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Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.

The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.

“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.

The full findings have now been published in Annals of the Rheumatic Diseases.
 

JAKi association questioned

These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.

However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.

“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.

“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”

Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”

Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
 

Performing the analysis

As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.

“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.

“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”

This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.

Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.

Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.

“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.

Four COVID-19 outcomes assessed

The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.

Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.

“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.

ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.

Rituximab use in patients with RA who develop COVID-19

So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.

“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”

More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”

The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.

Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.

The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.

“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.

The full findings have now been published in Annals of the Rheumatic Diseases.
 

JAKi association questioned

These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.

However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.

“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.

“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”

Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”

Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
 

Performing the analysis

As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.

“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.

“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”

This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.

Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.

Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.

“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.

Four COVID-19 outcomes assessed

The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.

Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.

“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.

ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.

Rituximab use in patients with RA who develop COVID-19

So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.

“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”

More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”

The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.

Patients with rheumatoid arthritis who were using rituximab at the time of COVID-19 onset had a fourfold higher risk of being hospitalized, needing mechanical ventilation, or dying, compared with patients taking a tumor necrosis factor inhibitor (TNFi), according to a report given at the annual European Congress of Rheumatology.

The use of Janus kinase inhibitors (JAKi) also was associated with a twofold higher risk for these COVID-19 outcomes, said Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in presenting the analysis from the COVID-19 Global Rheumatology Alliance (GRA) Physician Registry.

“The strong association of rituximab and JAK inhibitor use with poor COVID-19 outcomes highlights the prioritization of risk mitigation strategies for these patients,” Dr. Sparks said at the meeting.

The full findings have now been published in Annals of the Rheumatic Diseases.
 

JAKi association questioned

These findings provide “an important understanding for the risk of our patients in times before vaccination,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich, who chaired the session in which the study was presented.

However, “recently, baricitinib was licensed to prevent particular aspects of severe COVID. What’s the explanation for this discrepancy?” he asked.

“Certainly, the JAK inhibitor finding deserves further study,” Dr. Sparks acknowledged, adding that the data were analyzed by class rather than for individual drugs.

“One possible explanation could be when JAK inhibitors are used,” he suggested. “It might be different for patients who [have been] just infected – that might have different biologic effects – as opposed to choosing to treat patients right when there’s a hyperinflammatory cascade, or there’s oxygen need.”

Regarding the JAK inhibitor finding, Ronald van Vollenhoven, MD, PhD, of the University of Amsterdam, pointed out during the online Q&A that “JAKi have a very short half-life compared to biologics.”

Dr. van Vollenhoven asked: “Could the practice of stopping these drugs upon COVID infection have a negative impact on the course?” To which Dr. Sparks responded: “The different half-life of drugs would be a promising avenue to look at, to see whether increases in disease activity might have imparted some of the effects we saw.”
 

Performing the analysis

As of April 12, 2021, the GRA Physician Registry contained the records of more than 15,000 patients. Dr. Sparks, collaborator Zachary Wallace, MD, of Massachusetts General Hospital, Boston, and associates limited their analysis to 2,869 patients with RA who had been treated with either a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) at the time they were diagnosed with COVID-19.

“We wanted to limit it to a single disease and also limit it to drugs that are considered for that disease,” Dr. Sparks explained in an interview.

“Because patients with rheumatoid arthritis are often treated sequentially, we wanted to further limit the analysis to patients who were on advanced therapies so that they were at a similar disease state, and also had the opportunity to receive advanced therapies.”

This approach hopefully minimizes the possibility of confounding by indication, Dr. Sparks said.

Most of the patients included in the analysis had received a TNFi (n = 1,388), and they were used as the control arm of the analysis. Outcomes associated with treatment with the other b/tsDMARDs, which included abatacept (n = 237), rituximab (n = 364), interleukin-6 inhibitors (IL-6i; n = 317), and JAKi (n = 563), were then compared with TNFi.

Baseline characteristics of patients were broadly similar across the groups. The mean age was 56.7 years and 80.8% of the study population was female. There were a few expected differences among users of rituximab versus TNFi, notably a higher percentage of patients with interstitial lung disease (11% vs. 1.4% of TNFi users) or cancer (7.4% vs. 0.9%) among patients treated with rituximab since it is commonly used in these patients, Dr. Sparks said.

“We did perform a sensitivity analysis where we restricted the population to not having ILD or cancer and we actually found really similar findings,” he added.

Four COVID-19 outcomes assessed

The researchers used a four-point ordinal scale modeled after one set by the World Health Organization to assess four COVID-19 outcomes: not hospitalized, hospitalized without oxygenation, hospitalized with oxygenation or ventilation, and death.

Odds ratios (ORs) comparing rituximab to TNFi for these four COVID-19 outcomes were a respective 4.53, 2.87, 4.05, and 4.57. The ORs for JAKi versus TNFi were a respective 2.4, 1.55, 2.03, and 2.04.

“We found no consistent associations of abatacept or interleukin-6 inhibitors with COVID-19 severity, compared to TNF inhibitors,” which is reassuring, Dr. Sparks said.

ORs for the four COVID-19 outcomes with abatacept were a respective 1.18, 1.12, 1.41, and 1.46, and for IL-6i were 0.84, 0.72, 0.75, and 1.13.

Rituximab use in patients with RA who develop COVID-19

So, should rituximab be stopped in patients with RA if they develop COVID-19? “This is an important question and one that would be decided on a case-by-case basis,” Dr. Sparks said. “Of course, the drug has a very long half-life, so risk mitigation strategies are still of utmost importance,” he added.

“I think everyone’s a bit reticent to want to start rituximab in this environment, but it might also make me pause about starting a JAK inhibitor,” Dr. Sparks added. “Given that this is a first finding, I’m not sure I would necessarily change patients who are doing well on these medications. I think what it really makes me want to do is to try to obviously vaccinate the patients on JAK inhibitors as they do have a short half-life.”

More observational studies would be helpful, Dr. Sparks said, adding that “the most pressing need is to try to figure out how to protect our patients with rituximab.”

The COVID-19 Global Rheumatology Alliance Physician Registry is supported by the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Dr. Sparks disclosed serving as a consultant for Bristol Myers Squibb, Gilead, Inova, Optum, and Pfizer for work unrelated to this study. Dr. Wallace disclosed receiving grant support from Bristol Myers Squibb and Principia/Sanofi and serving as a consultant for Viela Bio and Medpace for work unrelated to this study.

Treating insulin resistance may improve treatment-resistant bipolar depression, early research suggests.

In a randomized, placebo-controlled trial, treatment with the diabetes drug metformin reversed insulin resistance in 50% of patients, and this reversal was associated with significant improvement of depressive symptoms. One patient randomly assigned to placebo also achieved a reversal of insulin resistance and improved depressive symptoms.

“The study needs replication, but this early clinical trial suggests that the mitigation of insulin resistance by metformin significantly improves depressive symptoms in a significant percentage of treatment resistant bipolar patients,” presenting author Jessica M. Gannon, MD, University of Pittsburgh Medical Center (UPMC), said in an interview.

“It looks like in treatment-resistant bipolar depression, treating insulin resistance is a way to get people well again, to get out of their depression,” principal investigator Cynthia Calkin, MD, Dalhousie University, Halifax, N.S., added.

The findings were presented at the virtual American Society of Clinical Psychopharmacology 2021 Annual Meeting.
 

Chronic inflammation

The study was a joint effort by UPMC and Dalhousie University and was sponsored by the Stanley Medical Research Institute.

Patients with bipolar disorder (BD) who are obese tend to have more serious illness, with a more chronic course, more rapid cycling, and more morbidity. These patients also fail to respond to lithium, Dr. Calkin said.

“Untreated hyperinsulinemia could be contributing to a state of chronic inflammation and be involved in disease progression. So the question for me was, if we treat this insulin resistance, would patients get better?” she said.

Dr. Calkin said investigators used metformin because it is already used by psychiatrists for weight management in patients on antipsychotics.

“I wanted to test the drug that would work to reverse insulin resistance and that psychiatrists would be comfortable prescribing,” she said.

The 26-week study randomly assigned 20 patients to receive metformin and 25 patients to placebo.

All participants were 18 years and older, had a diagnosis of BD I or II, and had nonremitting BD defined by moderate depressive symptoms as measured on the Montgomery-Asberg Depression Rating Scale (MADRS) score of 15 or greater, despite being on optimal, guideline-compatible treatment.

All patients were stable, were on optimal doses of mood-stabilizing medications for at least 4 weeks prior to study entry, and had insulin resistance as defined by a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥1.8.

Characteristics were similar between the two groups, including baseline MADRS scores, body mass index, fasting glucose and insulin serum levels.

Patients were titrated up to 2,000 mg of metformin, which was the full dose, over 2 weeks and then maintained on treatment for a further 24 weeks.
 

Highly resistant population

The study’s primary outcome measure was change in MADRS score, with a response defined as a 30% reduction in MADRS from baseline.

By week 14, 10 metformin-treated patients (50%) and one patient in the placebo group (4%) no longer met insulin resistance criteria.

“It was a bit of a surprise to me that 50% of patients converted to being insulin sensitive again. When you use metformin to treat diabetes, people respond to it at more than a 50% rate, so I was expecting more people to respond,” Dr. Calkin said.

Nevertheless, the 11 patients who did respond and reversed insulin resistance achieved greater reduction in MADRS scores compared with nonconverters.

“Those who reversed their insulin resistance showed a remarkable resolution in their depressive symptoms. The reduction in MADRS scores began at week six, and were maintained through to the end of the study, and the Cohen’s d effect size for MADRS depression scores for converters was 0.52 at week 14 and 0.55 at week 26,” Dr. Calkin said.

“They were moderately to severely depressed going in, and at the end of the study, they had mild residual depressive symptoms, or they were completely well. These were very treatment-resistant patients.”

“All had failed, on average, eight or nine trials in their lifetime. When they came to us, nothing else would work. That’s one of the remarkable things about our results, just how well they responded when they had not responded to any other psychotropic medications. This approach may be very helpful for some patients,” Dr. Calkin said.
 

A holistic approach

Commenting on the study, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, said the findings need to be replicated but provide further support for the broader strategy of taking a holistic approach to the care of patients with difficult-to-treat mood disorders.

“Approximately one-half of people with treatment-resistant bipolar depression showed evidence of glucose resistance, and that adjunctive treatment with metformin, a medication that enhances insulin sensitivity, was moderately effective in normalizing glucose metabolism, with about a 50% response rate. Among those who experienced improved glucose regulation, there was a significant reduction in depressive symptoms,” he noted.

The study was funded by the Stanley Medical Research Institute (SMRI). Dr. Calkin and Dr. Thase have disclosed no relevant financial relationships.

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

Treating insulin resistance may improve treatment-resistant bipolar depression, early research suggests.

In a randomized, placebo-controlled trial, treatment with the diabetes drug metformin reversed insulin resistance in 50% of patients, and this reversal was associated with significant improvement of depressive symptoms. One patient randomly assigned to placebo also achieved a reversal of insulin resistance and improved depressive symptoms.

“The study needs replication, but this early clinical trial suggests that the mitigation of insulin resistance by metformin significantly improves depressive symptoms in a significant percentage of treatment resistant bipolar patients,” presenting author Jessica M. Gannon, MD, University of Pittsburgh Medical Center (UPMC), said in an interview.

“It looks like in treatment-resistant bipolar depression, treating insulin resistance is a way to get people well again, to get out of their depression,” principal investigator Cynthia Calkin, MD, Dalhousie University, Halifax, N.S., added.

The findings were presented at the virtual American Society of Clinical Psychopharmacology 2021 Annual Meeting.
 

Chronic inflammation

The study was a joint effort by UPMC and Dalhousie University and was sponsored by the Stanley Medical Research Institute.

Patients with bipolar disorder (BD) who are obese tend to have more serious illness, with a more chronic course, more rapid cycling, and more morbidity. These patients also fail to respond to lithium, Dr. Calkin said.

“Untreated hyperinsulinemia could be contributing to a state of chronic inflammation and be involved in disease progression. So the question for me was, if we treat this insulin resistance, would patients get better?” she said.

Dr. Calkin said investigators used metformin because it is already used by psychiatrists for weight management in patients on antipsychotics.

“I wanted to test the drug that would work to reverse insulin resistance and that psychiatrists would be comfortable prescribing,” she said.

The 26-week study randomly assigned 20 patients to receive metformin and 25 patients to placebo.

All participants were 18 years and older, had a diagnosis of BD I or II, and had nonremitting BD defined by moderate depressive symptoms as measured on the Montgomery-Asberg Depression Rating Scale (MADRS) score of 15 or greater, despite being on optimal, guideline-compatible treatment.

All patients were stable, were on optimal doses of mood-stabilizing medications for at least 4 weeks prior to study entry, and had insulin resistance as defined by a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥1.8.

Characteristics were similar between the two groups, including baseline MADRS scores, body mass index, fasting glucose and insulin serum levels.

Patients were titrated up to 2,000 mg of metformin, which was the full dose, over 2 weeks and then maintained on treatment for a further 24 weeks.
 

Highly resistant population

The study’s primary outcome measure was change in MADRS score, with a response defined as a 30% reduction in MADRS from baseline.

By week 14, 10 metformin-treated patients (50%) and one patient in the placebo group (4%) no longer met insulin resistance criteria.

“It was a bit of a surprise to me that 50% of patients converted to being insulin sensitive again. When you use metformin to treat diabetes, people respond to it at more than a 50% rate, so I was expecting more people to respond,” Dr. Calkin said.

Nevertheless, the 11 patients who did respond and reversed insulin resistance achieved greater reduction in MADRS scores compared with nonconverters.

“Those who reversed their insulin resistance showed a remarkable resolution in their depressive symptoms. The reduction in MADRS scores began at week six, and were maintained through to the end of the study, and the Cohen’s d effect size for MADRS depression scores for converters was 0.52 at week 14 and 0.55 at week 26,” Dr. Calkin said.

“They were moderately to severely depressed going in, and at the end of the study, they had mild residual depressive symptoms, or they were completely well. These were very treatment-resistant patients.”

“All had failed, on average, eight or nine trials in their lifetime. When they came to us, nothing else would work. That’s one of the remarkable things about our results, just how well they responded when they had not responded to any other psychotropic medications. This approach may be very helpful for some patients,” Dr. Calkin said.
 

A holistic approach

Commenting on the study, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, said the findings need to be replicated but provide further support for the broader strategy of taking a holistic approach to the care of patients with difficult-to-treat mood disorders.

“Approximately one-half of people with treatment-resistant bipolar depression showed evidence of glucose resistance, and that adjunctive treatment with metformin, a medication that enhances insulin sensitivity, was moderately effective in normalizing glucose metabolism, with about a 50% response rate. Among those who experienced improved glucose regulation, there was a significant reduction in depressive symptoms,” he noted.

The study was funded by the Stanley Medical Research Institute (SMRI). Dr. Calkin and Dr. Thase have disclosed no relevant financial relationships.

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

Treating insulin resistance may improve treatment-resistant bipolar depression, early research suggests.

In a randomized, placebo-controlled trial, treatment with the diabetes drug metformin reversed insulin resistance in 50% of patients, and this reversal was associated with significant improvement of depressive symptoms. One patient randomly assigned to placebo also achieved a reversal of insulin resistance and improved depressive symptoms.

“The study needs replication, but this early clinical trial suggests that the mitigation of insulin resistance by metformin significantly improves depressive symptoms in a significant percentage of treatment resistant bipolar patients,” presenting author Jessica M. Gannon, MD, University of Pittsburgh Medical Center (UPMC), said in an interview.

“It looks like in treatment-resistant bipolar depression, treating insulin resistance is a way to get people well again, to get out of their depression,” principal investigator Cynthia Calkin, MD, Dalhousie University, Halifax, N.S., added.

The findings were presented at the virtual American Society of Clinical Psychopharmacology 2021 Annual Meeting.
 

Chronic inflammation

The study was a joint effort by UPMC and Dalhousie University and was sponsored by the Stanley Medical Research Institute.

Patients with bipolar disorder (BD) who are obese tend to have more serious illness, with a more chronic course, more rapid cycling, and more morbidity. These patients also fail to respond to lithium, Dr. Calkin said.

“Untreated hyperinsulinemia could be contributing to a state of chronic inflammation and be involved in disease progression. So the question for me was, if we treat this insulin resistance, would patients get better?” she said.

Dr. Calkin said investigators used metformin because it is already used by psychiatrists for weight management in patients on antipsychotics.

“I wanted to test the drug that would work to reverse insulin resistance and that psychiatrists would be comfortable prescribing,” she said.

The 26-week study randomly assigned 20 patients to receive metformin and 25 patients to placebo.

All participants were 18 years and older, had a diagnosis of BD I or II, and had nonremitting BD defined by moderate depressive symptoms as measured on the Montgomery-Asberg Depression Rating Scale (MADRS) score of 15 or greater, despite being on optimal, guideline-compatible treatment.

All patients were stable, were on optimal doses of mood-stabilizing medications for at least 4 weeks prior to study entry, and had insulin resistance as defined by a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥1.8.

Characteristics were similar between the two groups, including baseline MADRS scores, body mass index, fasting glucose and insulin serum levels.

Patients were titrated up to 2,000 mg of metformin, which was the full dose, over 2 weeks and then maintained on treatment for a further 24 weeks.
 

Highly resistant population

The study’s primary outcome measure was change in MADRS score, with a response defined as a 30% reduction in MADRS from baseline.

By week 14, 10 metformin-treated patients (50%) and one patient in the placebo group (4%) no longer met insulin resistance criteria.

“It was a bit of a surprise to me that 50% of patients converted to being insulin sensitive again. When you use metformin to treat diabetes, people respond to it at more than a 50% rate, so I was expecting more people to respond,” Dr. Calkin said.

Nevertheless, the 11 patients who did respond and reversed insulin resistance achieved greater reduction in MADRS scores compared with nonconverters.

“Those who reversed their insulin resistance showed a remarkable resolution in their depressive symptoms. The reduction in MADRS scores began at week six, and were maintained through to the end of the study, and the Cohen’s d effect size for MADRS depression scores for converters was 0.52 at week 14 and 0.55 at week 26,” Dr. Calkin said.

“They were moderately to severely depressed going in, and at the end of the study, they had mild residual depressive symptoms, or they were completely well. These were very treatment-resistant patients.”

“All had failed, on average, eight or nine trials in their lifetime. When they came to us, nothing else would work. That’s one of the remarkable things about our results, just how well they responded when they had not responded to any other psychotropic medications. This approach may be very helpful for some patients,” Dr. Calkin said.
 

A holistic approach

Commenting on the study, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, said the findings need to be replicated but provide further support for the broader strategy of taking a holistic approach to the care of patients with difficult-to-treat mood disorders.

“Approximately one-half of people with treatment-resistant bipolar depression showed evidence of glucose resistance, and that adjunctive treatment with metformin, a medication that enhances insulin sensitivity, was moderately effective in normalizing glucose metabolism, with about a 50% response rate. Among those who experienced improved glucose regulation, there was a significant reduction in depressive symptoms,” he noted.

The study was funded by the Stanley Medical Research Institute (SMRI). Dr. Calkin and Dr. Thase have disclosed no relevant financial relationships.

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

A group of 117 people who work at the Houston Methodist Health System has filed a lawsuit against the medical center, objecting to its policy of requiring employees and contractors to be vaccinated against COVID-19 or risk losing their jobs.

Plaintiffs include Jennifer Bridges, RN, a medical-surgical nurse at the hospital who has become the public face and voice of health care workers who object to mandatory vaccination, as well as Bob Nevens, the hospital’s director of corporate risk.

Mr. Nevens said the hospital was requiring him to be vaccinated even though he doesn’t treat patients and has been working from home for most of the past year.

“My civil rights and liberties have been trampled on,” he said in comments posted on an online petition. “My right to protect myself from unknown side effects of these vaccines has been placed below the optics of ‘leading medicine,’ “ he said.

Mr. Nevens says in his comments that he was fired on April 15, although the lawsuit says he is currently employed by the hospital’s corporate office.

The Texas attorney who filed the lawsuit, Jared Woodfill, is known to champion conservative causes. In March 2020, he challenged Harris County’s stay-at-home order, charging that it violated religious liberty. He was chairman of the Harris County Republican Party for more than a decade. His website says he is a frequent guest on the local Fox News affiliate.

The lawsuit hinges on a section of the federal law that authorizes emergency use of medical products – US Code 360bbb-3.

That law says that individuals to whom the product is administered should be informed “of the option to accept or refuse administration of the product, of the consequence, if any, of refusing administration of the product, and of the alternatives to the product that are available and of their benefits and risks.”

Legal experts are split as to what the provision means for vaccination mandates. Courts have not yet weighed in with their interpretations of the law.

The petition also repeats a popular antivaccination argument that likens requiring a vaccine approved for emergency use to the kind of medical experimentation performed by Nazi doctors on Jewish prisoners in concentration camps. It says forcing people to choose between an experimental vaccine and a job is a violation of the Nuremberg Code, which says that people must voluntarily and knowingly consent to participating in research.

The vaccines have already been tested in clinical trials. People who are getting them now are not part of those studies, though vaccine manufacturers, regulators, and safety experts are still watching closely for any sign of problems tied to the new shots.

It is true, however, that the emergency use authorization granted by the U.S. Food and Drug Administraiton sped up the process of getting the vaccines onto market. Vaccine manufacturers are currently completing the process of submitting documentation required for a full biologics license application, the mechanism the FDA uses for full approval.

Houston Methodist sent an email to employees in April notifying them that they had until June 7 to start the vaccination process or apply for a medical or religious exemption. Those who decide not to will be terminated.

Marc Boom, MD, the health care system’s president and CEO, has explained that the policy is in place to protect patients and that it was the first hospital in the United States to require it. Since then, other hospitals, including the University of Pennsylvania Health System, have required COVID vaccines.

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

A group of 117 people who work at the Houston Methodist Health System has filed a lawsuit against the medical center, objecting to its policy of requiring employees and contractors to be vaccinated against COVID-19 or risk losing their jobs.

Plaintiffs include Jennifer Bridges, RN, a medical-surgical nurse at the hospital who has become the public face and voice of health care workers who object to mandatory vaccination, as well as Bob Nevens, the hospital’s director of corporate risk.

Mr. Nevens said the hospital was requiring him to be vaccinated even though he doesn’t treat patients and has been working from home for most of the past year.

“My civil rights and liberties have been trampled on,” he said in comments posted on an online petition. “My right to protect myself from unknown side effects of these vaccines has been placed below the optics of ‘leading medicine,’ “ he said.

Mr. Nevens says in his comments that he was fired on April 15, although the lawsuit says he is currently employed by the hospital’s corporate office.

The Texas attorney who filed the lawsuit, Jared Woodfill, is known to champion conservative causes. In March 2020, he challenged Harris County’s stay-at-home order, charging that it violated religious liberty. He was chairman of the Harris County Republican Party for more than a decade. His website says he is a frequent guest on the local Fox News affiliate.

The lawsuit hinges on a section of the federal law that authorizes emergency use of medical products – US Code 360bbb-3.

That law says that individuals to whom the product is administered should be informed “of the option to accept or refuse administration of the product, of the consequence, if any, of refusing administration of the product, and of the alternatives to the product that are available and of their benefits and risks.”

Legal experts are split as to what the provision means for vaccination mandates. Courts have not yet weighed in with their interpretations of the law.

The petition also repeats a popular antivaccination argument that likens requiring a vaccine approved for emergency use to the kind of medical experimentation performed by Nazi doctors on Jewish prisoners in concentration camps. It says forcing people to choose between an experimental vaccine and a job is a violation of the Nuremberg Code, which says that people must voluntarily and knowingly consent to participating in research.

The vaccines have already been tested in clinical trials. People who are getting them now are not part of those studies, though vaccine manufacturers, regulators, and safety experts are still watching closely for any sign of problems tied to the new shots.

It is true, however, that the emergency use authorization granted by the U.S. Food and Drug Administraiton sped up the process of getting the vaccines onto market. Vaccine manufacturers are currently completing the process of submitting documentation required for a full biologics license application, the mechanism the FDA uses for full approval.

Houston Methodist sent an email to employees in April notifying them that they had until June 7 to start the vaccination process or apply for a medical or religious exemption. Those who decide not to will be terminated.

Marc Boom, MD, the health care system’s president and CEO, has explained that the policy is in place to protect patients and that it was the first hospital in the United States to require it. Since then, other hospitals, including the University of Pennsylvania Health System, have required COVID vaccines.

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

A group of 117 people who work at the Houston Methodist Health System has filed a lawsuit against the medical center, objecting to its policy of requiring employees and contractors to be vaccinated against COVID-19 or risk losing their jobs.

Plaintiffs include Jennifer Bridges, RN, a medical-surgical nurse at the hospital who has become the public face and voice of health care workers who object to mandatory vaccination, as well as Bob Nevens, the hospital’s director of corporate risk.

Mr. Nevens said the hospital was requiring him to be vaccinated even though he doesn’t treat patients and has been working from home for most of the past year.

“My civil rights and liberties have been trampled on,” he said in comments posted on an online petition. “My right to protect myself from unknown side effects of these vaccines has been placed below the optics of ‘leading medicine,’ “ he said.

Mr. Nevens says in his comments that he was fired on April 15, although the lawsuit says he is currently employed by the hospital’s corporate office.

The Texas attorney who filed the lawsuit, Jared Woodfill, is known to champion conservative causes. In March 2020, he challenged Harris County’s stay-at-home order, charging that it violated religious liberty. He was chairman of the Harris County Republican Party for more than a decade. His website says he is a frequent guest on the local Fox News affiliate.

The lawsuit hinges on a section of the federal law that authorizes emergency use of medical products – US Code 360bbb-3.

That law says that individuals to whom the product is administered should be informed “of the option to accept or refuse administration of the product, of the consequence, if any, of refusing administration of the product, and of the alternatives to the product that are available and of their benefits and risks.”

Legal experts are split as to what the provision means for vaccination mandates. Courts have not yet weighed in with their interpretations of the law.

The petition also repeats a popular antivaccination argument that likens requiring a vaccine approved for emergency use to the kind of medical experimentation performed by Nazi doctors on Jewish prisoners in concentration camps. It says forcing people to choose between an experimental vaccine and a job is a violation of the Nuremberg Code, which says that people must voluntarily and knowingly consent to participating in research.

The vaccines have already been tested in clinical trials. People who are getting them now are not part of those studies, though vaccine manufacturers, regulators, and safety experts are still watching closely for any sign of problems tied to the new shots.

It is true, however, that the emergency use authorization granted by the U.S. Food and Drug Administraiton sped up the process of getting the vaccines onto market. Vaccine manufacturers are currently completing the process of submitting documentation required for a full biologics license application, the mechanism the FDA uses for full approval.

Houston Methodist sent an email to employees in April notifying them that they had until June 7 to start the vaccination process or apply for a medical or religious exemption. Those who decide not to will be terminated.

Marc Boom, MD, the health care system’s president and CEO, has explained that the policy is in place to protect patients and that it was the first hospital in the United States to require it. Since then, other hospitals, including the University of Pennsylvania Health System, have required COVID vaccines.

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

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Medtronic has stopped the sale of its Heartware Ventricular Assist Device (HVAD) system and is advising that physicians cease implanting the device because problems with an internal pump can lead to death or serious injuries.

“There is an increased risk of neurological adverse events and mortality associated with the internal pump,” the U.S. Food and Drug Administration announced today.

There is also a potential for the internal pump to stop, and there may be delay or failure to restart. “Both problems may lead to death or serious injuries,” the agency said.

Between January 2009 and April 22, 2021, Medtronic received a total of 106 complaints involving delay or failure to restart with the HVAD pump. Of these, 26 complaints involved HVAD devices operating under normal conditions (dual stator mode) and 80 involved devices operating in a back-up mode (single stator mode) that allows for continued pump function if electrical continuity between the pump and controller is interrupted.

Of the 26 complaints that occurred under normal conditions, four resulted in patient death and five led to urgent explant. Of the 80 complaints that occurred in single stator mode, 10 deaths and eight explants were reported to Medtronic, according to an urgent medical device communication letter issued by the company today.

“Considering these findings and given the availability of alternative devices such as the Abbott HeartMate 3, Medtronic has made the decision to stop the distribution and sale of the HVAD System,” the letter says. “Medtronic advises that there be no further implantations of the HVAD System.”

Medtronic undertook a previous recall of the Heartware HVAD system in February, focusing on batteries, power, datalink cables, and other peripheral equipment, because of the “risk of wear and tear of the connector plugs (power sources, data cable, and alarm adapter), which could cause damage to the controller port metal pins (for example, bent pins).” The FDA deemed that recall Class I, the most serious category of safety alert, in April.

The company noted that patients who currently have an HVAD implant “may require support for many years,” and that it is moving as quickly as possible to create a plan to guide the ongoing support for patients, caregivers, and health care professionals.

In response to the restart failure issue and evolving data about neurologic risks associated with the HVAD pump, Medtronic said it engaged an Independent Practitioner Quality Panel (IPQP), composed of cardiologists, surgeons, and VAD coordinators, to advise on recommendations for appropriate patient management. Based on information collected to date and IPQP input, Medtronic is recommending that physicians continue following best clinical practices and manage patients implanted with the HVAD pump according to the recommendations in the Instructions for Use (IFU).

“Prophylactic explant of the HVAD™ device is not recommended, as risks associated with explantation may outweigh the potential benefits,” the letter says. “The decision regarding explant and exchange of the HVAD™ pump should be made by physicians on a case-by-case basis, considering the patient’s clinical condition and surgical risks. If a physician determines that pump exchange is appropriate, we recommend exchanging to an alternative commercial LVAD.”

For patients in urgent need of an LVAD, Medtronic said physicians should use an alternative commercial LVAD or, if one is not available, that “a Patient Information form is required to be completed by you and your patient to acknowledge the risks of an HVAD implant prior to implanting your HVAD inventory.”

Today’s letter also provides recommendations on blood pressure management goals and anticoagulation. For any other questions or concerns, physicians should contact the Medtronic Office of Medical Affairs at: [email protected].

Medtronic issued another urgent letter in December 2020, warning physicians that a subset of HVAD devices included an internal pump component from three specific lots that increased the risk for restart failure. At that time, the company had not been able to pinpoint a root cause of the pump restart failure.

Consistent with the December 2020 notice, the rate of failure among pumps outside of the subset of three specific lots currently remains at about 0.4%, according to today’s notice.

Although Medtronic has identified the root cause and mitigations for pumps within the three specific lots, it has not been able to identify a root cause of the other restart failures reported with the HVAD pumps, the company said.

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

Medtronic has stopped the sale of its Heartware Ventricular Assist Device (HVAD) system and is advising that physicians cease implanting the device because problems with an internal pump can lead to death or serious injuries.

“There is an increased risk of neurological adverse events and mortality associated with the internal pump,” the U.S. Food and Drug Administration announced today.

There is also a potential for the internal pump to stop, and there may be delay or failure to restart. “Both problems may lead to death or serious injuries,” the agency said.

Between January 2009 and April 22, 2021, Medtronic received a total of 106 complaints involving delay or failure to restart with the HVAD pump. Of these, 26 complaints involved HVAD devices operating under normal conditions (dual stator mode) and 80 involved devices operating in a back-up mode (single stator mode) that allows for continued pump function if electrical continuity between the pump and controller is interrupted.

Of the 26 complaints that occurred under normal conditions, four resulted in patient death and five led to urgent explant. Of the 80 complaints that occurred in single stator mode, 10 deaths and eight explants were reported to Medtronic, according to an urgent medical device communication letter issued by the company today.

“Considering these findings and given the availability of alternative devices such as the Abbott HeartMate 3, Medtronic has made the decision to stop the distribution and sale of the HVAD System,” the letter says. “Medtronic advises that there be no further implantations of the HVAD System.”

Medtronic undertook a previous recall of the Heartware HVAD system in February, focusing on batteries, power, datalink cables, and other peripheral equipment, because of the “risk of wear and tear of the connector plugs (power sources, data cable, and alarm adapter), which could cause damage to the controller port metal pins (for example, bent pins).” The FDA deemed that recall Class I, the most serious category of safety alert, in April.

The company noted that patients who currently have an HVAD implant “may require support for many years,” and that it is moving as quickly as possible to create a plan to guide the ongoing support for patients, caregivers, and health care professionals.

In response to the restart failure issue and evolving data about neurologic risks associated with the HVAD pump, Medtronic said it engaged an Independent Practitioner Quality Panel (IPQP), composed of cardiologists, surgeons, and VAD coordinators, to advise on recommendations for appropriate patient management. Based on information collected to date and IPQP input, Medtronic is recommending that physicians continue following best clinical practices and manage patients implanted with the HVAD pump according to the recommendations in the Instructions for Use (IFU).

“Prophylactic explant of the HVAD™ device is not recommended, as risks associated with explantation may outweigh the potential benefits,” the letter says. “The decision regarding explant and exchange of the HVAD™ pump should be made by physicians on a case-by-case basis, considering the patient’s clinical condition and surgical risks. If a physician determines that pump exchange is appropriate, we recommend exchanging to an alternative commercial LVAD.”

For patients in urgent need of an LVAD, Medtronic said physicians should use an alternative commercial LVAD or, if one is not available, that “a Patient Information form is required to be completed by you and your patient to acknowledge the risks of an HVAD implant prior to implanting your HVAD inventory.”

Today’s letter also provides recommendations on blood pressure management goals and anticoagulation. For any other questions or concerns, physicians should contact the Medtronic Office of Medical Affairs at: [email protected].

Medtronic issued another urgent letter in December 2020, warning physicians that a subset of HVAD devices included an internal pump component from three specific lots that increased the risk for restart failure. At that time, the company had not been able to pinpoint a root cause of the pump restart failure.

Consistent with the December 2020 notice, the rate of failure among pumps outside of the subset of three specific lots currently remains at about 0.4%, according to today’s notice.

Although Medtronic has identified the root cause and mitigations for pumps within the three specific lots, it has not been able to identify a root cause of the other restart failures reported with the HVAD pumps, the company said.

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

Medtronic has stopped the sale of its Heartware Ventricular Assist Device (HVAD) system and is advising that physicians cease implanting the device because problems with an internal pump can lead to death or serious injuries.

“There is an increased risk of neurological adverse events and mortality associated with the internal pump,” the U.S. Food and Drug Administration announced today.

There is also a potential for the internal pump to stop, and there may be delay or failure to restart. “Both problems may lead to death or serious injuries,” the agency said.

Between January 2009 and April 22, 2021, Medtronic received a total of 106 complaints involving delay or failure to restart with the HVAD pump. Of these, 26 complaints involved HVAD devices operating under normal conditions (dual stator mode) and 80 involved devices operating in a back-up mode (single stator mode) that allows for continued pump function if electrical continuity between the pump and controller is interrupted.

Of the 26 complaints that occurred under normal conditions, four resulted in patient death and five led to urgent explant. Of the 80 complaints that occurred in single stator mode, 10 deaths and eight explants were reported to Medtronic, according to an urgent medical device communication letter issued by the company today.

“Considering these findings and given the availability of alternative devices such as the Abbott HeartMate 3, Medtronic has made the decision to stop the distribution and sale of the HVAD System,” the letter says. “Medtronic advises that there be no further implantations of the HVAD System.”

Medtronic undertook a previous recall of the Heartware HVAD system in February, focusing on batteries, power, datalink cables, and other peripheral equipment, because of the “risk of wear and tear of the connector plugs (power sources, data cable, and alarm adapter), which could cause damage to the controller port metal pins (for example, bent pins).” The FDA deemed that recall Class I, the most serious category of safety alert, in April.

The company noted that patients who currently have an HVAD implant “may require support for many years,” and that it is moving as quickly as possible to create a plan to guide the ongoing support for patients, caregivers, and health care professionals.

In response to the restart failure issue and evolving data about neurologic risks associated with the HVAD pump, Medtronic said it engaged an Independent Practitioner Quality Panel (IPQP), composed of cardiologists, surgeons, and VAD coordinators, to advise on recommendations for appropriate patient management. Based on information collected to date and IPQP input, Medtronic is recommending that physicians continue following best clinical practices and manage patients implanted with the HVAD pump according to the recommendations in the Instructions for Use (IFU).

“Prophylactic explant of the HVAD™ device is not recommended, as risks associated with explantation may outweigh the potential benefits,” the letter says. “The decision regarding explant and exchange of the HVAD™ pump should be made by physicians on a case-by-case basis, considering the patient’s clinical condition and surgical risks. If a physician determines that pump exchange is appropriate, we recommend exchanging to an alternative commercial LVAD.”

For patients in urgent need of an LVAD, Medtronic said physicians should use an alternative commercial LVAD or, if one is not available, that “a Patient Information form is required to be completed by you and your patient to acknowledge the risks of an HVAD implant prior to implanting your HVAD inventory.”

Today’s letter also provides recommendations on blood pressure management goals and anticoagulation. For any other questions or concerns, physicians should contact the Medtronic Office of Medical Affairs at: [email protected].

Medtronic issued another urgent letter in December 2020, warning physicians that a subset of HVAD devices included an internal pump component from three specific lots that increased the risk for restart failure. At that time, the company had not been able to pinpoint a root cause of the pump restart failure.

Consistent with the December 2020 notice, the rate of failure among pumps outside of the subset of three specific lots currently remains at about 0.4%, according to today’s notice.

Although Medtronic has identified the root cause and mitigations for pumps within the three specific lots, it has not been able to identify a root cause of the other restart failures reported with the HVAD pumps, the company said.

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

Although recent trial results have established the sodium glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin as a key new part of the recommended multidrug treatment regimen for patients with heart failure with reduced ejection fraction, the current U.S. cost for dapagliflozin means it has merely “intermediate” value when it comes to cost-effectiveness.

adventtr/iStock/Getty Images Plus

A typical regimen with dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) costs about $474/month or roughly $5,700/year based on Medicare pricing. After factoring in the incremental clinical benefits producing by dapagliflozin seen in the DAPA-HF pivotal trial that helped establish its role, this price produces a cost per quality-adjusted life-year (QALY) gain of about $84,000, which puts dapagliflozin squarely in the intermediate range for value set in 2014 by a task force of the American College of Cardiology and the American Heart Association.

This cost-effectiveness value depends largely on the proven efficacy of dapagliflozin (Farxiga) for decreasing the incidence of cardiovascular death among treated patients with HFrEF, and puts the drug’s value roughly on par with another agent recently approved to treat such patients, sacubitril/valsartan (Entresto), which carries a cost-effectiveness value of about $45,000/QALY.

The U.S. cost per QALY for dapagliflozin treatment of patients with HFrEF dwarfed the value numbers calculated for several other countries that were generally one-tenth this size. This disparity stemmed from both the relatively high price for dapagliflozin in the U.S. compared with other countries – nearly tenfold higher – and relatively higher costs for all types of U.S. medical care, Justin T. Parizo, MD, and coauthors said in a recent report. But the cost, and hence the cost per QALY, of dapagliflozin may soon drop because certain patents on the drug expired in October 2020, added Dr. Parizo, a cardiologist at Stanford (Calif.) University, and associates. Despite the expired patents, as of June 2021 no generic form of dapagliflozin appeared available for U.S. sale.
 

Medicare patients pay about $1,630/year out-of-pocket

“A key caveat” to this finding for dapagliflozin is that being cost-effective “is not by itself a mandate for routine clinical use,” Derek S. Chew, MD, and Daniel B. Mark, MD, said in an editorial that accompanied the report.

A major stumbling block for widespread U.S. prescribing of dapagliflozin to patients with HFrEF is its overall price tag for U.S. patients, estimated at $12 billion/year, as well as an out-of-pocket annual cost for individual Medicare patients of roughly $1,630/year. Adding this out-of-pocket cost to the copay for sacubitril/valsartan and two other much less expensive drug classes that together form the current mainstay, quadruple-drug regimen for HFrEF treatment means a potential annual cost paid by each Medicare patient of about $3,000, wrote Dr. Chew, a cardiologist, and Dr. Mark, a cardiologist and professor, both at Duke University, Durham, N.C.

They cited the precedent of the “unexpectedly slow” and “anemic” uptake of sacubitril/valsartan since its U.S. approval in 2015, a cost-effective agent with “comparable clinical effectiveness” to dapagliflozin. “Even with full inclusion [of sacubitril/valsartan] on formularies and elimination of preapproval requirements, use remains very low, and patient-borne out-of-pocket costs may be a key factor,” wrote Dr. Chew and Dr. Mark. They cited a results from a study that showed abandonment of new prescriptions at retail U.S. pharmacies spiked to a 60% rate when out-of-pocket cost exceeded $500.
 

More than what patients ‘can afford or are willing to spend’

The estimated $3,000-plus total out-of-pocket cost currently borne by some Medicare beneficiaries with HFrEF who have to shell out for both sacubitril/valsartan and dapagliflozin “appears to substantially exceed what many patients with heart failure can afford or are willing to spend,” wrote Dr. Chew and Dr. Mark.

Dr. Parizo and coauthors developed their cost-effectiveness model for dapagliflozin in treating HFrEF using primarily data collected in the DAPA-HF trial, which proved the efficacy of the drug for reducing cardiovascular deaths or acute heart failure events that led to hospitalization or intravenous outpatient treatment in more than 4,700 randomized patients with HFrEF. The trial enrolled roughly similar numbers of patients with or without type 2 diabetes.

The model showed an overall incremental cost-effectiveness ratio of $83,650/QALY, which was about the same regardless of whether patients also had type 2 diabetes. On a more granular level, the cost-effectiveness value estimate was $78,483/QALY in patients with mild health-status impairment due to their heart failure, and $97,608/QALY in patients with moderate impairment, a finding that underscores the importance of starting dapagliflozin treatment early in the course of HFrEF when disease effects are less severe. The analysis could not address value in patients with more advanced heart failure and in New York Heart Association functional class IV because fewer than 1% of patients in DAPA-HF were in this category.

Drug cost was a major determinant of cost-effectiveness. A 50% drop in cost from the Medicare benchmark of $473.64/month resulted in an incremental cost-effectiveness ratio of about $45,000/QALY (putting it into the high-value category based on the 2014 ACC/AHA formula), while a 50% rise in price yielded a value of nearly $123,000/QALY (still in the intermediate range, which spans from $50,000/QALY to $150,000/QALY). No other cost parameters had a meaningful effect on the cost-effectiveness calculation. The analyses also showed that using the basic cost assumptions, treatment with dapagliflozin needs to persist and remain effective for at least 44 months to produce a cost per QALY that’s less than $150,000. The authors stressed that their analysis considered heart failure effects and did not account for added benefit from treatment with dapagliflozin on preservation of renal function.

While it’s indisputable that treatment with dapagliflozin decreases health care costs by, for example, reducing hospitalizations for heart failure, each hospitalization costs just over $12,000, according to the assumptions made by Dr. Parizo and coauthors. But given dapagliflozin’s impact on this outcome, this cost saving translates into about $500/patient during 18 months on treatment (the median duration of treatment in DAPA-HF), which means the savings barely counterbalances the current cost of dapagliflozin treatment for 1 month, noted Dr. Chew and Dr. Mark.

The DAPA-HF trial was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Parizo had no disclosures and none of his coauthors had a relationship with AstraZeneca. Dr. Chew had no disclosures. Dr. Mark has received research grants from HeartFlow, Mayo Clinic, and Merck.

[email protected]

Although recent trial results have established the sodium glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin as a key new part of the recommended multidrug treatment regimen for patients with heart failure with reduced ejection fraction, the current U.S. cost for dapagliflozin means it has merely “intermediate” value when it comes to cost-effectiveness.

adventtr/iStock/Getty Images Plus

A typical regimen with dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) costs about $474/month or roughly $5,700/year based on Medicare pricing. After factoring in the incremental clinical benefits producing by dapagliflozin seen in the DAPA-HF pivotal trial that helped establish its role, this price produces a cost per quality-adjusted life-year (QALY) gain of about $84,000, which puts dapagliflozin squarely in the intermediate range for value set in 2014 by a task force of the American College of Cardiology and the American Heart Association.

This cost-effectiveness value depends largely on the proven efficacy of dapagliflozin (Farxiga) for decreasing the incidence of cardiovascular death among treated patients with HFrEF, and puts the drug’s value roughly on par with another agent recently approved to treat such patients, sacubitril/valsartan (Entresto), which carries a cost-effectiveness value of about $45,000/QALY.

The U.S. cost per QALY for dapagliflozin treatment of patients with HFrEF dwarfed the value numbers calculated for several other countries that were generally one-tenth this size. This disparity stemmed from both the relatively high price for dapagliflozin in the U.S. compared with other countries – nearly tenfold higher – and relatively higher costs for all types of U.S. medical care, Justin T. Parizo, MD, and coauthors said in a recent report. But the cost, and hence the cost per QALY, of dapagliflozin may soon drop because certain patents on the drug expired in October 2020, added Dr. Parizo, a cardiologist at Stanford (Calif.) University, and associates. Despite the expired patents, as of June 2021 no generic form of dapagliflozin appeared available for U.S. sale.
 

Medicare patients pay about $1,630/year out-of-pocket

“A key caveat” to this finding for dapagliflozin is that being cost-effective “is not by itself a mandate for routine clinical use,” Derek S. Chew, MD, and Daniel B. Mark, MD, said in an editorial that accompanied the report.

A major stumbling block for widespread U.S. prescribing of dapagliflozin to patients with HFrEF is its overall price tag for U.S. patients, estimated at $12 billion/year, as well as an out-of-pocket annual cost for individual Medicare patients of roughly $1,630/year. Adding this out-of-pocket cost to the copay for sacubitril/valsartan and two other much less expensive drug classes that together form the current mainstay, quadruple-drug regimen for HFrEF treatment means a potential annual cost paid by each Medicare patient of about $3,000, wrote Dr. Chew, a cardiologist, and Dr. Mark, a cardiologist and professor, both at Duke University, Durham, N.C.

They cited the precedent of the “unexpectedly slow” and “anemic” uptake of sacubitril/valsartan since its U.S. approval in 2015, a cost-effective agent with “comparable clinical effectiveness” to dapagliflozin. “Even with full inclusion [of sacubitril/valsartan] on formularies and elimination of preapproval requirements, use remains very low, and patient-borne out-of-pocket costs may be a key factor,” wrote Dr. Chew and Dr. Mark. They cited a results from a study that showed abandonment of new prescriptions at retail U.S. pharmacies spiked to a 60% rate when out-of-pocket cost exceeded $500.
 

More than what patients ‘can afford or are willing to spend’

The estimated $3,000-plus total out-of-pocket cost currently borne by some Medicare beneficiaries with HFrEF who have to shell out for both sacubitril/valsartan and dapagliflozin “appears to substantially exceed what many patients with heart failure can afford or are willing to spend,” wrote Dr. Chew and Dr. Mark.

Dr. Parizo and coauthors developed their cost-effectiveness model for dapagliflozin in treating HFrEF using primarily data collected in the DAPA-HF trial, which proved the efficacy of the drug for reducing cardiovascular deaths or acute heart failure events that led to hospitalization or intravenous outpatient treatment in more than 4,700 randomized patients with HFrEF. The trial enrolled roughly similar numbers of patients with or without type 2 diabetes.

The model showed an overall incremental cost-effectiveness ratio of $83,650/QALY, which was about the same regardless of whether patients also had type 2 diabetes. On a more granular level, the cost-effectiveness value estimate was $78,483/QALY in patients with mild health-status impairment due to their heart failure, and $97,608/QALY in patients with moderate impairment, a finding that underscores the importance of starting dapagliflozin treatment early in the course of HFrEF when disease effects are less severe. The analysis could not address value in patients with more advanced heart failure and in New York Heart Association functional class IV because fewer than 1% of patients in DAPA-HF were in this category.

Drug cost was a major determinant of cost-effectiveness. A 50% drop in cost from the Medicare benchmark of $473.64/month resulted in an incremental cost-effectiveness ratio of about $45,000/QALY (putting it into the high-value category based on the 2014 ACC/AHA formula), while a 50% rise in price yielded a value of nearly $123,000/QALY (still in the intermediate range, which spans from $50,000/QALY to $150,000/QALY). No other cost parameters had a meaningful effect on the cost-effectiveness calculation. The analyses also showed that using the basic cost assumptions, treatment with dapagliflozin needs to persist and remain effective for at least 44 months to produce a cost per QALY that’s less than $150,000. The authors stressed that their analysis considered heart failure effects and did not account for added benefit from treatment with dapagliflozin on preservation of renal function.

While it’s indisputable that treatment with dapagliflozin decreases health care costs by, for example, reducing hospitalizations for heart failure, each hospitalization costs just over $12,000, according to the assumptions made by Dr. Parizo and coauthors. But given dapagliflozin’s impact on this outcome, this cost saving translates into about $500/patient during 18 months on treatment (the median duration of treatment in DAPA-HF), which means the savings barely counterbalances the current cost of dapagliflozin treatment for 1 month, noted Dr. Chew and Dr. Mark.

The DAPA-HF trial was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Parizo had no disclosures and none of his coauthors had a relationship with AstraZeneca. Dr. Chew had no disclosures. Dr. Mark has received research grants from HeartFlow, Mayo Clinic, and Merck.

[email protected]

Although recent trial results have established the sodium glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin as a key new part of the recommended multidrug treatment regimen for patients with heart failure with reduced ejection fraction, the current U.S. cost for dapagliflozin means it has merely “intermediate” value when it comes to cost-effectiveness.

adventtr/iStock/Getty Images Plus

A typical regimen with dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) costs about $474/month or roughly $5,700/year based on Medicare pricing. After factoring in the incremental clinical benefits producing by dapagliflozin seen in the DAPA-HF pivotal trial that helped establish its role, this price produces a cost per quality-adjusted life-year (QALY) gain of about $84,000, which puts dapagliflozin squarely in the intermediate range for value set in 2014 by a task force of the American College of Cardiology and the American Heart Association.

This cost-effectiveness value depends largely on the proven efficacy of dapagliflozin (Farxiga) for decreasing the incidence of cardiovascular death among treated patients with HFrEF, and puts the drug’s value roughly on par with another agent recently approved to treat such patients, sacubitril/valsartan (Entresto), which carries a cost-effectiveness value of about $45,000/QALY.

The U.S. cost per QALY for dapagliflozin treatment of patients with HFrEF dwarfed the value numbers calculated for several other countries that were generally one-tenth this size. This disparity stemmed from both the relatively high price for dapagliflozin in the U.S. compared with other countries – nearly tenfold higher – and relatively higher costs for all types of U.S. medical care, Justin T. Parizo, MD, and coauthors said in a recent report. But the cost, and hence the cost per QALY, of dapagliflozin may soon drop because certain patents on the drug expired in October 2020, added Dr. Parizo, a cardiologist at Stanford (Calif.) University, and associates. Despite the expired patents, as of June 2021 no generic form of dapagliflozin appeared available for U.S. sale.
 

Medicare patients pay about $1,630/year out-of-pocket

“A key caveat” to this finding for dapagliflozin is that being cost-effective “is not by itself a mandate for routine clinical use,” Derek S. Chew, MD, and Daniel B. Mark, MD, said in an editorial that accompanied the report.

A major stumbling block for widespread U.S. prescribing of dapagliflozin to patients with HFrEF is its overall price tag for U.S. patients, estimated at $12 billion/year, as well as an out-of-pocket annual cost for individual Medicare patients of roughly $1,630/year. Adding this out-of-pocket cost to the copay for sacubitril/valsartan and two other much less expensive drug classes that together form the current mainstay, quadruple-drug regimen for HFrEF treatment means a potential annual cost paid by each Medicare patient of about $3,000, wrote Dr. Chew, a cardiologist, and Dr. Mark, a cardiologist and professor, both at Duke University, Durham, N.C.

They cited the precedent of the “unexpectedly slow” and “anemic” uptake of sacubitril/valsartan since its U.S. approval in 2015, a cost-effective agent with “comparable clinical effectiveness” to dapagliflozin. “Even with full inclusion [of sacubitril/valsartan] on formularies and elimination of preapproval requirements, use remains very low, and patient-borne out-of-pocket costs may be a key factor,” wrote Dr. Chew and Dr. Mark. They cited a results from a study that showed abandonment of new prescriptions at retail U.S. pharmacies spiked to a 60% rate when out-of-pocket cost exceeded $500.
 

More than what patients ‘can afford or are willing to spend’

The estimated $3,000-plus total out-of-pocket cost currently borne by some Medicare beneficiaries with HFrEF who have to shell out for both sacubitril/valsartan and dapagliflozin “appears to substantially exceed what many patients with heart failure can afford or are willing to spend,” wrote Dr. Chew and Dr. Mark.

Dr. Parizo and coauthors developed their cost-effectiveness model for dapagliflozin in treating HFrEF using primarily data collected in the DAPA-HF trial, which proved the efficacy of the drug for reducing cardiovascular deaths or acute heart failure events that led to hospitalization or intravenous outpatient treatment in more than 4,700 randomized patients with HFrEF. The trial enrolled roughly similar numbers of patients with or without type 2 diabetes.

The model showed an overall incremental cost-effectiveness ratio of $83,650/QALY, which was about the same regardless of whether patients also had type 2 diabetes. On a more granular level, the cost-effectiveness value estimate was $78,483/QALY in patients with mild health-status impairment due to their heart failure, and $97,608/QALY in patients with moderate impairment, a finding that underscores the importance of starting dapagliflozin treatment early in the course of HFrEF when disease effects are less severe. The analysis could not address value in patients with more advanced heart failure and in New York Heart Association functional class IV because fewer than 1% of patients in DAPA-HF were in this category.

Drug cost was a major determinant of cost-effectiveness. A 50% drop in cost from the Medicare benchmark of $473.64/month resulted in an incremental cost-effectiveness ratio of about $45,000/QALY (putting it into the high-value category based on the 2014 ACC/AHA formula), while a 50% rise in price yielded a value of nearly $123,000/QALY (still in the intermediate range, which spans from $50,000/QALY to $150,000/QALY). No other cost parameters had a meaningful effect on the cost-effectiveness calculation. The analyses also showed that using the basic cost assumptions, treatment with dapagliflozin needs to persist and remain effective for at least 44 months to produce a cost per QALY that’s less than $150,000. The authors stressed that their analysis considered heart failure effects and did not account for added benefit from treatment with dapagliflozin on preservation of renal function.

While it’s indisputable that treatment with dapagliflozin decreases health care costs by, for example, reducing hospitalizations for heart failure, each hospitalization costs just over $12,000, according to the assumptions made by Dr. Parizo and coauthors. But given dapagliflozin’s impact on this outcome, this cost saving translates into about $500/patient during 18 months on treatment (the median duration of treatment in DAPA-HF), which means the savings barely counterbalances the current cost of dapagliflozin treatment for 1 month, noted Dr. Chew and Dr. Mark.

The DAPA-HF trial was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Parizo had no disclosures and none of his coauthors had a relationship with AstraZeneca. Dr. Chew had no disclosures. Dr. Mark has received research grants from HeartFlow, Mayo Clinic, and Merck.

[email protected]

The keys to effective resuscitation in the hospital setting include effective compression and early defibrillation, according to Jessica Nave Allen, MD, FHM, a hospitalist with Emory University Hospital in Atlanta. She spoke about best practices in resuscitation medicine recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

“We know CPR [cardiopulmonary resuscitation] and shocking are the two biggest determinants of outcomes, so really strive to make those chest compressions really high quality,” said Dr. Allen. She urged hospitalists to consider mechanical piston compressions and even “reverse CPR” when appropriate.

Dr. Allen offered several other tips about effective in-hospital resuscitation.
 

Don’t overcrowd the hospital room

There shouldn’t be more than eight people inside the room during a code, she said. If you’re the code leader, “make sure that somebody has already started high-quality chest compressions. You want to make sure that somebody is already on the airway. It’s usually two people, one person to actually hold the mask down to make sure there’s a good seal, and the other person to deliver the breaths.”

Two to three people should be assigned to chest compressions, Dr. Allen said, “and you need one or two nurses for medication delivery and grabbing things from the runners. And then you need to have a recorder and the code leader. Everyone else who’s not in one of those formalized roles needs to be outside the room. That includes the pharmacist, who usually stands at the door if you don’t have a code pharmacist at your institution.”

A helpful mnemonic for the resuscitation process is I(CA)RAMBO, which was developed at Tufts Medical Center and published in 2020, she said. The mnemonic stands for the following:

• I: Identify yourself as code leader.
• CA: Compression, Airway.
• R: Roles (assign roles in the resuscitation).
• A: Access (intravenous access is preferred to intraosseous, per the American Heart Association’s , unless intravenous access is unavailable, Dr. Allen noted).
• M: Monitor (make sure pads are placed correctly; turn the defibrillator on).
• B: Backboard.
• O: Oxygen.

Focus on high-quality chest compressions

The number of chest compressions must be 100-120 per minute, Dr. Allen said. You can time them to the beat of a song, such as “Stayin’ Alive,” or with a metronome, she said, “but whatever it is, you need to stay in that window.”

The correct compression depth is 2-2.4 inches. “That’s very difficult to do during the middle of a code, which is why it’s important to allow full recoil,” she said. “This doesn’t mean taking your hands off of the chest: You should actually never take your hands off of the chest. But you should allow the chest wall to return to its normal state. Also, make sure you aren’t off the chest for more for 10 seconds whenever you’re doing a rhythm check.”

Audiovisual feedback devices can provide insight into the quality of chest compressions. For example, some defibrillators are equipped with sensors that urge users to push harder and faster when appropriate. “Studies have shown that the quality of chest compressions goes up when you use these devices,” she said.
 

Don’t be afraid of mechanical chest compression

Although early research raised questions about the quality of resuscitation outcomes when mechanical piston chest compression devices are used, a 2015 systematic review and meta-analysis found that “man was equal to machine,” Dr. Allen said. “The bottom line is that these devices may be a reasonable alternative to conventional CPR in specific settings.”

American Heart Association guidelines state that mechanical compressions may be appropriate in certain specific situations “where the delivery of high-quality manual compressions may be challenging or dangerous for the provider.”

According to Dr. Allen, “there are times when it’s useful,” such as for a patient with COVID-19, in the cath lab, or in a medical helicopter.
 

Move quickly to defibrillation

“Most of us know that you want to shock as early as possible in shockable rhythms,” Dr. Allen said. Support, she said, comes from a 2008 study that linked delayed defibrillation to lower survival rates. “We want to shock as soon as possible, because your chances of surviving go down for every minute you wait.”

Take special care for patients with confirmed or suspected COVID-19

“Not surprisingly, the goals here are to minimize exposure to staff,” Dr. Allen said.

Put on personal protective equipment before entering the room even if care is delayed, she advised, and reduce the number of staff members in the room below the typical maximum of eight. “In COVID, it should be a maximum of six, and some institutions have even gotten it down to four where the code leaders are outside the room with an iPad.”

Use mechanical compression devices, she advised, and place patients on ventilators as soon as possible. She added: “Use a HEPA [high-efficiency particulate air] filter for all your airway modalities.”

CPR may be challenging in some cases, such as when a large, intubated patient is prone and cannot be quickly or safely flipped over. In those cases, consider posterior chest compressions, also known as reverse CPR, at vertebral positions T7-T10. “We have done reverse CPR on several COVID patients throughout the Emory system,” she said.
 

Debrief right after codes

“You really want to debrief with the code team,” Dr. Allen said. “If you don’t already have a policy in place at your institution, you should help come up with one where you sit down with the team and talk about what could you have done better as a group. It’s not a time to place blame. It’s a time to learn.”

Dr. Allen has disclosed no relevant financial relationships.

This article was updated 7/26/21.

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

The keys to effective resuscitation in the hospital setting include effective compression and early defibrillation, according to Jessica Nave Allen, MD, FHM, a hospitalist with Emory University Hospital in Atlanta. She spoke about best practices in resuscitation medicine recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

“We know CPR [cardiopulmonary resuscitation] and shocking are the two biggest determinants of outcomes, so really strive to make those chest compressions really high quality,” said Dr. Allen. She urged hospitalists to consider mechanical piston compressions and even “reverse CPR” when appropriate.

Dr. Allen offered several other tips about effective in-hospital resuscitation.
 

Don’t overcrowd the hospital room

There shouldn’t be more than eight people inside the room during a code, she said. If you’re the code leader, “make sure that somebody has already started high-quality chest compressions. You want to make sure that somebody is already on the airway. It’s usually two people, one person to actually hold the mask down to make sure there’s a good seal, and the other person to deliver the breaths.”

Two to three people should be assigned to chest compressions, Dr. Allen said, “and you need one or two nurses for medication delivery and grabbing things from the runners. And then you need to have a recorder and the code leader. Everyone else who’s not in one of those formalized roles needs to be outside the room. That includes the pharmacist, who usually stands at the door if you don’t have a code pharmacist at your institution.”

A helpful mnemonic for the resuscitation process is I(CA)RAMBO, which was developed at Tufts Medical Center and published in 2020, she said. The mnemonic stands for the following:

• I: Identify yourself as code leader.
• CA: Compression, Airway.
• R: Roles (assign roles in the resuscitation).
• A: Access (intravenous access is preferred to intraosseous, per the American Heart Association’s , unless intravenous access is unavailable, Dr. Allen noted).
• M: Monitor (make sure pads are placed correctly; turn the defibrillator on).
• B: Backboard.
• O: Oxygen.

Focus on high-quality chest compressions

The number of chest compressions must be 100-120 per minute, Dr. Allen said. You can time them to the beat of a song, such as “Stayin’ Alive,” or with a metronome, she said, “but whatever it is, you need to stay in that window.”

The correct compression depth is 2-2.4 inches. “That’s very difficult to do during the middle of a code, which is why it’s important to allow full recoil,” she said. “This doesn’t mean taking your hands off of the chest: You should actually never take your hands off of the chest. But you should allow the chest wall to return to its normal state. Also, make sure you aren’t off the chest for more for 10 seconds whenever you’re doing a rhythm check.”

Audiovisual feedback devices can provide insight into the quality of chest compressions. For example, some defibrillators are equipped with sensors that urge users to push harder and faster when appropriate. “Studies have shown that the quality of chest compressions goes up when you use these devices,” she said.
 

Don’t be afraid of mechanical chest compression

Although early research raised questions about the quality of resuscitation outcomes when mechanical piston chest compression devices are used, a 2015 systematic review and meta-analysis found that “man was equal to machine,” Dr. Allen said. “The bottom line is that these devices may be a reasonable alternative to conventional CPR in specific settings.”

American Heart Association guidelines state that mechanical compressions may be appropriate in certain specific situations “where the delivery of high-quality manual compressions may be challenging or dangerous for the provider.”

According to Dr. Allen, “there are times when it’s useful,” such as for a patient with COVID-19, in the cath lab, or in a medical helicopter.
 

Move quickly to defibrillation

“Most of us know that you want to shock as early as possible in shockable rhythms,” Dr. Allen said. Support, she said, comes from a 2008 study that linked delayed defibrillation to lower survival rates. “We want to shock as soon as possible, because your chances of surviving go down for every minute you wait.”

Take special care for patients with confirmed or suspected COVID-19

“Not surprisingly, the goals here are to minimize exposure to staff,” Dr. Allen said.

Put on personal protective equipment before entering the room even if care is delayed, she advised, and reduce the number of staff members in the room below the typical maximum of eight. “In COVID, it should be a maximum of six, and some institutions have even gotten it down to four where the code leaders are outside the room with an iPad.”

Use mechanical compression devices, she advised, and place patients on ventilators as soon as possible. She added: “Use a HEPA [high-efficiency particulate air] filter for all your airway modalities.”

CPR may be challenging in some cases, such as when a large, intubated patient is prone and cannot be quickly or safely flipped over. In those cases, consider posterior chest compressions, also known as reverse CPR, at vertebral positions T7-T10. “We have done reverse CPR on several COVID patients throughout the Emory system,” she said.
 

Debrief right after codes

“You really want to debrief with the code team,” Dr. Allen said. “If you don’t already have a policy in place at your institution, you should help come up with one where you sit down with the team and talk about what could you have done better as a group. It’s not a time to place blame. It’s a time to learn.”

Dr. Allen has disclosed no relevant financial relationships.

This article was updated 7/26/21.

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

The keys to effective resuscitation in the hospital setting include effective compression and early defibrillation, according to Jessica Nave Allen, MD, FHM, a hospitalist with Emory University Hospital in Atlanta. She spoke about best practices in resuscitation medicine recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

“We know CPR [cardiopulmonary resuscitation] and shocking are the two biggest determinants of outcomes, so really strive to make those chest compressions really high quality,” said Dr. Allen. She urged hospitalists to consider mechanical piston compressions and even “reverse CPR” when appropriate.

Dr. Allen offered several other tips about effective in-hospital resuscitation.
 

Don’t overcrowd the hospital room

There shouldn’t be more than eight people inside the room during a code, she said. If you’re the code leader, “make sure that somebody has already started high-quality chest compressions. You want to make sure that somebody is already on the airway. It’s usually two people, one person to actually hold the mask down to make sure there’s a good seal, and the other person to deliver the breaths.”

Two to three people should be assigned to chest compressions, Dr. Allen said, “and you need one or two nurses for medication delivery and grabbing things from the runners. And then you need to have a recorder and the code leader. Everyone else who’s not in one of those formalized roles needs to be outside the room. That includes the pharmacist, who usually stands at the door if you don’t have a code pharmacist at your institution.”

A helpful mnemonic for the resuscitation process is I(CA)RAMBO, which was developed at Tufts Medical Center and published in 2020, she said. The mnemonic stands for the following:

• I: Identify yourself as code leader.
• CA: Compression, Airway.
• R: Roles (assign roles in the resuscitation).
• A: Access (intravenous access is preferred to intraosseous, per the American Heart Association’s , unless intravenous access is unavailable, Dr. Allen noted).
• M: Monitor (make sure pads are placed correctly; turn the defibrillator on).
• B: Backboard.
• O: Oxygen.

Focus on high-quality chest compressions

The number of chest compressions must be 100-120 per minute, Dr. Allen said. You can time them to the beat of a song, such as “Stayin’ Alive,” or with a metronome, she said, “but whatever it is, you need to stay in that window.”

The correct compression depth is 2-2.4 inches. “That’s very difficult to do during the middle of a code, which is why it’s important to allow full recoil,” she said. “This doesn’t mean taking your hands off of the chest: You should actually never take your hands off of the chest. But you should allow the chest wall to return to its normal state. Also, make sure you aren’t off the chest for more for 10 seconds whenever you’re doing a rhythm check.”

Audiovisual feedback devices can provide insight into the quality of chest compressions. For example, some defibrillators are equipped with sensors that urge users to push harder and faster when appropriate. “Studies have shown that the quality of chest compressions goes up when you use these devices,” she said.
 

Don’t be afraid of mechanical chest compression

Although early research raised questions about the quality of resuscitation outcomes when mechanical piston chest compression devices are used, a 2015 systematic review and meta-analysis found that “man was equal to machine,” Dr. Allen said. “The bottom line is that these devices may be a reasonable alternative to conventional CPR in specific settings.”

American Heart Association guidelines state that mechanical compressions may be appropriate in certain specific situations “where the delivery of high-quality manual compressions may be challenging or dangerous for the provider.”

According to Dr. Allen, “there are times when it’s useful,” such as for a patient with COVID-19, in the cath lab, or in a medical helicopter.
 

Move quickly to defibrillation

“Most of us know that you want to shock as early as possible in shockable rhythms,” Dr. Allen said. Support, she said, comes from a 2008 study that linked delayed defibrillation to lower survival rates. “We want to shock as soon as possible, because your chances of surviving go down for every minute you wait.”

Take special care for patients with confirmed or suspected COVID-19

“Not surprisingly, the goals here are to minimize exposure to staff,” Dr. Allen said.

Put on personal protective equipment before entering the room even if care is delayed, she advised, and reduce the number of staff members in the room below the typical maximum of eight. “In COVID, it should be a maximum of six, and some institutions have even gotten it down to four where the code leaders are outside the room with an iPad.”

Use mechanical compression devices, she advised, and place patients on ventilators as soon as possible. She added: “Use a HEPA [high-efficiency particulate air] filter for all your airway modalities.”

CPR may be challenging in some cases, such as when a large, intubated patient is prone and cannot be quickly or safely flipped over. In those cases, consider posterior chest compressions, also known as reverse CPR, at vertebral positions T7-T10. “We have done reverse CPR on several COVID patients throughout the Emory system,” she said.
 

Debrief right after codes

“You really want to debrief with the code team,” Dr. Allen said. “If you don’t already have a policy in place at your institution, you should help come up with one where you sit down with the team and talk about what could you have done better as a group. It’s not a time to place blame. It’s a time to learn.”

Dr. Allen has disclosed no relevant financial relationships.

This article was updated 7/26/21.

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

Botulinum toxin is said to be the most lethal substance known. Inhaling just 1-3 nanograms of toxin per kilogram of body mass constitutes a lethal dose. 

Now the Centers for Disease Control and Prevention has published the first comprehensive guide to the diagnosis and treatment of botulism. The CDC has been working on these guidelines since 2015, initially establishing a technical development group and steering committee to prioritize topics for review and make recommendations. Since then, the agency published 15 systematic reviews in  Clinical Infectious Diseases early in 2018. The reviews addressed the recognition of botulism clinically, treatment with botulinum antitoxin, and complications from that treatment. They also looked at the epidemiology of botulism outbreaks and botulism in the special populations of vulnerable pediatric and pregnant patients.

In 2016, the CDC held two extended forums and convened a workshop with 72 experts. In addition to the more standard topics of diagnosis and treatment, attention was given to crisis standards of care, caring for multiple patients at once, and ethical considerations in management.

Amesh Adalja, MD, senior scholar, Johns Hopkins Center for Health Security, Baltimore, said in an interview that the new guidance “was really specific [and] was meant to address the gap in guidance for mass casualty settings.”

While clinicians are used to focusing on an individual patient, in times of crises, with multiple patients from a food-borne outbreak or a bioterrorism attack, the focus must shift to the population rather than the individual. The workshop explored issues of triaging, adding beds, and caring for patients when a hospital is overwhelmed with an acute influx of severely ill patients.

Such a mass casualty event is similar to the stress encountered this past year with COVID-19 patients swamping the hospitals, which had too little oxygen, too few ventilators, and too few staff members to care for the sudden influx of critically ill patients.
 

Diagnosis

Leslie Edwards, MHS, BSN, a CDC epidemiologist and botulism expert, said that “botulism is rare and [so] could be difficult to diagnose.” The CDC “wanted to highlight some of those key clinical factors” to speed recognition.

Hospitals and health officials are being urged to develop crisis protocols as part of emergency preparedness plans. And clinicians should be able to recognize four major syndromes: botulism from food, wounds, and inhalation, as well as iatrogenic botulism (from exposure via injection of the neurotoxin).

Botulism has a characteristic and unusual pattern of symptoms, which begin with cranial nerve palsies. Then there is typically a descending, symmetric flaccid paralysis. Symptoms might progress to respiratory failure and death. Other critical clues that implicate botulism include a lack of sensory deficits and the absence of pain.

Symptoms are most likely to be mistaken for myasthenia gravis or Guillain-Barré syndrome, but the latter has an ascending paralysis. Cranial nerve involvement can present as blurred vision, ptosis (drooping lid), diplopia (double vision), ophthalmoplegia (weak eye muscles), or difficulty with speech and swallowing. Shortness of breath and abdominal discomfort can also occur. Respiratory failure may occur from weakness or paralysis of cranial nerves. Cranial nerve signs and symptoms in the absence of fever, along with a descending paralysis, should strongly suggest the diagnosis.

With food-borne botulism, vomiting occurs in half the patients. Improperly sterilized home-canned food is the major risk factor. While the toxin is rapidly destroyed by heat, the bacterial spores are not. Wound botulism is most commonly associated with the injection of drugs, particularly black tar heroin.

Dr. Edwards stressed that “time is of the essence when it comes to botulism diagnostics and treating. Timely administration of the botulism antitoxin early in the course of illness can arrest the progression of paralysis and possibly avert the need for intubation or ventilation.”

It’s essential to note that botulism is an urgent diagnosis that has to be made on clinical grounds. Lab assays for botulinum neurotoxins take too long and are only conducted in public health laboratories. The decision to use antitoxin must not be delayed to wait for confirmation.

Clinicians should immediately contact the local or state health department’s emergency on-call team if botulism is suspected. They will arrange for expert consultation.
 

Treatment

Botulinum antitoxin is the only specific therapy for this infection. If given early – preferably within 24-48 hours of symptom onset – it can stop the progression of paralysis. But antitoxin will not reverse existing paralysis. If paralysis is still progressing outside of that 24- to 48-hour window, the antitoxin should still provide benefit. The antitoxin is available only through state health departments and a request to the CDC.

Botulism antitoxin is made from horse serum and therefore may cause a variety of allergic reactions. The risk for anaphylaxis is less than 2%, far lower than the mortality from untreated botulism.

While these guidelines have an important focus on triaging and treating mass casualties from botulism, it’s important to note that food-borne outbreaks and prevention issues are covered elsewhere on the CDC site.

Dr. Edwards has disclosed no relevant financial relationships. Dr. Adalja is a consultant for Emergent BioSolutions, which makes the heptavalent botulism antitoxin.

Dr. Stone is an infectious disease specialist and author of “Resilience: One Family’s Story of Hope and Triumph Over Evil” and of “Conducting Clinical Research,” the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

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

Botulinum toxin is said to be the most lethal substance known. Inhaling just 1-3 nanograms of toxin per kilogram of body mass constitutes a lethal dose. 

Now the Centers for Disease Control and Prevention has published the first comprehensive guide to the diagnosis and treatment of botulism. The CDC has been working on these guidelines since 2015, initially establishing a technical development group and steering committee to prioritize topics for review and make recommendations. Since then, the agency published 15 systematic reviews in  Clinical Infectious Diseases early in 2018. The reviews addressed the recognition of botulism clinically, treatment with botulinum antitoxin, and complications from that treatment. They also looked at the epidemiology of botulism outbreaks and botulism in the special populations of vulnerable pediatric and pregnant patients.

In 2016, the CDC held two extended forums and convened a workshop with 72 experts. In addition to the more standard topics of diagnosis and treatment, attention was given to crisis standards of care, caring for multiple patients at once, and ethical considerations in management.

Amesh Adalja, MD, senior scholar, Johns Hopkins Center for Health Security, Baltimore, said in an interview that the new guidance “was really specific [and] was meant to address the gap in guidance for mass casualty settings.”

While clinicians are used to focusing on an individual patient, in times of crises, with multiple patients from a food-borne outbreak or a bioterrorism attack, the focus must shift to the population rather than the individual. The workshop explored issues of triaging, adding beds, and caring for patients when a hospital is overwhelmed with an acute influx of severely ill patients.

Such a mass casualty event is similar to the stress encountered this past year with COVID-19 patients swamping the hospitals, which had too little oxygen, too few ventilators, and too few staff members to care for the sudden influx of critically ill patients.
 

Diagnosis

Leslie Edwards, MHS, BSN, a CDC epidemiologist and botulism expert, said that “botulism is rare and [so] could be difficult to diagnose.” The CDC “wanted to highlight some of those key clinical factors” to speed recognition.

Hospitals and health officials are being urged to develop crisis protocols as part of emergency preparedness plans. And clinicians should be able to recognize four major syndromes: botulism from food, wounds, and inhalation, as well as iatrogenic botulism (from exposure via injection of the neurotoxin).

Botulism has a characteristic and unusual pattern of symptoms, which begin with cranial nerve palsies. Then there is typically a descending, symmetric flaccid paralysis. Symptoms might progress to respiratory failure and death. Other critical clues that implicate botulism include a lack of sensory deficits and the absence of pain.

Symptoms are most likely to be mistaken for myasthenia gravis or Guillain-Barré syndrome, but the latter has an ascending paralysis. Cranial nerve involvement can present as blurred vision, ptosis (drooping lid), diplopia (double vision), ophthalmoplegia (weak eye muscles), or difficulty with speech and swallowing. Shortness of breath and abdominal discomfort can also occur. Respiratory failure may occur from weakness or paralysis of cranial nerves. Cranial nerve signs and symptoms in the absence of fever, along with a descending paralysis, should strongly suggest the diagnosis.

With food-borne botulism, vomiting occurs in half the patients. Improperly sterilized home-canned food is the major risk factor. While the toxin is rapidly destroyed by heat, the bacterial spores are not. Wound botulism is most commonly associated with the injection of drugs, particularly black tar heroin.

Dr. Edwards stressed that “time is of the essence when it comes to botulism diagnostics and treating. Timely administration of the botulism antitoxin early in the course of illness can arrest the progression of paralysis and possibly avert the need for intubation or ventilation.”

It’s essential to note that botulism is an urgent diagnosis that has to be made on clinical grounds. Lab assays for botulinum neurotoxins take too long and are only conducted in public health laboratories. The decision to use antitoxin must not be delayed to wait for confirmation.

Clinicians should immediately contact the local or state health department’s emergency on-call team if botulism is suspected. They will arrange for expert consultation.
 

Treatment

Botulinum antitoxin is the only specific therapy for this infection. If given early – preferably within 24-48 hours of symptom onset – it can stop the progression of paralysis. But antitoxin will not reverse existing paralysis. If paralysis is still progressing outside of that 24- to 48-hour window, the antitoxin should still provide benefit. The antitoxin is available only through state health departments and a request to the CDC.

Botulism antitoxin is made from horse serum and therefore may cause a variety of allergic reactions. The risk for anaphylaxis is less than 2%, far lower than the mortality from untreated botulism.

While these guidelines have an important focus on triaging and treating mass casualties from botulism, it’s important to note that food-borne outbreaks and prevention issues are covered elsewhere on the CDC site.

Dr. Edwards has disclosed no relevant financial relationships. Dr. Adalja is a consultant for Emergent BioSolutions, which makes the heptavalent botulism antitoxin.

Dr. Stone is an infectious disease specialist and author of “Resilience: One Family’s Story of Hope and Triumph Over Evil” and of “Conducting Clinical Research,” the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

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

Botulinum toxin is said to be the most lethal substance known. Inhaling just 1-3 nanograms of toxin per kilogram of body mass constitutes a lethal dose. 

Now the Centers for Disease Control and Prevention has published the first comprehensive guide to the diagnosis and treatment of botulism. The CDC has been working on these guidelines since 2015, initially establishing a technical development group and steering committee to prioritize topics for review and make recommendations. Since then, the agency published 15 systematic reviews in  Clinical Infectious Diseases early in 2018. The reviews addressed the recognition of botulism clinically, treatment with botulinum antitoxin, and complications from that treatment. They also looked at the epidemiology of botulism outbreaks and botulism in the special populations of vulnerable pediatric and pregnant patients.

In 2016, the CDC held two extended forums and convened a workshop with 72 experts. In addition to the more standard topics of diagnosis and treatment, attention was given to crisis standards of care, caring for multiple patients at once, and ethical considerations in management.

Amesh Adalja, MD, senior scholar, Johns Hopkins Center for Health Security, Baltimore, said in an interview that the new guidance “was really specific [and] was meant to address the gap in guidance for mass casualty settings.”

While clinicians are used to focusing on an individual patient, in times of crises, with multiple patients from a food-borne outbreak or a bioterrorism attack, the focus must shift to the population rather than the individual. The workshop explored issues of triaging, adding beds, and caring for patients when a hospital is overwhelmed with an acute influx of severely ill patients.

Such a mass casualty event is similar to the stress encountered this past year with COVID-19 patients swamping the hospitals, which had too little oxygen, too few ventilators, and too few staff members to care for the sudden influx of critically ill patients.
 

Diagnosis

Leslie Edwards, MHS, BSN, a CDC epidemiologist and botulism expert, said that “botulism is rare and [so] could be difficult to diagnose.” The CDC “wanted to highlight some of those key clinical factors” to speed recognition.

Hospitals and health officials are being urged to develop crisis protocols as part of emergency preparedness plans. And clinicians should be able to recognize four major syndromes: botulism from food, wounds, and inhalation, as well as iatrogenic botulism (from exposure via injection of the neurotoxin).

Botulism has a characteristic and unusual pattern of symptoms, which begin with cranial nerve palsies. Then there is typically a descending, symmetric flaccid paralysis. Symptoms might progress to respiratory failure and death. Other critical clues that implicate botulism include a lack of sensory deficits and the absence of pain.

Symptoms are most likely to be mistaken for myasthenia gravis or Guillain-Barré syndrome, but the latter has an ascending paralysis. Cranial nerve involvement can present as blurred vision, ptosis (drooping lid), diplopia (double vision), ophthalmoplegia (weak eye muscles), or difficulty with speech and swallowing. Shortness of breath and abdominal discomfort can also occur. Respiratory failure may occur from weakness or paralysis of cranial nerves. Cranial nerve signs and symptoms in the absence of fever, along with a descending paralysis, should strongly suggest the diagnosis.

With food-borne botulism, vomiting occurs in half the patients. Improperly sterilized home-canned food is the major risk factor. While the toxin is rapidly destroyed by heat, the bacterial spores are not. Wound botulism is most commonly associated with the injection of drugs, particularly black tar heroin.

Dr. Edwards stressed that “time is of the essence when it comes to botulism diagnostics and treating. Timely administration of the botulism antitoxin early in the course of illness can arrest the progression of paralysis and possibly avert the need for intubation or ventilation.”

It’s essential to note that botulism is an urgent diagnosis that has to be made on clinical grounds. Lab assays for botulinum neurotoxins take too long and are only conducted in public health laboratories. The decision to use antitoxin must not be delayed to wait for confirmation.

Clinicians should immediately contact the local or state health department’s emergency on-call team if botulism is suspected. They will arrange for expert consultation.
 

Treatment

Botulinum antitoxin is the only specific therapy for this infection. If given early – preferably within 24-48 hours of symptom onset – it can stop the progression of paralysis. But antitoxin will not reverse existing paralysis. If paralysis is still progressing outside of that 24- to 48-hour window, the antitoxin should still provide benefit. The antitoxin is available only through state health departments and a request to the CDC.

Botulism antitoxin is made from horse serum and therefore may cause a variety of allergic reactions. The risk for anaphylaxis is less than 2%, far lower than the mortality from untreated botulism.

While these guidelines have an important focus on triaging and treating mass casualties from botulism, it’s important to note that food-borne outbreaks and prevention issues are covered elsewhere on the CDC site.

Dr. Edwards has disclosed no relevant financial relationships. Dr. Adalja is a consultant for Emergent BioSolutions, which makes the heptavalent botulism antitoxin.

Dr. Stone is an infectious disease specialist and author of “Resilience: One Family’s Story of Hope and Triumph Over Evil” and of “Conducting Clinical Research,” the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

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

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]