared to just 7% of patients undergoing the standard balloon dilation.

Nevertheless, there were no serious adverse events among 63 POEM-treated patients, while one patient out of 63 undergoing pneumatic dilation had a perforation that required endoscopic closure and hospitalization, according to senior study author Albert J. Bredenoord, MD, PhD, of Amsterdam University Medical Center.

“These findings support consideration of POEM as an initial treatment option for patients with achalasia,” Dr. Bredenoord and coinvestigators said in a report on the study appearing in JAMA.

While endoscopic pneumatic dilation is the usual treatment for achalasia, POEM has become more commonly used following case series showing high rates of efficacy, according to the authors.

The POEM procedure also offers advantages over laparoscopic Heller myotomy, which is invasive and associated with severe complications, including a transmural perforation rate of 4%-10%, they said in their report.

Their randomized trial included 133 adults with newly diagnosed achalasia enrolled at one of six hospitals in Germany, Hong Kong, Italy, Netherlands, and the United States.

Patients were randomly assigned to undergo 1-2 pneumatic dilations performed by an endoscopist who had performed at least 20 such procedures in the past, or to a POEM procedure likewise performed by an expert who had already done more than 20 such procedures.

At baseline, patients’ Eckardt symptom scores ranged from 6 to 9 on a scale with 0 indicating the lowest severity, to 12 indicating the highest. The median Eckardt scores were 8 in the POEM group and 7 in the pneumatic dilation group.

Treatment success, defined as an Eckardt score under 3 and no severe complications or retreatment at 2 years, was achieved by 58 of 63 patients (92%) in the POEM group, compared with 34 of 63 patients (54%) in the pneumatic dilation group (P less than .001), investigators reported.

Reflux esophagitis was observed in 22 of 54 POEM-treated patients (41%) who underwent endoscopy at a 2-year evaluation, compared with only 2 of 29 patients (7%) who had received the balloon dilation procedure (P = .002). In line with that finding, both reflux symptoms and daily proton pump inhibitor use were more common in the POEM group, investigators said.

However, there were no differences between POEM and pneumatic dilation groups in quality of life and other secondary endpoints, including median barium column height and median integrated relaxation pressure, they reported.

Two serious adverse events related to treatment were seen, according to investigators, including one perforation requiring an endoscopic closure plus antibiotics and hospitalization for 13 days, and one hospital admission for a night because of severe chest pain with no signs of perforation.

“Although POEM is more invasive and requires more technical endoscopic skills, the risk of severe complications was not higher than with pneumatic dilation, especially when performed by experienced endoscopists,” Dr. Bredenoord and coauthors said in their report.

However, these results do not imply that the traditional dilation procedure should be abandoned, they said, as POEM is more invasive, more involved, and more likely to result in reflux esophagitis.

“It seems reasonable to offer both options to treatment-naive patients with achalasia and counsel them to select treatment based on the patient’s characteristics, personal preference, comorbidity, and disease subtype,” they said.

Funding for the study came from Fonds NutsOhra and the European Society of Gastrointestinal Endoscopy. Dr. Bredenoord reported disclosures related to Norgine, Laborie, Medtronic, Diversatek, Nutricia, Regeneron, Celgene, Bayer, and Dr. Falk Pharma.

SOURCE: Ponds FA et al. JAMA. 2019;322(2):134-44. doi: 10.1001/jama.2019.8859.

In patients with previously untreated achalasia, peroral endoscopic myotomy had a high procedural success rate as compared to pneumatic dilation, results of a randomized clinical trial show.

Peroral endoscopic myotomy (POEM) had a success rate exceeding 90%, versus just about 50% for standard balloon dilation in what investigators say is, to their knowledge, the first-ever randomized trial to evaluate POEM as a first-line modality for this esophageal motility disorder.

Reflux esophagitis was the major downside of POEM, according to investigators, who reported the complication in 41% of patients at a 2-year follow-up, as compared to just 7% of patients undergoing the standard balloon dilation.

Nevertheless, there were no serious adverse events among 63 POEM-treated patients, while one patient out of 63 undergoing pneumatic dilation had a perforation that required endoscopic closure and hospitalization, according to senior study author Albert J. Bredenoord, MD, PhD, of Amsterdam University Medical Center.

“These findings support consideration of POEM as an initial treatment option for patients with achalasia,” Dr. Bredenoord and coinvestigators said in a report on the study appearing in JAMA.

While endoscopic pneumatic dilation is the usual treatment for achalasia, POEM has become more commonly used following case series showing high rates of efficacy, according to the authors.

The POEM procedure also offers advantages over laparoscopic Heller myotomy, which is invasive and associated with severe complications, including a transmural perforation rate of 4%-10%, they said in their report.

Their randomized trial included 133 adults with newly diagnosed achalasia enrolled at one of six hospitals in Germany, Hong Kong, Italy, Netherlands, and the United States.

Patients were randomly assigned to undergo 1-2 pneumatic dilations performed by an endoscopist who had performed at least 20 such procedures in the past, or to a POEM procedure likewise performed by an expert who had already done more than 20 such procedures.

At baseline, patients’ Eckardt symptom scores ranged from 6 to 9 on a scale with 0 indicating the lowest severity, to 12 indicating the highest. The median Eckardt scores were 8 in the POEM group and 7 in the pneumatic dilation group.

Treatment success, defined as an Eckardt score under 3 and no severe complications or retreatment at 2 years, was achieved by 58 of 63 patients (92%) in the POEM group, compared with 34 of 63 patients (54%) in the pneumatic dilation group (P less than .001), investigators reported.

Reflux esophagitis was observed in 22 of 54 POEM-treated patients (41%) who underwent endoscopy at a 2-year evaluation, compared with only 2 of 29 patients (7%) who had received the balloon dilation procedure (P = .002). In line with that finding, both reflux symptoms and daily proton pump inhibitor use were more common in the POEM group, investigators said.

However, there were no differences between POEM and pneumatic dilation groups in quality of life and other secondary endpoints, including median barium column height and median integrated relaxation pressure, they reported.

Two serious adverse events related to treatment were seen, according to investigators, including one perforation requiring an endoscopic closure plus antibiotics and hospitalization for 13 days, and one hospital admission for a night because of severe chest pain with no signs of perforation.

“Although POEM is more invasive and requires more technical endoscopic skills, the risk of severe complications was not higher than with pneumatic dilation, especially when performed by experienced endoscopists,” Dr. Bredenoord and coauthors said in their report.

However, these results do not imply that the traditional dilation procedure should be abandoned, they said, as POEM is more invasive, more involved, and more likely to result in reflux esophagitis.

“It seems reasonable to offer both options to treatment-naive patients with achalasia and counsel them to select treatment based on the patient’s characteristics, personal preference, comorbidity, and disease subtype,” they said.

Funding for the study came from Fonds NutsOhra and the European Society of Gastrointestinal Endoscopy. Dr. Bredenoord reported disclosures related to Norgine, Laborie, Medtronic, Diversatek, Nutricia, Regeneron, Celgene, Bayer, and Dr. Falk Pharma.

SOURCE: Ponds FA et al. JAMA. 2019;322(2):134-44. doi: 10.1001/jama.2019.8859.

The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.

©Ed Uthman/Flickr

“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.

In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.

Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.

Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.

Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”


Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.

The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.

SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.

The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.

©Ed Uthman/Flickr

“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.

In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.

Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.

Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.

Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”


Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.

The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.

SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.

The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.

©Ed Uthman/Flickr

“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.

In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.

Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.

Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.

Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”


Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.

The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.

SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.

BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.

Bruce Jancin/MDedge News

Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.

This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.

He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.

Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.

Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.

In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.

Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.

The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).

As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.

Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.

He reported having no financial conflicts regarding the study, conducted free of commercial support.

[email protected]

SOURCE: Matsubara S et al. IEC 219, Abstract P002.

BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.

Bruce Jancin/MDedge News

Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.

This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.

He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.

Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.

Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.

In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.

Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.

The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).

As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.

Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.

He reported having no financial conflicts regarding the study, conducted free of commercial support.

[email protected]

SOURCE: Matsubara S et al. IEC 219, Abstract P002.

BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.

Bruce Jancin/MDedge News

Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.

This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.

He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.

Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.

Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.

In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.

Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.

The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).

As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.

Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.

He reported having no financial conflicts regarding the study, conducted free of commercial support.

[email protected]

SOURCE: Matsubara S et al. IEC 219, Abstract P002.

LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

JackF/thinkstockphotos.com

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.


Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

[email protected]

*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.

LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

JackF/thinkstockphotos.com

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.


Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

[email protected]

*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.

LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

JackF/thinkstockphotos.com

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.


Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

[email protected]

*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.