How old is too old for a patient to undergo hematopoietic cell transplantation (HCT)? That’s the wrong question to ask, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus. Instead, he said, look at other factors such as disease status and genetics.

“Transplantation for older patients, even beyond the age of 70, is acceptable, as long as it’s done with caution, care, and wisdom. So we’re all not too old for transplantation, at least not today,” said Daniel Weisdorf, MD, professor of medicine and deputy director of the University of Minnesota Clinical and Translational Science Institute.

As he noted, acute myeloid leukemia (AML) is often fatal. Among the general population, “the expected survival life expectancy at age 75 is 98% at 1 year, and most people living at 75 go on to live more than 10 years,” he said. “But if you have AML, at age 75, you have 20% survival at 1 year, 4% at 3 years. And since the median age of AML diagnosis is 68, and 75% of patients are diagnosed beyond the age of 55, this becomes relevant.”

Risk factors that affect survival after transplantation “certainly include age, but that interacts directly with the comorbidities people accumulate with age, their assessments of frailty, and their Karnofsky performance status, as well as the disease phenotype and molecular genetic markers,” Dr. Weisdorf said. “Perhaps most importantly, though not addressed very much, is patients’ willingness to undertake intensive therapy and their life outlook related to patient-reported outcomes when they get older.”

Despite the lack of indications that higher age by itself is an influential factor in survival after transplant, “we are generally reluctant to push the age of eligibility,” Dr. Weisdorf said. He noted that recently published American Society of Hematology guidelines for treatment of AML over the age of 55 “don’t discuss anything about transplantation fitness because they didn’t want to tackle that.”

Overall survival (OS) at 1 year after allogenic transplants only dipped slightly from ages 51-60 to 71 and above, according to Dr. Weisdorf’s analysis of U.S. data collected by the Center for International Blood and Marrow Transplant Research for the time period 2005-2019.

OS was 67.6% (66.8%-68.3%) for the 41-50 age group (n = 9,287) and 57.9% (56.1%-59.8%) for the 71 and older group, Dr. Weisdorf found. Overall, OS dropped by about 4 percentage points per decade of age, he said, revealing a “modest influence” of advancing years.

His analysis of autologous transplant data from the same source, also for 2005-2019, revealed “essentially no age influence.” OS was 90.8% (90.3%-91.2%) for the 41-50 age group (n = 15,075) and 86.6% (85.9%-87.3%) for the 71 and older group (n = 7,247).

Dr. Weisdorf also highlighted unpublished research that suggests that cord-blood transplant recipients older than 70 face a significantly higher risk of death than that of younger patients in the same category. Cord blood “may be option of last resort” because of a lack of other options, he explained. “And it may be part of the learning curve of cord blood transplantation, which grew a little bit in the early 2000s, and maybe past 2010, and then fell off as everybody got enamored with the haploidentical transplant option.”

How can physicians make decisions about transplants in older patients? “The transplant comorbidity index, the specific comorbidities themselves, performance score, and frailty are all measures of somebody’s fitness to be a good candidate for transplant, really at any age,” Dr. Weisdorf said. “But we also have to recognize that disease status, genetics, and the risk phenotype remain critical and should influence decision making.”

However, even as transplant survival improves overall, “very few people are incorporating any very specific biological markers” in decision-making, he said. “We’ve gotten to measures of frailty, but we haven’t gotten to any biologic measures of cytokines or other things that would predict poor chances for doing well. So I’m afraid we’re still standing at the foot of the bed saying: ‘You look okay.’ Or we’re measuring their comorbidity index. But it is disappointing that we’re using mostly very simple clinical measures to decide if somebody is sturdy enough to proceed, and we perhaps need something better. But I don’t have a great suggestion what it should be.”

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Weisdorf disclosed consulting fees from Fate Therapeutics and Incyte Corp.

SOURCE: “The Ever-Increasing Upper Age for Transplant: Is This Evidence-Based?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

How old is too old for a patient to undergo hematopoietic cell transplantation (HCT)? That’s the wrong question to ask, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus. Instead, he said, look at other factors such as disease status and genetics.

“Transplantation for older patients, even beyond the age of 70, is acceptable, as long as it’s done with caution, care, and wisdom. So we’re all not too old for transplantation, at least not today,” said Daniel Weisdorf, MD, professor of medicine and deputy director of the University of Minnesota Clinical and Translational Science Institute.

As he noted, acute myeloid leukemia (AML) is often fatal. Among the general population, “the expected survival life expectancy at age 75 is 98% at 1 year, and most people living at 75 go on to live more than 10 years,” he said. “But if you have AML, at age 75, you have 20% survival at 1 year, 4% at 3 years. And since the median age of AML diagnosis is 68, and 75% of patients are diagnosed beyond the age of 55, this becomes relevant.”

Risk factors that affect survival after transplantation “certainly include age, but that interacts directly with the comorbidities people accumulate with age, their assessments of frailty, and their Karnofsky performance status, as well as the disease phenotype and molecular genetic markers,” Dr. Weisdorf said. “Perhaps most importantly, though not addressed very much, is patients’ willingness to undertake intensive therapy and their life outlook related to patient-reported outcomes when they get older.”

Despite the lack of indications that higher age by itself is an influential factor in survival after transplant, “we are generally reluctant to push the age of eligibility,” Dr. Weisdorf said. He noted that recently published American Society of Hematology guidelines for treatment of AML over the age of 55 “don’t discuss anything about transplantation fitness because they didn’t want to tackle that.”

Overall survival (OS) at 1 year after allogenic transplants only dipped slightly from ages 51-60 to 71 and above, according to Dr. Weisdorf’s analysis of U.S. data collected by the Center for International Blood and Marrow Transplant Research for the time period 2005-2019.

OS was 67.6% (66.8%-68.3%) for the 41-50 age group (n = 9,287) and 57.9% (56.1%-59.8%) for the 71 and older group, Dr. Weisdorf found. Overall, OS dropped by about 4 percentage points per decade of age, he said, revealing a “modest influence” of advancing years.

His analysis of autologous transplant data from the same source, also for 2005-2019, revealed “essentially no age influence.” OS was 90.8% (90.3%-91.2%) for the 41-50 age group (n = 15,075) and 86.6% (85.9%-87.3%) for the 71 and older group (n = 7,247).

Dr. Weisdorf also highlighted unpublished research that suggests that cord-blood transplant recipients older than 70 face a significantly higher risk of death than that of younger patients in the same category. Cord blood “may be option of last resort” because of a lack of other options, he explained. “And it may be part of the learning curve of cord blood transplantation, which grew a little bit in the early 2000s, and maybe past 2010, and then fell off as everybody got enamored with the haploidentical transplant option.”

How can physicians make decisions about transplants in older patients? “The transplant comorbidity index, the specific comorbidities themselves, performance score, and frailty are all measures of somebody’s fitness to be a good candidate for transplant, really at any age,” Dr. Weisdorf said. “But we also have to recognize that disease status, genetics, and the risk phenotype remain critical and should influence decision making.”

However, even as transplant survival improves overall, “very few people are incorporating any very specific biological markers” in decision-making, he said. “We’ve gotten to measures of frailty, but we haven’t gotten to any biologic measures of cytokines or other things that would predict poor chances for doing well. So I’m afraid we’re still standing at the foot of the bed saying: ‘You look okay.’ Or we’re measuring their comorbidity index. But it is disappointing that we’re using mostly very simple clinical measures to decide if somebody is sturdy enough to proceed, and we perhaps need something better. But I don’t have a great suggestion what it should be.”

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Weisdorf disclosed consulting fees from Fate Therapeutics and Incyte Corp.

SOURCE: “The Ever-Increasing Upper Age for Transplant: Is This Evidence-Based?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

How old is too old for a patient to undergo hematopoietic cell transplantation (HCT)? That’s the wrong question to ask, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus. Instead, he said, look at other factors such as disease status and genetics.

“Transplantation for older patients, even beyond the age of 70, is acceptable, as long as it’s done with caution, care, and wisdom. So we’re all not too old for transplantation, at least not today,” said Daniel Weisdorf, MD, professor of medicine and deputy director of the University of Minnesota Clinical and Translational Science Institute.

As he noted, acute myeloid leukemia (AML) is often fatal. Among the general population, “the expected survival life expectancy at age 75 is 98% at 1 year, and most people living at 75 go on to live more than 10 years,” he said. “But if you have AML, at age 75, you have 20% survival at 1 year, 4% at 3 years. And since the median age of AML diagnosis is 68, and 75% of patients are diagnosed beyond the age of 55, this becomes relevant.”

Risk factors that affect survival after transplantation “certainly include age, but that interacts directly with the comorbidities people accumulate with age, their assessments of frailty, and their Karnofsky performance status, as well as the disease phenotype and molecular genetic markers,” Dr. Weisdorf said. “Perhaps most importantly, though not addressed very much, is patients’ willingness to undertake intensive therapy and their life outlook related to patient-reported outcomes when they get older.”

Despite the lack of indications that higher age by itself is an influential factor in survival after transplant, “we are generally reluctant to push the age of eligibility,” Dr. Weisdorf said. He noted that recently published American Society of Hematology guidelines for treatment of AML over the age of 55 “don’t discuss anything about transplantation fitness because they didn’t want to tackle that.”

Overall survival (OS) at 1 year after allogenic transplants only dipped slightly from ages 51-60 to 71 and above, according to Dr. Weisdorf’s analysis of U.S. data collected by the Center for International Blood and Marrow Transplant Research for the time period 2005-2019.

OS was 67.6% (66.8%-68.3%) for the 41-50 age group (n = 9,287) and 57.9% (56.1%-59.8%) for the 71 and older group, Dr. Weisdorf found. Overall, OS dropped by about 4 percentage points per decade of age, he said, revealing a “modest influence” of advancing years.

His analysis of autologous transplant data from the same source, also for 2005-2019, revealed “essentially no age influence.” OS was 90.8% (90.3%-91.2%) for the 41-50 age group (n = 15,075) and 86.6% (85.9%-87.3%) for the 71 and older group (n = 7,247).

Dr. Weisdorf also highlighted unpublished research that suggests that cord-blood transplant recipients older than 70 face a significantly higher risk of death than that of younger patients in the same category. Cord blood “may be option of last resort” because of a lack of other options, he explained. “And it may be part of the learning curve of cord blood transplantation, which grew a little bit in the early 2000s, and maybe past 2010, and then fell off as everybody got enamored with the haploidentical transplant option.”

How can physicians make decisions about transplants in older patients? “The transplant comorbidity index, the specific comorbidities themselves, performance score, and frailty are all measures of somebody’s fitness to be a good candidate for transplant, really at any age,” Dr. Weisdorf said. “But we also have to recognize that disease status, genetics, and the risk phenotype remain critical and should influence decision making.”

However, even as transplant survival improves overall, “very few people are incorporating any very specific biological markers” in decision-making, he said. “We’ve gotten to measures of frailty, but we haven’t gotten to any biologic measures of cytokines or other things that would predict poor chances for doing well. So I’m afraid we’re still standing at the foot of the bed saying: ‘You look okay.’ Or we’re measuring their comorbidity index. But it is disappointing that we’re using mostly very simple clinical measures to decide if somebody is sturdy enough to proceed, and we perhaps need something better. But I don’t have a great suggestion what it should be.”

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Weisdorf disclosed consulting fees from Fate Therapeutics and Incyte Corp.

SOURCE: “The Ever-Increasing Upper Age for Transplant: Is This Evidence-Based?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

Women account for approximately 78% of the pediatric dermatology workforce, and continue to gain influence through increased numbers of leadership positions and published research, based on data from a review of professional society leaders, grant recipients, and annual meeting presenters from 2010 to 2019.

“Despite extensive research on gender equality in general dermatology, studies have yet to explore the evolving representation of women as leaders and researchers in pediatric dermatology, a field where the majority of board-certified physicians are women,” wrote Catherine Baker, MD, and colleagues. Dr. Baker was a medical student at Geisel School of Medicine at Dartmouth, Hanover, N.H., at the time of the study and is now a resident physician at Brigham and Women’s Hospital, Boston.

In a study published in Pediatric Dermatology, the researchers reviewed data on society leadership, research grants, and annual meeting speakers in order to evaluate the impact of women in pediatric dermatology.

Overall, the Society for Pediatric Dermatology has had 20 women presidents since its founding in 1975 (45%), and 7 of the last 10 since 2011 have been women (70%). The Pediatric Dermatology Research Alliance, founded in 2013, has two cochairs each year, and 75% have been women.

The percentage of women as lead authors of published research in pediatric dermatology increased significantly from 1983 to 2019; 71% of first authors and 65% of senior authors of papers in the journal Pediatric Dermatology in 2019 were women.

In addition, 26 of the 31 physicians (84%) who received SPD/PeDRA pilot project awards between 2008 and 2018 were women, as were 88% of SPD/PeDRA team/collaborative grant winners from 2016 to 2018.

However, named lectures at annual meetings remain an area in which women are underrepresented, the researchers wrote. Although women have been well represented at PeDRA meetings, accounting for 65% of plenary speakers, but they accounted for less than half (44%) of Hurwitz and Founders’ lectures at SPD annual meetings from 2010 to 2019.

The study findings were limited by a lack of data on nonbinary genders and the possibility of error in assessing gender based on name and online profiles, the researchers noted. However, the results suggest that women have increased their influence in pediatric dermatology through leadership and research, although a gender gap persists in roles as senior authors and named lecturers at meetings, they wrote.

Overall, “we expect increasing gender equity in these positions as women continue to play important roles as leaders and researchers in pediatric dermatology,” the researchers concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Baker C et al. Pediatr Dermatol. 2020 Jul 9. doi: 10.1111/pde.14266.

Women account for approximately 78% of the pediatric dermatology workforce, and continue to gain influence through increased numbers of leadership positions and published research, based on data from a review of professional society leaders, grant recipients, and annual meeting presenters from 2010 to 2019.

“Despite extensive research on gender equality in general dermatology, studies have yet to explore the evolving representation of women as leaders and researchers in pediatric dermatology, a field where the majority of board-certified physicians are women,” wrote Catherine Baker, MD, and colleagues. Dr. Baker was a medical student at Geisel School of Medicine at Dartmouth, Hanover, N.H., at the time of the study and is now a resident physician at Brigham and Women’s Hospital, Boston.

In a study published in Pediatric Dermatology, the researchers reviewed data on society leadership, research grants, and annual meeting speakers in order to evaluate the impact of women in pediatric dermatology.

Overall, the Society for Pediatric Dermatology has had 20 women presidents since its founding in 1975 (45%), and 7 of the last 10 since 2011 have been women (70%). The Pediatric Dermatology Research Alliance, founded in 2013, has two cochairs each year, and 75% have been women.

The percentage of women as lead authors of published research in pediatric dermatology increased significantly from 1983 to 2019; 71% of first authors and 65% of senior authors of papers in the journal Pediatric Dermatology in 2019 were women.

In addition, 26 of the 31 physicians (84%) who received SPD/PeDRA pilot project awards between 2008 and 2018 were women, as were 88% of SPD/PeDRA team/collaborative grant winners from 2016 to 2018.

However, named lectures at annual meetings remain an area in which women are underrepresented, the researchers wrote. Although women have been well represented at PeDRA meetings, accounting for 65% of plenary speakers, but they accounted for less than half (44%) of Hurwitz and Founders’ lectures at SPD annual meetings from 2010 to 2019.

The study findings were limited by a lack of data on nonbinary genders and the possibility of error in assessing gender based on name and online profiles, the researchers noted. However, the results suggest that women have increased their influence in pediatric dermatology through leadership and research, although a gender gap persists in roles as senior authors and named lecturers at meetings, they wrote.

Overall, “we expect increasing gender equity in these positions as women continue to play important roles as leaders and researchers in pediatric dermatology,” the researchers concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Baker C et al. Pediatr Dermatol. 2020 Jul 9. doi: 10.1111/pde.14266.

Women account for approximately 78% of the pediatric dermatology workforce, and continue to gain influence through increased numbers of leadership positions and published research, based on data from a review of professional society leaders, grant recipients, and annual meeting presenters from 2010 to 2019.

“Despite extensive research on gender equality in general dermatology, studies have yet to explore the evolving representation of women as leaders and researchers in pediatric dermatology, a field where the majority of board-certified physicians are women,” wrote Catherine Baker, MD, and colleagues. Dr. Baker was a medical student at Geisel School of Medicine at Dartmouth, Hanover, N.H., at the time of the study and is now a resident physician at Brigham and Women’s Hospital, Boston.

In a study published in Pediatric Dermatology, the researchers reviewed data on society leadership, research grants, and annual meeting speakers in order to evaluate the impact of women in pediatric dermatology.

Overall, the Society for Pediatric Dermatology has had 20 women presidents since its founding in 1975 (45%), and 7 of the last 10 since 2011 have been women (70%). The Pediatric Dermatology Research Alliance, founded in 2013, has two cochairs each year, and 75% have been women.

The percentage of women as lead authors of published research in pediatric dermatology increased significantly from 1983 to 2019; 71% of first authors and 65% of senior authors of papers in the journal Pediatric Dermatology in 2019 were women.

In addition, 26 of the 31 physicians (84%) who received SPD/PeDRA pilot project awards between 2008 and 2018 were women, as were 88% of SPD/PeDRA team/collaborative grant winners from 2016 to 2018.

However, named lectures at annual meetings remain an area in which women are underrepresented, the researchers wrote. Although women have been well represented at PeDRA meetings, accounting for 65% of plenary speakers, but they accounted for less than half (44%) of Hurwitz and Founders’ lectures at SPD annual meetings from 2010 to 2019.

The study findings were limited by a lack of data on nonbinary genders and the possibility of error in assessing gender based on name and online profiles, the researchers noted. However, the results suggest that women have increased their influence in pediatric dermatology through leadership and research, although a gender gap persists in roles as senior authors and named lecturers at meetings, they wrote.

Overall, “we expect increasing gender equity in these positions as women continue to play important roles as leaders and researchers in pediatric dermatology,” the researchers concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Baker C et al. Pediatr Dermatol. 2020 Jul 9. doi: 10.1111/pde.14266.

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

[email protected]

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

[email protected]

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

[email protected]

Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.

The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).

At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.

Viewers underwhelmed

“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.

Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.

However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”

Strong rationale for monitoring post-MI

There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.

“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.

Mitchel L. Zoler/MDedge News

Pragmatic trial design

LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.

“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.

Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.

“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
 

What else was shown?

“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.

Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”

Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.

There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.

“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.

Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.

There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.

The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.

SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.

Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.

The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).

At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.

Viewers underwhelmed

“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.

Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.

However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”

Strong rationale for monitoring post-MI

There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.

“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.

Mitchel L. Zoler/MDedge News

Pragmatic trial design

LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.

“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.

Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.

“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
 

What else was shown?

“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.

Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”

Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.

There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.

“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.

Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.

There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.

The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.

SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.

Following a heart attack, there appears to be a “modest” benefit of using flash glucose monitoring over fingerstick testing to monitor blood glucose levels in patients with type 2 diabetes being treated with insulin or a sulfonylurea, according to investigators of the LIBERATES trial.

The results showed a nonsignificant increase in the time that subjects’ blood glucose was spent in the target range of 3.9-10.00 mmol/L (70-180 mg/dL) 3 months after experiencing an acute coronary syndrome (ACS).

At best, flash monitoring using Abbott’s Freestyle Libre system was associated with an increase in time spent in range (TIR) of 17-28 or 48 minutes per day over self-monitoring of blood glucose (SMBG), depending on the type of statistical analysis used. There was no difference in glycated hemoglobin A1c levels between the two groups, but there was a trend for less time spent in hypoglycemia in the flash monitoring arm.

Viewers underwhelmed

“My overall impression is that the effects were less pronounced than anticipated,” Kare Birkeland, MD, PhD, a specialist in internal medicine and endocrinology at Oslo University Hospital, Rikshospitalet, Norway, observed after the findings were presented at the virtual annual meeting of the European Association for the Study of Diabetes.

Others who had watched the live session seemed similarly underwhelmed by the findings, with one viewer questioning the value of devoting an hour-and-a-half session to the phase 2 trial.

However, the session chair Simon Heller, BA, MB, BChir, DM, professor of clinical diabetes at the University of Sheffield, and trial coinvestigator, defended the detailed look at the trial’s findings, noting that it was worthwhile to present the data from the trial as it “really helps explain why we do phase 2 and phase 3 trials.”

Strong rationale for monitoring post-MI

There is a strong rationale for ensuring that blood glucose is well controlled in type 2 diabetes patients who have experienced a myocardial infarction, observed Robert Storey, BSc, BM, DM, professor of cardiology at the University of Sheffield. One way to do that potentially is through improved glucose monitoring.

“There’s clearly a close link between diabetes and the risk of MI: Both high and low HbA1c are associated with adverse outcome, and high and low glucose levels following MI are also associated with adverse outcome,” he observed, noting also that hypoglycemia was not given enough attention in post-ACS patients.

Mitchel L. Zoler/MDedge News

Pragmatic trial design

LIBERATES was a prospective, multicenter, parallel group, randomized controlled trial, explained the study’s statistician Deborah Stocken, PhD, professor of clinical trials research at the University of Leeds. There was “limited ability to blind the interventions,” so it was an open-label design.

“The patient population in LIBERATES was kept as inclusive and as pragmatic as possible to ensure that the results at the end of the trial are generalizable,” said Dr. Stocken. Patients with type 2 diabetes were recruited within 5 days of hospital admission for ACS, which could include both ST- and non-ST elevation MI. In all, 141 of a calculated 150 patients that would be needed were recruited and randomized to the flash monitoring (69) or SMBG (72) arm.

Dr. Stocken noted that early in the recruitment phase, the trials oversight committee recommended that Bayesian methodology should be used as the most robust analytical approach.

“Essentially, a Bayesian approach would avoid a hypothesis test, and instead would provide a probability of there being a treatment benefit for continuous monitoring. And if this probability was high enough, this would warrant further research in the phase 3 setting,” Dr. Stocken said.
 

What else was shown?

“We had a number of prespecified secondary endpoints, which to me are equally important,” said Ramzi Ajjan, MD, MMed.Sci, PhD, associate professor and consultant in diabetes and endocrinology at Leeds University and Leeds Teaching Hospitals Trust.

Among these was the TIR at days 16-30, which showed a 90-minute increase per day in favor of flash monitoring over SMBG. This “seems to be driven by those who are an insulin,” Dr. Ajjan said, adding that “you get almost a 3-hour increase in time in range in people who are on insulin at baseline, and you don’t see that in people who are on sulfonylurea.”

Conversely, sulfonylurea treatment seemed to drive the reduction in the time spent in hypoglycemia defined as 3.9 mmol/L (70 g/dL) at 3 months. For the whole group, there was a 1.3-hour reduction in hypoglycemia per day with flash monitoring versus SMBG, which increased to 2 hours for those on sulfonylureas.

There also was a “pattern of reduction” in time spent in hypoglycemia defined as less than 3.0 mmol/L (54 g/dL) both early on and becoming more pronounced with time.

“Flash glucose monitoring is associated with higher treatment satisfaction score, compared with SMBG,” Dr. Ajjan said.

Although A1c dropped in both groups to a similar extent, he noted that the reduction seen in the flash monitoring group was associated with a decrease in hypoglycemia.

There was a huge amount of data collected during the trial and there are many more analyses that could be done, Dr. Ajjan said. The outcome of those may determine whether a phase 3 trial is likely, assuming sponsorship can be secured.

The LIBERATES Trial was funded by grants from the UK National Institute for Health Research and Abbott Diabetes Care. None of the investigators were additionally compensated for their work within the trial. Dr. Stocken had no disclosures in relation to this trial. Dr. Ajjan has received research funding and other financial support from Abbott, Bayer, Eli Lilly, Johnson & Johnson, and Novo Nordisk.

SOURCE: Ajjan R et al. EASD 2020. S11 – The LIBERATES Trial.

Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.

Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.

Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.

Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.

And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.

This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.

“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
 

Diabetes and hyperglycemia worsen COVID-19 outcomes

The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.

Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.

Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.

Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.

In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
 

Antibody response similar in patients with and without diabetes

The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.

After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).

“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).

These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.

They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”

“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”

“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.

The authors have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.

Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.

Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.

Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.

And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.

This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.

“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
 

Diabetes and hyperglycemia worsen COVID-19 outcomes

The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.

Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.

Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.

Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.

In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
 

Antibody response similar in patients with and without diabetes

The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.

After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).

“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).

These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.

They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”

“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”

“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.

The authors have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.

Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.

Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.

Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.

And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.

This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.

“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
 

Diabetes and hyperglycemia worsen COVID-19 outcomes

The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.

Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.

Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.

Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.

In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
 

Antibody response similar in patients with and without diabetes

The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.

After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).

“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).

These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.

They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”

“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”

“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.

The authors have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.

CoRus13/Wikimedia Commons/Creative Commons 4.0

Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.

These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.

The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
 

Promising results for many

There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.

With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.

The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).

Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.

“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.

The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.

[email protected]

SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.

Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.

CoRus13/Wikimedia Commons/Creative Commons 4.0

Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.

These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.

The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
 

Promising results for many

There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.

With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.

The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).

Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.

“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.

The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.

[email protected]

SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.

Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.

CoRus13/Wikimedia Commons/Creative Commons 4.0

Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.

These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.

The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
 

Promising results for many

There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.

With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.

The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).

Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.

“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.

The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.

[email protected]

SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.