Photo from University of Texas Southwestern Medical Center

Efforts to determine why immune checkpoint blockade is not successful in treating leukemia have resulted in a “compelling” new target to treat monocytic acute myeloid leukemia (AML), according to researchers.

They discovered that leukocyte immunoglobulin-like receptor B4 (LILRB4), a marker of monocytic leukemia, creates an immunosuppressive microenvironment by mediating T-cell suppression.

Using a mouse model and human cells, the research team showed that LILRB4 supports tumor infiltration into tissues and suppresses T-cell activity through a signaling pathway involving APOE, LILRB4, SHP-2, uPAR, and ARG1.

Senior author Chengcheng “Alec” Zhang, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported their findings in Nature.

The team first compared surface expression of LILRB4 on normal monocytes and neoplastic monocytes from 105 AML patient samples. They observed that LILRB4 levels were higher on monocytic AML cells than on normal monocytes.

The researchers then tested whether LILRB4 expressed on AML cells suppressed T cells. They cultured LILRB4-positive leukemia cells, LILRB4-negative leukemia cells, and normal hematopoietic cells with either autologous T cells or T cells from healthy donors. The team determined that only LILRB4-positive monocytic AML cells substantially suppressed T-cell proliferation.

When the researchers knocked out LILRB4, the ability of AML cells to suppress T cells was reduced and could be restored with forced expression of wild-type LILRB4. Additionally, LILRB4-mediated T-cell inhibition could be reversed by LILRB4-blocking antibodies.

The team then used a humanized mouse xenograft model and an immunocompetent mouse model to investigate LILRB4 function in immune checkpoint blockade. Blocking LILRB4 lowered tumor burden and prolonged survival in the mice.

The researchers performed numerous in vitro and in vivo experiments and observed that antibody blockade of LILRB4 shrank tumors and decreased leukemic infiltration into internal organs, including the bone marrow, liver, and brain.

And so the team hypothesized that LILRB4 promotes leukemia infiltration in addition to inhibiting T cells.

To test the hypothesis, they performed transendothelial migration and homing assays and monitored leukemia infiltration relative to LILRB4 expression on leukemia cells. They observed that LILRB4-mediated migration enhanced extramedullary infiltration of monocytic AML cells, thus contributing to immune evasion.

The researchers also found that APOE protein activated the immune inhibitory receptor LILRB4.

To ascertain whether suppression of T cells by LILRB4 depends on APOE, the team co-cultured T cells with control or human AML cells with APOE knocked out.

Through a series of experiments, they determined that APOE is an extracellular binding protein of LILRB4 and that APOE activates LILRB4 to support T-cell proliferation and AML cell migration.

The researchers believe that targeting LILRB4 may have minimal toxicity. This is because LILRB4 expression on normal monocytic cells is limited, LILRB4 signaling may differ in leukemia cells, and LILRB4 blockade did not significantly interfere with normal hematopoietic function.

Dr. Zhang anticipates that if the preclinical studies go well, clinical trials could begin as early as next year.

The University of Texas System has exclusively licensed LILRB4-related patent applications to California-based Immune-Onc Therapeutics Inc., which contributed to the research and is conducting preclinical studies.

Dr. Zhang and another author are scientific advisory board members with Immune-Onc Therapeutics. Two other authors are employees of and hold equities in Immune-Onc Therapeutics.

The researchers received additional funding for this work from the National Cancer Institute, Leukemia & Lymphoma Society, the March of Dimes, the Cancer Prevention and Research Institute of Texas, the Robert A. Welch Foundation, the National Natural Science Foundation of China, the National Basic Research Program of China, and the China Scholarship Council. 

Photo from University of Texas Southwestern Medical Center

Efforts to determine why immune checkpoint blockade is not successful in treating leukemia have resulted in a “compelling” new target to treat monocytic acute myeloid leukemia (AML), according to researchers.

They discovered that leukocyte immunoglobulin-like receptor B4 (LILRB4), a marker of monocytic leukemia, creates an immunosuppressive microenvironment by mediating T-cell suppression.

Using a mouse model and human cells, the research team showed that LILRB4 supports tumor infiltration into tissues and suppresses T-cell activity through a signaling pathway involving APOE, LILRB4, SHP-2, uPAR, and ARG1.

Senior author Chengcheng “Alec” Zhang, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported their findings in Nature.

The team first compared surface expression of LILRB4 on normal monocytes and neoplastic monocytes from 105 AML patient samples. They observed that LILRB4 levels were higher on monocytic AML cells than on normal monocytes.

The researchers then tested whether LILRB4 expressed on AML cells suppressed T cells. They cultured LILRB4-positive leukemia cells, LILRB4-negative leukemia cells, and normal hematopoietic cells with either autologous T cells or T cells from healthy donors. The team determined that only LILRB4-positive monocytic AML cells substantially suppressed T-cell proliferation.

When the researchers knocked out LILRB4, the ability of AML cells to suppress T cells was reduced and could be restored with forced expression of wild-type LILRB4. Additionally, LILRB4-mediated T-cell inhibition could be reversed by LILRB4-blocking antibodies.

The team then used a humanized mouse xenograft model and an immunocompetent mouse model to investigate LILRB4 function in immune checkpoint blockade. Blocking LILRB4 lowered tumor burden and prolonged survival in the mice.

The researchers performed numerous in vitro and in vivo experiments and observed that antibody blockade of LILRB4 shrank tumors and decreased leukemic infiltration into internal organs, including the bone marrow, liver, and brain.

And so the team hypothesized that LILRB4 promotes leukemia infiltration in addition to inhibiting T cells.

To test the hypothesis, they performed transendothelial migration and homing assays and monitored leukemia infiltration relative to LILRB4 expression on leukemia cells. They observed that LILRB4-mediated migration enhanced extramedullary infiltration of monocytic AML cells, thus contributing to immune evasion.

The researchers also found that APOE protein activated the immune inhibitory receptor LILRB4.

To ascertain whether suppression of T cells by LILRB4 depends on APOE, the team co-cultured T cells with control or human AML cells with APOE knocked out.

Through a series of experiments, they determined that APOE is an extracellular binding protein of LILRB4 and that APOE activates LILRB4 to support T-cell proliferation and AML cell migration.

The researchers believe that targeting LILRB4 may have minimal toxicity. This is because LILRB4 expression on normal monocytic cells is limited, LILRB4 signaling may differ in leukemia cells, and LILRB4 blockade did not significantly interfere with normal hematopoietic function.

Dr. Zhang anticipates that if the preclinical studies go well, clinical trials could begin as early as next year.

The University of Texas System has exclusively licensed LILRB4-related patent applications to California-based Immune-Onc Therapeutics Inc., which contributed to the research and is conducting preclinical studies.

Dr. Zhang and another author are scientific advisory board members with Immune-Onc Therapeutics. Two other authors are employees of and hold equities in Immune-Onc Therapeutics.

The researchers received additional funding for this work from the National Cancer Institute, Leukemia & Lymphoma Society, the March of Dimes, the Cancer Prevention and Research Institute of Texas, the Robert A. Welch Foundation, the National Natural Science Foundation of China, the National Basic Research Program of China, and the China Scholarship Council. 

Photo from University of Texas Southwestern Medical Center

Efforts to determine why immune checkpoint blockade is not successful in treating leukemia have resulted in a “compelling” new target to treat monocytic acute myeloid leukemia (AML), according to researchers.

They discovered that leukocyte immunoglobulin-like receptor B4 (LILRB4), a marker of monocytic leukemia, creates an immunosuppressive microenvironment by mediating T-cell suppression.

Using a mouse model and human cells, the research team showed that LILRB4 supports tumor infiltration into tissues and suppresses T-cell activity through a signaling pathway involving APOE, LILRB4, SHP-2, uPAR, and ARG1.

Senior author Chengcheng “Alec” Zhang, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported their findings in Nature.

The team first compared surface expression of LILRB4 on normal monocytes and neoplastic monocytes from 105 AML patient samples. They observed that LILRB4 levels were higher on monocytic AML cells than on normal monocytes.

The researchers then tested whether LILRB4 expressed on AML cells suppressed T cells. They cultured LILRB4-positive leukemia cells, LILRB4-negative leukemia cells, and normal hematopoietic cells with either autologous T cells or T cells from healthy donors. The team determined that only LILRB4-positive monocytic AML cells substantially suppressed T-cell proliferation.

When the researchers knocked out LILRB4, the ability of AML cells to suppress T cells was reduced and could be restored with forced expression of wild-type LILRB4. Additionally, LILRB4-mediated T-cell inhibition could be reversed by LILRB4-blocking antibodies.

The team then used a humanized mouse xenograft model and an immunocompetent mouse model to investigate LILRB4 function in immune checkpoint blockade. Blocking LILRB4 lowered tumor burden and prolonged survival in the mice.

The researchers performed numerous in vitro and in vivo experiments and observed that antibody blockade of LILRB4 shrank tumors and decreased leukemic infiltration into internal organs, including the bone marrow, liver, and brain.

And so the team hypothesized that LILRB4 promotes leukemia infiltration in addition to inhibiting T cells.

To test the hypothesis, they performed transendothelial migration and homing assays and monitored leukemia infiltration relative to LILRB4 expression on leukemia cells. They observed that LILRB4-mediated migration enhanced extramedullary infiltration of monocytic AML cells, thus contributing to immune evasion.

The researchers also found that APOE protein activated the immune inhibitory receptor LILRB4.

To ascertain whether suppression of T cells by LILRB4 depends on APOE, the team co-cultured T cells with control or human AML cells with APOE knocked out.

Through a series of experiments, they determined that APOE is an extracellular binding protein of LILRB4 and that APOE activates LILRB4 to support T-cell proliferation and AML cell migration.

The researchers believe that targeting LILRB4 may have minimal toxicity. This is because LILRB4 expression on normal monocytic cells is limited, LILRB4 signaling may differ in leukemia cells, and LILRB4 blockade did not significantly interfere with normal hematopoietic function.

Dr. Zhang anticipates that if the preclinical studies go well, clinical trials could begin as early as next year.

The University of Texas System has exclusively licensed LILRB4-related patent applications to California-based Immune-Onc Therapeutics Inc., which contributed to the research and is conducting preclinical studies.

Dr. Zhang and another author are scientific advisory board members with Immune-Onc Therapeutics. Two other authors are employees of and hold equities in Immune-Onc Therapeutics.

The researchers received additional funding for this work from the National Cancer Institute, Leukemia & Lymphoma Society, the March of Dimes, the Cancer Prevention and Research Institute of Texas, the Robert A. Welch Foundation, the National Natural Science Foundation of China, the National Basic Research Program of China, and the China Scholarship Council. 

CHICAGO – New U.S. cholesterol guidelines spell out the role for ezetimibe and PCSK9 inhibitors, expand the scope of individualized risk assessment, and cite the potential value of a coronary artery calcium score as an additional risk determinant.

Neil J. Stone MD, vice chair of the of the 2018 Cholesterol Guidelines Committee, sat down for an interview and detailed the research behind the guidelines and how new features can help guide treatment decisions for patients at risk for a cardiovascular event.

[email protected]

CHICAGO – New U.S. cholesterol guidelines spell out the role for ezetimibe and PCSK9 inhibitors, expand the scope of individualized risk assessment, and cite the potential value of a coronary artery calcium score as an additional risk determinant.

Neil J. Stone MD, vice chair of the of the 2018 Cholesterol Guidelines Committee, sat down for an interview and detailed the research behind the guidelines and how new features can help guide treatment decisions for patients at risk for a cardiovascular event.

[email protected]

CHICAGO – New U.S. cholesterol guidelines spell out the role for ezetimibe and PCSK9 inhibitors, expand the scope of individualized risk assessment, and cite the potential value of a coronary artery calcium score as an additional risk determinant.

Neil J. Stone MD, vice chair of the of the 2018 Cholesterol Guidelines Committee, sat down for an interview and detailed the research behind the guidelines and how new features can help guide treatment decisions for patients at risk for a cardiovascular event.

[email protected]

For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, dapagliflozin is associated with a lower composite rate of cardiovascular death or hospitalization for heart failure, compared with placebo, according to investigators.

A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead author Stephen D. Wiviott, MD at the American Heart Association scientific sessions.

“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.

“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”

The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).

SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389

For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, dapagliflozin is associated with a lower composite rate of cardiovascular death or hospitalization for heart failure, compared with placebo, according to investigators.

A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead author Stephen D. Wiviott, MD at the American Heart Association scientific sessions.

“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.

“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”

The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).

SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389

For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, dapagliflozin is associated with a lower composite rate of cardiovascular death or hospitalization for heart failure, compared with placebo, according to investigators.

A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead author Stephen D. Wiviott, MD at the American Heart Association scientific sessions.

“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.

“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”

The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).

SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389

CHICAGO – Detailed results of the REDUCE-IT trial have confirmed earlier-reported top line results that showed a 25% reduction in the risk of cardiovascular death or nonfatal cardiovascular event with the fish-derived, triglyceride-reducing agent icosapent acid in combination with statin.

But they should not be interpreted as validation of the cardiovascular benefits of fish-oil supplements, according to Deepak L. Bhatt, MD, principal investigator and steering committee chair for REDUCE-IT, who presented the results at the American Heart Association scientific sessions.

He reported the results from 8,179 patients followed for a median of 4.9 years. The treatment group received 4 g/day of icosapent ethyl (Vascepa, Amarin), a single-molecule agent consisting of the omega-3 acid known as eicosapentaeonoic acid (EPA) in ethyl-ester form, which Dr. Bhatt called “a highly purified” formulation. Vascepa is derived from fish but it is not fish oil, a company press release states. Amarin, sponsor of the study, released top line results in September.

To qualify for the trial, patients had to have a diagnosis of cardiovascular disease or diabetes and other risk factors, had been on statin therapy and had above normal triglyceride (135-499 mg/dL) and optimal LDL (41-100 mg/dL) levels. Patients were randomly assigned to receive 4 g/day of icosapent ethyl or placebo.

Dr. Bhatt stressed that the REDUCE-IT results do not necessarily validate the use of fish oil to lower cardiovascular risk. “It would be mistake if patients and physicians” to interpret the results that way, and that classifying the purified formulation of icosapent ethyl used in REDUCE-IT as fish oil is a “misnomer.” He added, “Really, what we’re talking about is prescription therapy icosapent ethyl vs. over-the-counter supplements.” Icosapent ethyl is approved in the United States for patients with triglyceride levels of more than 500 mg/dL.

Dr. Bhatt and the study coauthors acknowledged that the results of REDUCE-IT deviate from other trials of triglyceride-lowering agents, including other n-3 fatty acids. They noted two potential explanations: a high dose; or higher ratios of EPA to docosahexaenoic acid in the REDUCE-IT formulation vs. agents used in the other studies. For example, the ASCEND study, presented at the European Society of Cardiology in September, reported no cardiovascular benefit from a 1-g/day dose of omega-3 fatty acids and low-dose aspirin in patients with diabetes.

The primary endpoint of REDUCE-IT was a composite of cardiovascular death, nonfatal MI or stroke, coronary revascularization or unstable angina, which occurred in 17.2% of the patients taking icosapent ethyl, compared with 22% of the controls, for a risk reduction of 25% (P less than .001). The key secondary endpoint was composite of cardiovascular death and nonfatal MI or stroke, which occurred in 11.2% and 14.8% of the treated and placebo groups, respectively, for a risk reduction of 26% (P less than .001).

The study investigators also zeroed in on specific ischemic endpoints. Cardiovascular death rates were 20% lower in the treated patients (4.2% vs. 5.2%, P less than .03).

The study also evaluated lipid levels. The median change in triglyceride levels after a year of treatment was a decrease of 18.3%, or 39 mg/dL, in the treatment group while triglyceride levels rose 2.2% in the placebo patients (P less than .001). LDL levels increased in the treated patients by 3.1%, or 2 mg/dL (median) vs. 10.2%, or 7 mg/dL, in controls (P less than .001).

The trial also reported a 33% greater risk of hospitalization for atrial fibrillation or flutter and about a 30% heightened risk of serious bleeding among patients taking icosapent ethyl. Dr. Bhatt pointed out that, while the high rate of atrial fibrillation among treated patients was statistically significant, “the most feared complication of atrial fibrillation is stroke, but in this study we saw a 28% reduction in stroke.”

Likewise the nonsignificantly higher rate of bleeding in the treatment group was inconsequential. “When we looked at specific types of serious bleeding – GI or stomach bleeding, CNS or bleeding into the brain or fatal bleeding – there were no significant differences,” he said.

Discussant Carl Orringer, MD, of the University of Miami, said, “My perspective of this is that the likelihood of atrial fibrillation, although statistically higher, is something that should not prevent physicians from prescribing the drug because of the tremendous benefit that we’ve seen in those appropriate patients on high intensity statin.” However, he said, it does merit further investigation. He also pointed out that one limitation of the study was that the population was 90% white. “Thus the potential benefits of icosapent ethyl in patients of other ethnicities remains unclear,” he said.

The results were published simultaneously online in the New England Journal of Medicine.

Dr. Bhatt receives funding from Amarin, which sponsored the REDUCE-IT trial.

SOURCE: Bhatt DL, et al. N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa181279.

CHICAGO – Detailed results of the REDUCE-IT trial have confirmed earlier-reported top line results that showed a 25% reduction in the risk of cardiovascular death or nonfatal cardiovascular event with the fish-derived, triglyceride-reducing agent icosapent acid in combination with statin.

But they should not be interpreted as validation of the cardiovascular benefits of fish-oil supplements, according to Deepak L. Bhatt, MD, principal investigator and steering committee chair for REDUCE-IT, who presented the results at the American Heart Association scientific sessions.

He reported the results from 8,179 patients followed for a median of 4.9 years. The treatment group received 4 g/day of icosapent ethyl (Vascepa, Amarin), a single-molecule agent consisting of the omega-3 acid known as eicosapentaeonoic acid (EPA) in ethyl-ester form, which Dr. Bhatt called “a highly purified” formulation. Vascepa is derived from fish but it is not fish oil, a company press release states. Amarin, sponsor of the study, released top line results in September.

To qualify for the trial, patients had to have a diagnosis of cardiovascular disease or diabetes and other risk factors, had been on statin therapy and had above normal triglyceride (135-499 mg/dL) and optimal LDL (41-100 mg/dL) levels. Patients were randomly assigned to receive 4 g/day of icosapent ethyl or placebo.

Dr. Bhatt stressed that the REDUCE-IT results do not necessarily validate the use of fish oil to lower cardiovascular risk. “It would be mistake if patients and physicians” to interpret the results that way, and that classifying the purified formulation of icosapent ethyl used in REDUCE-IT as fish oil is a “misnomer.” He added, “Really, what we’re talking about is prescription therapy icosapent ethyl vs. over-the-counter supplements.” Icosapent ethyl is approved in the United States for patients with triglyceride levels of more than 500 mg/dL.

Dr. Bhatt and the study coauthors acknowledged that the results of REDUCE-IT deviate from other trials of triglyceride-lowering agents, including other n-3 fatty acids. They noted two potential explanations: a high dose; or higher ratios of EPA to docosahexaenoic acid in the REDUCE-IT formulation vs. agents used in the other studies. For example, the ASCEND study, presented at the European Society of Cardiology in September, reported no cardiovascular benefit from a 1-g/day dose of omega-3 fatty acids and low-dose aspirin in patients with diabetes.

The primary endpoint of REDUCE-IT was a composite of cardiovascular death, nonfatal MI or stroke, coronary revascularization or unstable angina, which occurred in 17.2% of the patients taking icosapent ethyl, compared with 22% of the controls, for a risk reduction of 25% (P less than .001). The key secondary endpoint was composite of cardiovascular death and nonfatal MI or stroke, which occurred in 11.2% and 14.8% of the treated and placebo groups, respectively, for a risk reduction of 26% (P less than .001).

The study investigators also zeroed in on specific ischemic endpoints. Cardiovascular death rates were 20% lower in the treated patients (4.2% vs. 5.2%, P less than .03).

The study also evaluated lipid levels. The median change in triglyceride levels after a year of treatment was a decrease of 18.3%, or 39 mg/dL, in the treatment group while triglyceride levels rose 2.2% in the placebo patients (P less than .001). LDL levels increased in the treated patients by 3.1%, or 2 mg/dL (median) vs. 10.2%, or 7 mg/dL, in controls (P less than .001).

The trial also reported a 33% greater risk of hospitalization for atrial fibrillation or flutter and about a 30% heightened risk of serious bleeding among patients taking icosapent ethyl. Dr. Bhatt pointed out that, while the high rate of atrial fibrillation among treated patients was statistically significant, “the most feared complication of atrial fibrillation is stroke, but in this study we saw a 28% reduction in stroke.”

Likewise the nonsignificantly higher rate of bleeding in the treatment group was inconsequential. “When we looked at specific types of serious bleeding – GI or stomach bleeding, CNS or bleeding into the brain or fatal bleeding – there were no significant differences,” he said.

Discussant Carl Orringer, MD, of the University of Miami, said, “My perspective of this is that the likelihood of atrial fibrillation, although statistically higher, is something that should not prevent physicians from prescribing the drug because of the tremendous benefit that we’ve seen in those appropriate patients on high intensity statin.” However, he said, it does merit further investigation. He also pointed out that one limitation of the study was that the population was 90% white. “Thus the potential benefits of icosapent ethyl in patients of other ethnicities remains unclear,” he said.

The results were published simultaneously online in the New England Journal of Medicine.

Dr. Bhatt receives funding from Amarin, which sponsored the REDUCE-IT trial.

SOURCE: Bhatt DL, et al. N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa181279.

CHICAGO – Detailed results of the REDUCE-IT trial have confirmed earlier-reported top line results that showed a 25% reduction in the risk of cardiovascular death or nonfatal cardiovascular event with the fish-derived, triglyceride-reducing agent icosapent acid in combination with statin.

But they should not be interpreted as validation of the cardiovascular benefits of fish-oil supplements, according to Deepak L. Bhatt, MD, principal investigator and steering committee chair for REDUCE-IT, who presented the results at the American Heart Association scientific sessions.

He reported the results from 8,179 patients followed for a median of 4.9 years. The treatment group received 4 g/day of icosapent ethyl (Vascepa, Amarin), a single-molecule agent consisting of the omega-3 acid known as eicosapentaeonoic acid (EPA) in ethyl-ester form, which Dr. Bhatt called “a highly purified” formulation. Vascepa is derived from fish but it is not fish oil, a company press release states. Amarin, sponsor of the study, released top line results in September.

To qualify for the trial, patients had to have a diagnosis of cardiovascular disease or diabetes and other risk factors, had been on statin therapy and had above normal triglyceride (135-499 mg/dL) and optimal LDL (41-100 mg/dL) levels. Patients were randomly assigned to receive 4 g/day of icosapent ethyl or placebo.

Dr. Bhatt stressed that the REDUCE-IT results do not necessarily validate the use of fish oil to lower cardiovascular risk. “It would be mistake if patients and physicians” to interpret the results that way, and that classifying the purified formulation of icosapent ethyl used in REDUCE-IT as fish oil is a “misnomer.” He added, “Really, what we’re talking about is prescription therapy icosapent ethyl vs. over-the-counter supplements.” Icosapent ethyl is approved in the United States for patients with triglyceride levels of more than 500 mg/dL.

Dr. Bhatt and the study coauthors acknowledged that the results of REDUCE-IT deviate from other trials of triglyceride-lowering agents, including other n-3 fatty acids. They noted two potential explanations: a high dose; or higher ratios of EPA to docosahexaenoic acid in the REDUCE-IT formulation vs. agents used in the other studies. For example, the ASCEND study, presented at the European Society of Cardiology in September, reported no cardiovascular benefit from a 1-g/day dose of omega-3 fatty acids and low-dose aspirin in patients with diabetes.

The primary endpoint of REDUCE-IT was a composite of cardiovascular death, nonfatal MI or stroke, coronary revascularization or unstable angina, which occurred in 17.2% of the patients taking icosapent ethyl, compared with 22% of the controls, for a risk reduction of 25% (P less than .001). The key secondary endpoint was composite of cardiovascular death and nonfatal MI or stroke, which occurred in 11.2% and 14.8% of the treated and placebo groups, respectively, for a risk reduction of 26% (P less than .001).

The study investigators also zeroed in on specific ischemic endpoints. Cardiovascular death rates were 20% lower in the treated patients (4.2% vs. 5.2%, P less than .03).

The study also evaluated lipid levels. The median change in triglyceride levels after a year of treatment was a decrease of 18.3%, or 39 mg/dL, in the treatment group while triglyceride levels rose 2.2% in the placebo patients (P less than .001). LDL levels increased in the treated patients by 3.1%, or 2 mg/dL (median) vs. 10.2%, or 7 mg/dL, in controls (P less than .001).

The trial also reported a 33% greater risk of hospitalization for atrial fibrillation or flutter and about a 30% heightened risk of serious bleeding among patients taking icosapent ethyl. Dr. Bhatt pointed out that, while the high rate of atrial fibrillation among treated patients was statistically significant, “the most feared complication of atrial fibrillation is stroke, but in this study we saw a 28% reduction in stroke.”

Likewise the nonsignificantly higher rate of bleeding in the treatment group was inconsequential. “When we looked at specific types of serious bleeding – GI or stomach bleeding, CNS or bleeding into the brain or fatal bleeding – there were no significant differences,” he said.

Discussant Carl Orringer, MD, of the University of Miami, said, “My perspective of this is that the likelihood of atrial fibrillation, although statistically higher, is something that should not prevent physicians from prescribing the drug because of the tremendous benefit that we’ve seen in those appropriate patients on high intensity statin.” However, he said, it does merit further investigation. He also pointed out that one limitation of the study was that the population was 90% white. “Thus the potential benefits of icosapent ethyl in patients of other ethnicities remains unclear,” he said.

The results were published simultaneously online in the New England Journal of Medicine.

Dr. Bhatt receives funding from Amarin, which sponsored the REDUCE-IT trial.

SOURCE: Bhatt DL, et al. N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa181279.

ATLANTA – After undergoing 10 days of noninvasive magnetic brain stimulation with a novel device, eight of nine persons who stutter experienced improvements in speech fluency.

“This is the first step in what we believe is a major breakthrough in treatment,” lead study author David B. Rosenfield, MD, said in an interview at the annual meeting of the American Neurological Association.

In previously published work, Dr. Rosenfield, Director of the Speech and Language Center at Houston Methodist Neurological Institute, and his colleagues showed significant reduction in functional connectivity between Broca’s and Wernicke’s areas in persons who stutter, compared with normal speakers, by performing resting-state functional MRI of the brain. In the current open-label pilot trial, they tested the hypothesis that using direct noninvasive synchronous bifocal stimulation to potentiate the strength of connectivity between Broca’s and Wernicke’s areas in persons who stutter should improve their fluency.

Courtesy David B. Rosenfield, MD

The researchers found that all study participants significantly improved in fluency on either day 5 (P = 0.01) or day 10 (P = 0.02). Only one subject failed to show improvement on day 10 compared with day 1 after showing it on day 5. “This wasn’t meant to be a 10-day treatment that would last forever; this was meant to be a 10-day treatment to see whether the magnetic stimulation would work,” Dr. Rosenfield said. “It might well be that patients need treatment every day, once a week, or once a month. All we can say is that we have an input and an output. We gave them the treatment and they improved. One patient was so happy with it that he begged us to come back for additional treatment. It seems as though it’s a robust therapy.”

Doug Brunk/MDedge News

The TRPMS device was coinvented by Santosh A. Helekar, MD, PhD, and Henning Voss, PhD, both at Weill Cornell Medical College. The study received funding support from The Houston Methodist Hospital System Physicians Organization. Dr. Rosenfield reported having no financial disclosures. He noted that commercialization of the patented technology underlying the TRPMS device used in this study and in other diseases is currently being advanced by Seraya Medical Systems LLC.

[email protected]

Source: Ann Neurol. 2018;84[S22]:S45-6. Abstract S115.


 

ATLANTA – After undergoing 10 days of noninvasive magnetic brain stimulation with a novel device, eight of nine persons who stutter experienced improvements in speech fluency.

“This is the first step in what we believe is a major breakthrough in treatment,” lead study author David B. Rosenfield, MD, said in an interview at the annual meeting of the American Neurological Association.

In previously published work, Dr. Rosenfield, Director of the Speech and Language Center at Houston Methodist Neurological Institute, and his colleagues showed significant reduction in functional connectivity between Broca’s and Wernicke’s areas in persons who stutter, compared with normal speakers, by performing resting-state functional MRI of the brain. In the current open-label pilot trial, they tested the hypothesis that using direct noninvasive synchronous bifocal stimulation to potentiate the strength of connectivity between Broca’s and Wernicke’s areas in persons who stutter should improve their fluency.

Courtesy David B. Rosenfield, MD

The researchers found that all study participants significantly improved in fluency on either day 5 (P = 0.01) or day 10 (P = 0.02). Only one subject failed to show improvement on day 10 compared with day 1 after showing it on day 5. “This wasn’t meant to be a 10-day treatment that would last forever; this was meant to be a 10-day treatment to see whether the magnetic stimulation would work,” Dr. Rosenfield said. “It might well be that patients need treatment every day, once a week, or once a month. All we can say is that we have an input and an output. We gave them the treatment and they improved. One patient was so happy with it that he begged us to come back for additional treatment. It seems as though it’s a robust therapy.”

Doug Brunk/MDedge News

The TRPMS device was coinvented by Santosh A. Helekar, MD, PhD, and Henning Voss, PhD, both at Weill Cornell Medical College. The study received funding support from The Houston Methodist Hospital System Physicians Organization. Dr. Rosenfield reported having no financial disclosures. He noted that commercialization of the patented technology underlying the TRPMS device used in this study and in other diseases is currently being advanced by Seraya Medical Systems LLC.

[email protected]

Source: Ann Neurol. 2018;84[S22]:S45-6. Abstract S115.


 

ATLANTA – After undergoing 10 days of noninvasive magnetic brain stimulation with a novel device, eight of nine persons who stutter experienced improvements in speech fluency.

“This is the first step in what we believe is a major breakthrough in treatment,” lead study author David B. Rosenfield, MD, said in an interview at the annual meeting of the American Neurological Association.

In previously published work, Dr. Rosenfield, Director of the Speech and Language Center at Houston Methodist Neurological Institute, and his colleagues showed significant reduction in functional connectivity between Broca’s and Wernicke’s areas in persons who stutter, compared with normal speakers, by performing resting-state functional MRI of the brain. In the current open-label pilot trial, they tested the hypothesis that using direct noninvasive synchronous bifocal stimulation to potentiate the strength of connectivity between Broca’s and Wernicke’s areas in persons who stutter should improve their fluency.

Courtesy David B. Rosenfield, MD

The researchers found that all study participants significantly improved in fluency on either day 5 (P = 0.01) or day 10 (P = 0.02). Only one subject failed to show improvement on day 10 compared with day 1 after showing it on day 5. “This wasn’t meant to be a 10-day treatment that would last forever; this was meant to be a 10-day treatment to see whether the magnetic stimulation would work,” Dr. Rosenfield said. “It might well be that patients need treatment every day, once a week, or once a month. All we can say is that we have an input and an output. We gave them the treatment and they improved. One patient was so happy with it that he begged us to come back for additional treatment. It seems as though it’s a robust therapy.”

Doug Brunk/MDedge News

The TRPMS device was coinvented by Santosh A. Helekar, MD, PhD, and Henning Voss, PhD, both at Weill Cornell Medical College. The study received funding support from The Houston Methodist Hospital System Physicians Organization. Dr. Rosenfield reported having no financial disclosures. He noted that commercialization of the patented technology underlying the TRPMS device used in this study and in other diseases is currently being advanced by Seraya Medical Systems LLC.

[email protected]

Source: Ann Neurol. 2018;84[S22]:S45-6. Abstract S115.


 

Atopic dermatitis (AD) places a considerable burden on mental health and quality of life for patients with disease of even moderate severity, according to a cross-sectional study of data from the Atopic Dermatitis in America survey.

Among adults with severe AD, the mean score on the Dermatology Life Quality Index was 11.4, with a score of 6-30 representing a moderate to large effect on quality of life. The mean for those with moderate disease, 5.9, was just below that range, but 37% of that group did have scores between 6 and 30, Zelma C. Chiesa Fuxench, MD, of the University of Pennsylvania, Philadelphia, and her associates said in the Journal of Investigative Dermatology.

The mean on the Dermatology Life Quality Index for all AD patients was 4.1, with 24% falling into the moderate to large effect range, compared with 1% and 5% for controls. Results were similar on the mental health measure used, the Hospital Anxiety and Depression Scale (HADS). Mean HADS-anxiety scores were 7.0 for all AD patients and 4.7 for controls, and HADS-depression means were 5.8 for AD patients and 3.6 for controls, the investigators reported.

Analysis by disease severity found that 32% of those with moderate AD and almost 56% with severe AD had clinical anxiety (HADS-A score of 11-21), while somewhat lower prevalences were seen for clinical depression (HADS-D score of 11-21): 19.5% for those with moderate AD and 19.7% for patients with severe AD, Dr. Chiesa Fuxench and her associates said.

“An increasing number of studies provide evidence that AD is associated with marked [quality of life] impairment and increased health care costs with higher burden and costs in those with more severe disease. Additional studies should center on exploring those factors associated with AD, and AD disease severity, which lead to increased disease burden in this population,” they wrote.

Respondents to the Atopic Dermatitis in America survey were part of the GfK Knowledge Panel. The study involved a two-stage sampling process: one group of 1,278 adults determined prevalence ,and an oversample of 602 AD patients assessed severity differences.

Dr. Chiesa Fuxench has received research grants from Regeneron, Sanofi, Tioga, and Vanda for work related to atopic dermatitis and has received honoraria for CME work in atopic dermatitis sponsored by educational grants from Regeneron and Sanofi.

[email protected]

SOURCE: J Invest Dermatol. 2018. doi: 10.1016/j.jid.2018.08.028.

Atopic dermatitis (AD) places a considerable burden on mental health and quality of life for patients with disease of even moderate severity, according to a cross-sectional study of data from the Atopic Dermatitis in America survey.

Among adults with severe AD, the mean score on the Dermatology Life Quality Index was 11.4, with a score of 6-30 representing a moderate to large effect on quality of life. The mean for those with moderate disease, 5.9, was just below that range, but 37% of that group did have scores between 6 and 30, Zelma C. Chiesa Fuxench, MD, of the University of Pennsylvania, Philadelphia, and her associates said in the Journal of Investigative Dermatology.

The mean on the Dermatology Life Quality Index for all AD patients was 4.1, with 24% falling into the moderate to large effect range, compared with 1% and 5% for controls. Results were similar on the mental health measure used, the Hospital Anxiety and Depression Scale (HADS). Mean HADS-anxiety scores were 7.0 for all AD patients and 4.7 for controls, and HADS-depression means were 5.8 for AD patients and 3.6 for controls, the investigators reported.

Analysis by disease severity found that 32% of those with moderate AD and almost 56% with severe AD had clinical anxiety (HADS-A score of 11-21), while somewhat lower prevalences were seen for clinical depression (HADS-D score of 11-21): 19.5% for those with moderate AD and 19.7% for patients with severe AD, Dr. Chiesa Fuxench and her associates said.

“An increasing number of studies provide evidence that AD is associated with marked [quality of life] impairment and increased health care costs with higher burden and costs in those with more severe disease. Additional studies should center on exploring those factors associated with AD, and AD disease severity, which lead to increased disease burden in this population,” they wrote.

Respondents to the Atopic Dermatitis in America survey were part of the GfK Knowledge Panel. The study involved a two-stage sampling process: one group of 1,278 adults determined prevalence ,and an oversample of 602 AD patients assessed severity differences.

Dr. Chiesa Fuxench has received research grants from Regeneron, Sanofi, Tioga, and Vanda for work related to atopic dermatitis and has received honoraria for CME work in atopic dermatitis sponsored by educational grants from Regeneron and Sanofi.

[email protected]

SOURCE: J Invest Dermatol. 2018. doi: 10.1016/j.jid.2018.08.028.

Atopic dermatitis (AD) places a considerable burden on mental health and quality of life for patients with disease of even moderate severity, according to a cross-sectional study of data from the Atopic Dermatitis in America survey.

Among adults with severe AD, the mean score on the Dermatology Life Quality Index was 11.4, with a score of 6-30 representing a moderate to large effect on quality of life. The mean for those with moderate disease, 5.9, was just below that range, but 37% of that group did have scores between 6 and 30, Zelma C. Chiesa Fuxench, MD, of the University of Pennsylvania, Philadelphia, and her associates said in the Journal of Investigative Dermatology.

The mean on the Dermatology Life Quality Index for all AD patients was 4.1, with 24% falling into the moderate to large effect range, compared with 1% and 5% for controls. Results were similar on the mental health measure used, the Hospital Anxiety and Depression Scale (HADS). Mean HADS-anxiety scores were 7.0 for all AD patients and 4.7 for controls, and HADS-depression means were 5.8 for AD patients and 3.6 for controls, the investigators reported.

Analysis by disease severity found that 32% of those with moderate AD and almost 56% with severe AD had clinical anxiety (HADS-A score of 11-21), while somewhat lower prevalences were seen for clinical depression (HADS-D score of 11-21): 19.5% for those with moderate AD and 19.7% for patients with severe AD, Dr. Chiesa Fuxench and her associates said.

“An increasing number of studies provide evidence that AD is associated with marked [quality of life] impairment and increased health care costs with higher burden and costs in those with more severe disease. Additional studies should center on exploring those factors associated with AD, and AD disease severity, which lead to increased disease burden in this population,” they wrote.

Respondents to the Atopic Dermatitis in America survey were part of the GfK Knowledge Panel. The study involved a two-stage sampling process: one group of 1,278 adults determined prevalence ,and an oversample of 602 AD patients assessed severity differences.

Dr. Chiesa Fuxench has received research grants from Regeneron, Sanofi, Tioga, and Vanda for work related to atopic dermatitis and has received honoraria for CME work in atopic dermatitis sponsored by educational grants from Regeneron and Sanofi.

[email protected]

SOURCE: J Invest Dermatol. 2018. doi: 10.1016/j.jid.2018.08.028.

Among direct oral anticoagulants, apixaban (Eliquis) has shown fewer stroke events and bleeding than warfarin in patients with atrial fibrillation, according to results of an updated comparative effectiveness review.

Dabigatran (Pradaxa), by contrast, has shown reductions in stroke events but a similar rate of bleeding events compared to warfarin, according to the report from the Duke Evidence-based Practice Center, Durham, N.C.

Rivaroxaban (Xarelto), meanwhile, is “similar in both benefits and harms with warfarin” in evidence to date, investigators wrote in the report, which was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI).

Finally, edoxaban (Savaysa) is “most likely similar” to warfarin with respect to preventing stroke or systemic embolism, with less risk for major bleeding and hemorrhagic stroke, investigators wrote in a summary of their findings on the AHRQ website.

“Effectiveness of these direct oral anticoagulants as compared to one another however is limited by the lack of randomized studies directly comparing their safety and effectiveness,” concluded investigators, led by Gillian D. Sanders, PhD, of Duke University.

The 612-page report details a systematic review based on 320 articles representing 185 unique studies. The review was designed to update a 2013 AHRQ report that evaluated evidence not only for treatment options to prevent stroke in patients with atrial fibrillation, but also for tools used to predict risk of stroke or bleeding.

In the 2013 report, investigators concluded that the newer anticoagulants showed “early promise” in reducing stroke and bleeding events compared with warfarin.

That earlier report said that CHA₂ and CHA₂DS₂-VASc had the best evidence to support prediction of stroke events, while HAS-BLED provided the best discrimination of bleeding risk.

The updated report adds the ABC stroke risk score as a tool that, along with CHADS2 and CHA2DS2-VASc, has the “best evidence” predicting thromboembolic risk, authors said.

Imaging tools, on the other hand, still need more evidence supporting their use to predict thromboembolic risk, Dr. Sanders and colleagues said in their report.

The literature review, which covered the January 2000 through February 2018, turned up 61 studies relevant to predicting thromboembolic risk, 38 on bleeding risk, and 117 on preventing thromboembolic events with anticoagulation therapies, antiplatelet therapies, or procedures.

Direct oral anticoagulants were evaluated in randomized clinical trials that were “often very large, of good quality, and considered definitive in the field,” Dr. Sanders and colleagues wrote in their report.

However, these trials were constrained to comparing direct oral anticoagulants with warfarin or aspirin, and have not involved head-to-head comparison among the newer agents, they added.

“Based on these trials though, clinical leaders and professional societies have determined that these newer agents are better than the prior lone treatment of warfarin in terms of stroke prevention, side effects, and risk of bleeding,” they said in the published report.
 

SOURCE: Sanders GD, et al. 2018 Oct 30. AHRQ Publication No. 18(19)-EHC018-EF.
 

Among direct oral anticoagulants, apixaban (Eliquis) has shown fewer stroke events and bleeding than warfarin in patients with atrial fibrillation, according to results of an updated comparative effectiveness review.

Dabigatran (Pradaxa), by contrast, has shown reductions in stroke events but a similar rate of bleeding events compared to warfarin, according to the report from the Duke Evidence-based Practice Center, Durham, N.C.

Rivaroxaban (Xarelto), meanwhile, is “similar in both benefits and harms with warfarin” in evidence to date, investigators wrote in the report, which was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI).

Finally, edoxaban (Savaysa) is “most likely similar” to warfarin with respect to preventing stroke or systemic embolism, with less risk for major bleeding and hemorrhagic stroke, investigators wrote in a summary of their findings on the AHRQ website.

“Effectiveness of these direct oral anticoagulants as compared to one another however is limited by the lack of randomized studies directly comparing their safety and effectiveness,” concluded investigators, led by Gillian D. Sanders, PhD, of Duke University.

The 612-page report details a systematic review based on 320 articles representing 185 unique studies. The review was designed to update a 2013 AHRQ report that evaluated evidence not only for treatment options to prevent stroke in patients with atrial fibrillation, but also for tools used to predict risk of stroke or bleeding.

In the 2013 report, investigators concluded that the newer anticoagulants showed “early promise” in reducing stroke and bleeding events compared with warfarin.

That earlier report said that CHA₂ and CHA₂DS₂-VASc had the best evidence to support prediction of stroke events, while HAS-BLED provided the best discrimination of bleeding risk.

The updated report adds the ABC stroke risk score as a tool that, along with CHADS2 and CHA2DS2-VASc, has the “best evidence” predicting thromboembolic risk, authors said.

Imaging tools, on the other hand, still need more evidence supporting their use to predict thromboembolic risk, Dr. Sanders and colleagues said in their report.

The literature review, which covered the January 2000 through February 2018, turned up 61 studies relevant to predicting thromboembolic risk, 38 on bleeding risk, and 117 on preventing thromboembolic events with anticoagulation therapies, antiplatelet therapies, or procedures.

Direct oral anticoagulants were evaluated in randomized clinical trials that were “often very large, of good quality, and considered definitive in the field,” Dr. Sanders and colleagues wrote in their report.

However, these trials were constrained to comparing direct oral anticoagulants with warfarin or aspirin, and have not involved head-to-head comparison among the newer agents, they added.

“Based on these trials though, clinical leaders and professional societies have determined that these newer agents are better than the prior lone treatment of warfarin in terms of stroke prevention, side effects, and risk of bleeding,” they said in the published report.
 

SOURCE: Sanders GD, et al. 2018 Oct 30. AHRQ Publication No. 18(19)-EHC018-EF.
 

Among direct oral anticoagulants, apixaban (Eliquis) has shown fewer stroke events and bleeding than warfarin in patients with atrial fibrillation, according to results of an updated comparative effectiveness review.

Dabigatran (Pradaxa), by contrast, has shown reductions in stroke events but a similar rate of bleeding events compared to warfarin, according to the report from the Duke Evidence-based Practice Center, Durham, N.C.

Rivaroxaban (Xarelto), meanwhile, is “similar in both benefits and harms with warfarin” in evidence to date, investigators wrote in the report, which was prepared for the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI).

Finally, edoxaban (Savaysa) is “most likely similar” to warfarin with respect to preventing stroke or systemic embolism, with less risk for major bleeding and hemorrhagic stroke, investigators wrote in a summary of their findings on the AHRQ website.

“Effectiveness of these direct oral anticoagulants as compared to one another however is limited by the lack of randomized studies directly comparing their safety and effectiveness,” concluded investigators, led by Gillian D. Sanders, PhD, of Duke University.

The 612-page report details a systematic review based on 320 articles representing 185 unique studies. The review was designed to update a 2013 AHRQ report that evaluated evidence not only for treatment options to prevent stroke in patients with atrial fibrillation, but also for tools used to predict risk of stroke or bleeding.

In the 2013 report, investigators concluded that the newer anticoagulants showed “early promise” in reducing stroke and bleeding events compared with warfarin.

That earlier report said that CHA₂ and CHA₂DS₂-VASc had the best evidence to support prediction of stroke events, while HAS-BLED provided the best discrimination of bleeding risk.

The updated report adds the ABC stroke risk score as a tool that, along with CHADS2 and CHA2DS2-VASc, has the “best evidence” predicting thromboembolic risk, authors said.

Imaging tools, on the other hand, still need more evidence supporting their use to predict thromboembolic risk, Dr. Sanders and colleagues said in their report.

The literature review, which covered the January 2000 through February 2018, turned up 61 studies relevant to predicting thromboembolic risk, 38 on bleeding risk, and 117 on preventing thromboembolic events with anticoagulation therapies, antiplatelet therapies, or procedures.

Direct oral anticoagulants were evaluated in randomized clinical trials that were “often very large, of good quality, and considered definitive in the field,” Dr. Sanders and colleagues wrote in their report.

However, these trials were constrained to comparing direct oral anticoagulants with warfarin or aspirin, and have not involved head-to-head comparison among the newer agents, they added.

“Based on these trials though, clinical leaders and professional societies have determined that these newer agents are better than the prior lone treatment of warfarin in terms of stroke prevention, side effects, and risk of bleeding,” they said in the published report.
 

SOURCE: Sanders GD, et al. 2018 Oct 30. AHRQ Publication No. 18(19)-EHC018-EF.
 

multiple myeloma

Adding elotuzumab to pomalidomide and low-dose dexamethasone can improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to the ELOQUENT-3 trial.

These results support the recent U.S. approval of elotuzumab, pomalidomide, and dexamethasone in adults with MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Results from ELOQUENT-3 were recently published in The New England Journal of Medicine and previously presented at the 23rd Congress of the European Hematology Association in June.

The phase 2 trial included patients with refractory or relapsed and refractory MM who had received lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and low-dose dexamethasone (EPd, n=60) or pomalidomide and low-dose dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).

There were two stringent complete responses (CRs) and three CRs in the EPd arm, and there was one CR in the Pd arm.

The median duration of response was 8.3 months in the Pd arm and was not reached in the EPd arm.

The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.008).

Overall survival data were not mature at the time of analysis, but there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 in the Pd arm.

The most common treatment-related adverse events (in the EPd and Pd arms, respectively) were neutropenia (18% and 20%), hyperglycemia (18% and 11%), and anemia (10% and 15%).

This trial was supported by Bristol-Myers Squibb and AbbVie Biotherapeutics, and researchers reported relationships with several other companies.

multiple myeloma

Adding elotuzumab to pomalidomide and low-dose dexamethasone can improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to the ELOQUENT-3 trial.

These results support the recent U.S. approval of elotuzumab, pomalidomide, and dexamethasone in adults with MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Results from ELOQUENT-3 were recently published in The New England Journal of Medicine and previously presented at the 23rd Congress of the European Hematology Association in June.

The phase 2 trial included patients with refractory or relapsed and refractory MM who had received lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and low-dose dexamethasone (EPd, n=60) or pomalidomide and low-dose dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).

There were two stringent complete responses (CRs) and three CRs in the EPd arm, and there was one CR in the Pd arm.

The median duration of response was 8.3 months in the Pd arm and was not reached in the EPd arm.

The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.008).

Overall survival data were not mature at the time of analysis, but there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 in the Pd arm.

The most common treatment-related adverse events (in the EPd and Pd arms, respectively) were neutropenia (18% and 20%), hyperglycemia (18% and 11%), and anemia (10% and 15%).

This trial was supported by Bristol-Myers Squibb and AbbVie Biotherapeutics, and researchers reported relationships with several other companies.

multiple myeloma

Adding elotuzumab to pomalidomide and low-dose dexamethasone can improve progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to the ELOQUENT-3 trial.

These results support the recent U.S. approval of elotuzumab, pomalidomide, and dexamethasone in adults with MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Results from ELOQUENT-3 were recently published in The New England Journal of Medicine and previously presented at the 23rd Congress of the European Hematology Association in June.

The phase 2 trial included patients with refractory or relapsed and refractory MM who had received lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and low-dose dexamethasone (EPd, n=60) or pomalidomide and low-dose dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).

There were two stringent complete responses (CRs) and three CRs in the EPd arm, and there was one CR in the Pd arm.

The median duration of response was 8.3 months in the Pd arm and was not reached in the EPd arm.

The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.008).

Overall survival data were not mature at the time of analysis, but there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 in the Pd arm.

The most common treatment-related adverse events (in the EPd and Pd arms, respectively) were neutropenia (18% and 20%), hyperglycemia (18% and 11%), and anemia (10% and 15%).

This trial was supported by Bristol-Myers Squibb and AbbVie Biotherapeutics, and researchers reported relationships with several other companies.

CHICAGO – A multifaceted quality initiative that consists of staff education, patient reminders and a feedback loop may help to improve therapy adherence and encourage lifestyle changes of at-risk cardiovascular patients in settings with limited resources, according to results of a clinical trial from Brazil presented at the American Heart Association scientific sessions 2018.

“In patients at high cardiovascular risk – in this case patients with established cardiovascular disease – a multifaceted quality-improvement intervention resulted in significant improvement in the use of evidence-based therapies,” said Otavio Berwanger, MD, PhD, of the Heart Hospital in Sao Paolo. He reported results of the BRIDGE Cardiovascular Prevention Cluster Randomized Trial. “The tools used in our trial can become the basis for developing quality-improvement programs to maximize the use of evidence-based therapies for the management of these high-risk patients with, especially in limited-resource settings.”

BRIDGE-CV included 1,619 patients from 40 care settings. Institutions that adopted the multifaceted intervention adhered to 73.5% of the evidence-based therapies (antiplatelet agents, statins and ACE inhibitors) while those in the control group adhered to 58.7% of the performance measures, Dr. Berwanger said. That represents a gain of 25%. The study employed an “all-or-none” model. That is, participating sites were required to adopt all components of the quality-improvement initiative or none.

SOURCE: Berwanger O, et al. AHA 2018 Abstr.19360.

CHICAGO – A multifaceted quality initiative that consists of staff education, patient reminders and a feedback loop may help to improve therapy adherence and encourage lifestyle changes of at-risk cardiovascular patients in settings with limited resources, according to results of a clinical trial from Brazil presented at the American Heart Association scientific sessions 2018.

“In patients at high cardiovascular risk – in this case patients with established cardiovascular disease – a multifaceted quality-improvement intervention resulted in significant improvement in the use of evidence-based therapies,” said Otavio Berwanger, MD, PhD, of the Heart Hospital in Sao Paolo. He reported results of the BRIDGE Cardiovascular Prevention Cluster Randomized Trial. “The tools used in our trial can become the basis for developing quality-improvement programs to maximize the use of evidence-based therapies for the management of these high-risk patients with, especially in limited-resource settings.”

BRIDGE-CV included 1,619 patients from 40 care settings. Institutions that adopted the multifaceted intervention adhered to 73.5% of the evidence-based therapies (antiplatelet agents, statins and ACE inhibitors) while those in the control group adhered to 58.7% of the performance measures, Dr. Berwanger said. That represents a gain of 25%. The study employed an “all-or-none” model. That is, participating sites were required to adopt all components of the quality-improvement initiative or none.

SOURCE: Berwanger O, et al. AHA 2018 Abstr.19360.

CHICAGO – A multifaceted quality initiative that consists of staff education, patient reminders and a feedback loop may help to improve therapy adherence and encourage lifestyle changes of at-risk cardiovascular patients in settings with limited resources, according to results of a clinical trial from Brazil presented at the American Heart Association scientific sessions 2018.

“In patients at high cardiovascular risk – in this case patients with established cardiovascular disease – a multifaceted quality-improvement intervention resulted in significant improvement in the use of evidence-based therapies,” said Otavio Berwanger, MD, PhD, of the Heart Hospital in Sao Paolo. He reported results of the BRIDGE Cardiovascular Prevention Cluster Randomized Trial. “The tools used in our trial can become the basis for developing quality-improvement programs to maximize the use of evidence-based therapies for the management of these high-risk patients with, especially in limited-resource settings.”

BRIDGE-CV included 1,619 patients from 40 care settings. Institutions that adopted the multifaceted intervention adhered to 73.5% of the evidence-based therapies (antiplatelet agents, statins and ACE inhibitors) while those in the control group adhered to 58.7% of the performance measures, Dr. Berwanger said. That represents a gain of 25%. The study employed an “all-or-none” model. That is, participating sites were required to adopt all components of the quality-improvement initiative or none.

SOURCE: Berwanger O, et al. AHA 2018 Abstr.19360.

SAN FRANCISCO – Patients with chronic liver disease are prescribed opioids and benzodiazepines at very high rates, despite risk for adverse consequences because of hepatic metabolism, according to results from a large longitudinal study of national data.

“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.

In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.

Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.

“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.

She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.

Dr. Konerman reported having no financial disclosures.

[email protected]

SAN FRANCISCO – Patients with chronic liver disease are prescribed opioids and benzodiazepines at very high rates, despite risk for adverse consequences because of hepatic metabolism, according to results from a large longitudinal study of national data.

“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.

In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.

Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.

“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.

She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.

Dr. Konerman reported having no financial disclosures.

[email protected]

SAN FRANCISCO – Patients with chronic liver disease are prescribed opioids and benzodiazepines at very high rates, despite risk for adverse consequences because of hepatic metabolism, according to results from a large longitudinal study of national data.

“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.

In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.

Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.

“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.

She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.

Dr. Konerman reported having no financial disclosures.

[email protected]