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Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Zoonoses are no respecter of biological boundaries and are notorious for crossing genus and even higher taxonomic boundaries. SARS-CoV-2 is no exception, the current outbreak most probably having originated in bats, a common source of human-affecting zoonoses throughout history. But it is not a one-way street, and the virus has been shown to spread from infected humans to a variety of other land mammals, including our domesticated animals and kept zoo species.

A recent troubling report, however, has indicated that sea mammals may be part of a next wave of likely candidates for infection, put at risk by the current human pandemic and environmental degradation on a global scale, according to a the results of a genomic analysis of four major groups of sea mammals.

Researchers Sabateeshan Mathavarajah and colleagues from Dalhousie University, Halifax, N.S., examined the sequences of the ACE2 receptors in the various marine mammal species. The ACE2 receptor has recently been identified as the SARS-CoV-2 receptor, which allows for infection.

The researchers examined genomic databases of the marine species to determine if their ACE2 receptor sequences indicated the potential for high, medium, or low susceptibility to infection, as reported in Science of the Total Environment. Database analysis was performed for four groups: Cetacea (whales and dolphins), Pinnepidia (seals), Sirenia (sea cows), and Fissipedia (sea otters and polar bears).

The researchers defined susceptibility values based on comparable binding with the receptor and came up with the following subgroups: higher than human, high (resembles human ACE2), medium (resembles cat ACE2), and low (resembles dog ACE2). It has yet to be established if these marine mammals actually are infected with SARS-CoV-2 and what the impact of such an infection might have on animal health or humans who come in contact with infected animals.

They also cross-referenced for the level of species endangerment and with maps of potential wastewater contamination for certain areas that species came in contact with, using Alaska as the model.
 

Populations in danger

The researchers found 15 species that are already at risk globally that fall under the categories of near threatened, vulnerable, endangered, and critically endangered that were predicted to be medium to higher susceptibility to the SARS-CoV-2 virus than humans. Cross infection is of particular concern because other coronaviruses have been shown to have severe and lethal effects among many of these species.

Among the potentially impacted species were the near threatened–status Antarctic Mink whale and the stellar sea lion; the vulnerable sperm whale, northern fur seal, and Atlantic walrus; the endangered northern and southern sea otters, the North Pacific right whale, and the Amazon River dolphin; and the critically threatened Baiji and Vaquita dolphin species.
 

Pollution risks

In Alaska, as of Aug. 7th, 2020, there were 4,221 confirmed cases of COVID-19 and this number continues to rise, according to the researchers. Since there is a diversity of marine mammals in Alaska and their populations are well documented, they compared this information with available data on the wastewater treatment plants in the state. They were thus able to determine the potential geographic locations and species at high risk for transmission of SARS-CoV-2 via wastewater effluent.

Among their findings, the city of Cold Bay discharges wastewater into Cold Bay, where there are Northern sea otter populations that are predicted to be highly susceptible to the virus. Beluga whales are also predicted to have high susceptibility and they can be found in Bristol Bay near Naknek, a city which relies only on lagoon treatment prior to the discharge of wastewater effluent; the city of Dillingham discharges wastewater into the Nushagak River where beluga whales are found. In Palmer, wastewater effluent flows into the Talkeetna River, which is a tributary to the Susitna River and home to two species predicted to have high susceptibility, beluga whales and harbor seals, the authors added.

Based on these results, the researchers predicted that there was likely a significant risk to sea mammals across the globe, especially where less-adequate treatment facilities and high population densities may lead to greater wastewater contamination.

“Given the proximity of marine animals to high-risk environments where viral spill over is likely, we must act with foresight to protect marine mammal species predicted to be at risk and mitigate the environmental impact of the COVID-19 pandemic,” the researchers concluded.

The authors reported that they had no disclosures.

mlesney@mdedge.com

SOURCE: Mathavarajah S et al. Sci Total Environ. 2020 Oct 29. doi: 10.1016/j.scitotenv.2020.143346.

Zoonoses are no respecter of biological boundaries and are notorious for crossing genus and even higher taxonomic boundaries. SARS-CoV-2 is no exception, the current outbreak most probably having originated in bats, a common source of human-affecting zoonoses throughout history. But it is not a one-way street, and the virus has been shown to spread from infected humans to a variety of other land mammals, including our domesticated animals and kept zoo species.

A recent troubling report, however, has indicated that sea mammals may be part of a next wave of likely candidates for infection, put at risk by the current human pandemic and environmental degradation on a global scale, according to a the results of a genomic analysis of four major groups of sea mammals.

Researchers Sabateeshan Mathavarajah and colleagues from Dalhousie University, Halifax, N.S., examined the sequences of the ACE2 receptors in the various marine mammal species. The ACE2 receptor has recently been identified as the SARS-CoV-2 receptor, which allows for infection.

The researchers examined genomic databases of the marine species to determine if their ACE2 receptor sequences indicated the potential for high, medium, or low susceptibility to infection, as reported in Science of the Total Environment. Database analysis was performed for four groups: Cetacea (whales and dolphins), Pinnepidia (seals), Sirenia (sea cows), and Fissipedia (sea otters and polar bears).

The researchers defined susceptibility values based on comparable binding with the receptor and came up with the following subgroups: higher than human, high (resembles human ACE2), medium (resembles cat ACE2), and low (resembles dog ACE2). It has yet to be established if these marine mammals actually are infected with SARS-CoV-2 and what the impact of such an infection might have on animal health or humans who come in contact with infected animals.

They also cross-referenced for the level of species endangerment and with maps of potential wastewater contamination for certain areas that species came in contact with, using Alaska as the model.
 

Populations in danger

The researchers found 15 species that are already at risk globally that fall under the categories of near threatened, vulnerable, endangered, and critically endangered that were predicted to be medium to higher susceptibility to the SARS-CoV-2 virus than humans. Cross infection is of particular concern because other coronaviruses have been shown to have severe and lethal effects among many of these species.

Among the potentially impacted species were the near threatened–status Antarctic Mink whale and the stellar sea lion; the vulnerable sperm whale, northern fur seal, and Atlantic walrus; the endangered northern and southern sea otters, the North Pacific right whale, and the Amazon River dolphin; and the critically threatened Baiji and Vaquita dolphin species.
 

Pollution risks

In Alaska, as of Aug. 7th, 2020, there were 4,221 confirmed cases of COVID-19 and this number continues to rise, according to the researchers. Since there is a diversity of marine mammals in Alaska and their populations are well documented, they compared this information with available data on the wastewater treatment plants in the state. They were thus able to determine the potential geographic locations and species at high risk for transmission of SARS-CoV-2 via wastewater effluent.

Among their findings, the city of Cold Bay discharges wastewater into Cold Bay, where there are Northern sea otter populations that are predicted to be highly susceptible to the virus. Beluga whales are also predicted to have high susceptibility and they can be found in Bristol Bay near Naknek, a city which relies only on lagoon treatment prior to the discharge of wastewater effluent; the city of Dillingham discharges wastewater into the Nushagak River where beluga whales are found. In Palmer, wastewater effluent flows into the Talkeetna River, which is a tributary to the Susitna River and home to two species predicted to have high susceptibility, beluga whales and harbor seals, the authors added.

Based on these results, the researchers predicted that there was likely a significant risk to sea mammals across the globe, especially where less-adequate treatment facilities and high population densities may lead to greater wastewater contamination.

“Given the proximity of marine animals to high-risk environments where viral spill over is likely, we must act with foresight to protect marine mammal species predicted to be at risk and mitigate the environmental impact of the COVID-19 pandemic,” the researchers concluded.

The authors reported that they had no disclosures.

mlesney@mdedge.com

SOURCE: Mathavarajah S et al. Sci Total Environ. 2020 Oct 29. doi: 10.1016/j.scitotenv.2020.143346.

Zoonoses are no respecter of biological boundaries and are notorious for crossing genus and even higher taxonomic boundaries. SARS-CoV-2 is no exception, the current outbreak most probably having originated in bats, a common source of human-affecting zoonoses throughout history. But it is not a one-way street, and the virus has been shown to spread from infected humans to a variety of other land mammals, including our domesticated animals and kept zoo species.

A recent troubling report, however, has indicated that sea mammals may be part of a next wave of likely candidates for infection, put at risk by the current human pandemic and environmental degradation on a global scale, according to a the results of a genomic analysis of four major groups of sea mammals.

Researchers Sabateeshan Mathavarajah and colleagues from Dalhousie University, Halifax, N.S., examined the sequences of the ACE2 receptors in the various marine mammal species. The ACE2 receptor has recently been identified as the SARS-CoV-2 receptor, which allows for infection.

The researchers examined genomic databases of the marine species to determine if their ACE2 receptor sequences indicated the potential for high, medium, or low susceptibility to infection, as reported in Science of the Total Environment. Database analysis was performed for four groups: Cetacea (whales and dolphins), Pinnepidia (seals), Sirenia (sea cows), and Fissipedia (sea otters and polar bears).

The researchers defined susceptibility values based on comparable binding with the receptor and came up with the following subgroups: higher than human, high (resembles human ACE2), medium (resembles cat ACE2), and low (resembles dog ACE2). It has yet to be established if these marine mammals actually are infected with SARS-CoV-2 and what the impact of such an infection might have on animal health or humans who come in contact with infected animals.

They also cross-referenced for the level of species endangerment and with maps of potential wastewater contamination for certain areas that species came in contact with, using Alaska as the model.
 

Populations in danger

The researchers found 15 species that are already at risk globally that fall under the categories of near threatened, vulnerable, endangered, and critically endangered that were predicted to be medium to higher susceptibility to the SARS-CoV-2 virus than humans. Cross infection is of particular concern because other coronaviruses have been shown to have severe and lethal effects among many of these species.

Among the potentially impacted species were the near threatened–status Antarctic Mink whale and the stellar sea lion; the vulnerable sperm whale, northern fur seal, and Atlantic walrus; the endangered northern and southern sea otters, the North Pacific right whale, and the Amazon River dolphin; and the critically threatened Baiji and Vaquita dolphin species.
 

Pollution risks

In Alaska, as of Aug. 7th, 2020, there were 4,221 confirmed cases of COVID-19 and this number continues to rise, according to the researchers. Since there is a diversity of marine mammals in Alaska and their populations are well documented, they compared this information with available data on the wastewater treatment plants in the state. They were thus able to determine the potential geographic locations and species at high risk for transmission of SARS-CoV-2 via wastewater effluent.

Among their findings, the city of Cold Bay discharges wastewater into Cold Bay, where there are Northern sea otter populations that are predicted to be highly susceptible to the virus. Beluga whales are also predicted to have high susceptibility and they can be found in Bristol Bay near Naknek, a city which relies only on lagoon treatment prior to the discharge of wastewater effluent; the city of Dillingham discharges wastewater into the Nushagak River where beluga whales are found. In Palmer, wastewater effluent flows into the Talkeetna River, which is a tributary to the Susitna River and home to two species predicted to have high susceptibility, beluga whales and harbor seals, the authors added.

Based on these results, the researchers predicted that there was likely a significant risk to sea mammals across the globe, especially where less-adequate treatment facilities and high population densities may lead to greater wastewater contamination.

“Given the proximity of marine animals to high-risk environments where viral spill over is likely, we must act with foresight to protect marine mammal species predicted to be at risk and mitigate the environmental impact of the COVID-19 pandemic,” the researchers concluded.

The authors reported that they had no disclosures.

mlesney@mdedge.com

SOURCE: Mathavarajah S et al. Sci Total Environ. 2020 Oct 29. doi: 10.1016/j.scitotenv.2020.143346.

A vaccine candidate against SARS-CoV-2 has been found to be 90% effective in preventing COVID-19 in trial volunteers who were without evidence of prior infection of the virus, results from an interim analysis of a phase 3 study demonstrated.

BTN162b2, a messenger RNA–based vaccine candidate that requires two doses, is being developed by Pfizer and BioNTech SE independently of the Trump administration’s Operation Warp Speed. A global phase 3 clinical trial of BTN162b2 began on July 27 and has enrolled 43,538 participants to date; 42% of enrollees have racially and ethnically diverse backgrounds.

According to a press release issued by the two companies, 38,955 trial volunteers had received a second dose of either vaccine or placebo as of Nov. 8. An interim analysis of 94 individuals conducted by an independent data monitoring committee (DMC) found that the vaccine efficacy rate was above 90% 7 days after the second dose. This means that protection was achieved 28 days after the first vaccine dose.

“It’s promising in that it validates the genetic strategy – whether it’s mRNA vaccines or DNA vaccines,” Paul A. Offit, MD, told Medscape Medical News. Offit is a member of the US Food and Drug Administraiton’s COVID-19 Vaccine Advisory Committee. “All of them have the same approach, which is that they introduce the gene that codes for the coronavirus spike protein into the cell. Your cell makes the spike protein, and your immune system makes antibodies to the spike protein. At least in these preliminary data, which involved 94 people getting sick, it looks like it’s effective. That’s good. We knew that it seemed to work in experimental animals, but you never know until you put it into people.”

According to Pfizer and BioNTech SE, a final data analysis is planned once 164 confirmed COVID-19 cases have accrued. So far, the DMC has not reported any serious safety concerns. It recommends that the study continue to collect safety and efficacy data as planned. The companies plan to apply to the FDA for emergency use authorization soon after the required safety milestone is achieved.

Pfizer CEO Albert Bourla, DVM, PhD, added in a separate press release, “It’s important to note that we cannot apply for FDA Emergency Use Authorization based on these efficacy results alone. More data on safety is also needed, and we are continuing to accumulate that safety data as part of our ongoing clinical study.

“We estimate that a median of two months of safety data following the second and final dose of the vaccine candidate – required by FDA’s guidance for potential Emergency Use Authorization – will be available by the third week of November.”

Offit, professor of pediatrics in the Division of Infectious Diseases at the Children’s Hospital of Philadelphia, said that, if BTN162b2 is approved, administering it will be tricky. “This particular vaccine has to be shipped and stored at –70° C or –80° C, which we’ve never done before in this country,” he said. “That means maintaining the product on dry ice. That’s going to be a challenge for distribution, I think.”
 

Good news, but…

In the press release, BioNTech SE’s cofounder and CEO, Ugur Sahin, MD, characterized the findings as “a victory for innovation, science and a global collaborative effort. When we embarked on this journey 10 months ago this is what we aspired to achieve. Especially today, while we are all in the midst of a second wave and many of us in lockdown, we appreciate even more how important this milestone is on our path towards ending this pandemic and for all of us to regain a sense of normality.”

President-elect Joe Biden also weighed in, calling the results “excellent news” in a news release.

“At the same time, it is also important to understand that the end of the battle against COVID-19 is still months away,” he said. “This news follows a previously announced timeline by industry officials that forecast vaccine approval by late November. Even if that is achieved, and some Americans are vaccinated later this year, it will be many more months before there is widespread vaccination in this country.

“Today’s news does not change this urgent reality. Americans will have to rely on masking, distancing, contact tracing, hand washing, and other measures to keep themselves safe well into next year,” Biden added.
 

This article first appeared on Medscape.com.

A vaccine candidate against SARS-CoV-2 has been found to be 90% effective in preventing COVID-19 in trial volunteers who were without evidence of prior infection of the virus, results from an interim analysis of a phase 3 study demonstrated.

BTN162b2, a messenger RNA–based vaccine candidate that requires two doses, is being developed by Pfizer and BioNTech SE independently of the Trump administration’s Operation Warp Speed. A global phase 3 clinical trial of BTN162b2 began on July 27 and has enrolled 43,538 participants to date; 42% of enrollees have racially and ethnically diverse backgrounds.

According to a press release issued by the two companies, 38,955 trial volunteers had received a second dose of either vaccine or placebo as of Nov. 8. An interim analysis of 94 individuals conducted by an independent data monitoring committee (DMC) found that the vaccine efficacy rate was above 90% 7 days after the second dose. This means that protection was achieved 28 days after the first vaccine dose.

“It’s promising in that it validates the genetic strategy – whether it’s mRNA vaccines or DNA vaccines,” Paul A. Offit, MD, told Medscape Medical News. Offit is a member of the US Food and Drug Administraiton’s COVID-19 Vaccine Advisory Committee. “All of them have the same approach, which is that they introduce the gene that codes for the coronavirus spike protein into the cell. Your cell makes the spike protein, and your immune system makes antibodies to the spike protein. At least in these preliminary data, which involved 94 people getting sick, it looks like it’s effective. That’s good. We knew that it seemed to work in experimental animals, but you never know until you put it into people.”

According to Pfizer and BioNTech SE, a final data analysis is planned once 164 confirmed COVID-19 cases have accrued. So far, the DMC has not reported any serious safety concerns. It recommends that the study continue to collect safety and efficacy data as planned. The companies plan to apply to the FDA for emergency use authorization soon after the required safety milestone is achieved.

Pfizer CEO Albert Bourla, DVM, PhD, added in a separate press release, “It’s important to note that we cannot apply for FDA Emergency Use Authorization based on these efficacy results alone. More data on safety is also needed, and we are continuing to accumulate that safety data as part of our ongoing clinical study.

“We estimate that a median of two months of safety data following the second and final dose of the vaccine candidate – required by FDA’s guidance for potential Emergency Use Authorization – will be available by the third week of November.”

Offit, professor of pediatrics in the Division of Infectious Diseases at the Children’s Hospital of Philadelphia, said that, if BTN162b2 is approved, administering it will be tricky. “This particular vaccine has to be shipped and stored at –70° C or –80° C, which we’ve never done before in this country,” he said. “That means maintaining the product on dry ice. That’s going to be a challenge for distribution, I think.”
 

Good news, but…

In the press release, BioNTech SE’s cofounder and CEO, Ugur Sahin, MD, characterized the findings as “a victory for innovation, science and a global collaborative effort. When we embarked on this journey 10 months ago this is what we aspired to achieve. Especially today, while we are all in the midst of a second wave and many of us in lockdown, we appreciate even more how important this milestone is on our path towards ending this pandemic and for all of us to regain a sense of normality.”

President-elect Joe Biden also weighed in, calling the results “excellent news” in a news release.

“At the same time, it is also important to understand that the end of the battle against COVID-19 is still months away,” he said. “This news follows a previously announced timeline by industry officials that forecast vaccine approval by late November. Even if that is achieved, and some Americans are vaccinated later this year, it will be many more months before there is widespread vaccination in this country.

“Today’s news does not change this urgent reality. Americans will have to rely on masking, distancing, contact tracing, hand washing, and other measures to keep themselves safe well into next year,” Biden added.
 

This article first appeared on Medscape.com.

A vaccine candidate against SARS-CoV-2 has been found to be 90% effective in preventing COVID-19 in trial volunteers who were without evidence of prior infection of the virus, results from an interim analysis of a phase 3 study demonstrated.

BTN162b2, a messenger RNA–based vaccine candidate that requires two doses, is being developed by Pfizer and BioNTech SE independently of the Trump administration’s Operation Warp Speed. A global phase 3 clinical trial of BTN162b2 began on July 27 and has enrolled 43,538 participants to date; 42% of enrollees have racially and ethnically diverse backgrounds.

According to a press release issued by the two companies, 38,955 trial volunteers had received a second dose of either vaccine or placebo as of Nov. 8. An interim analysis of 94 individuals conducted by an independent data monitoring committee (DMC) found that the vaccine efficacy rate was above 90% 7 days after the second dose. This means that protection was achieved 28 days after the first vaccine dose.

“It’s promising in that it validates the genetic strategy – whether it’s mRNA vaccines or DNA vaccines,” Paul A. Offit, MD, told Medscape Medical News. Offit is a member of the US Food and Drug Administraiton’s COVID-19 Vaccine Advisory Committee. “All of them have the same approach, which is that they introduce the gene that codes for the coronavirus spike protein into the cell. Your cell makes the spike protein, and your immune system makes antibodies to the spike protein. At least in these preliminary data, which involved 94 people getting sick, it looks like it’s effective. That’s good. We knew that it seemed to work in experimental animals, but you never know until you put it into people.”

According to Pfizer and BioNTech SE, a final data analysis is planned once 164 confirmed COVID-19 cases have accrued. So far, the DMC has not reported any serious safety concerns. It recommends that the study continue to collect safety and efficacy data as planned. The companies plan to apply to the FDA for emergency use authorization soon after the required safety milestone is achieved.

Pfizer CEO Albert Bourla, DVM, PhD, added in a separate press release, “It’s important to note that we cannot apply for FDA Emergency Use Authorization based on these efficacy results alone. More data on safety is also needed, and we are continuing to accumulate that safety data as part of our ongoing clinical study.

“We estimate that a median of two months of safety data following the second and final dose of the vaccine candidate – required by FDA’s guidance for potential Emergency Use Authorization – will be available by the third week of November.”

Offit, professor of pediatrics in the Division of Infectious Diseases at the Children’s Hospital of Philadelphia, said that, if BTN162b2 is approved, administering it will be tricky. “This particular vaccine has to be shipped and stored at –70° C or –80° C, which we’ve never done before in this country,” he said. “That means maintaining the product on dry ice. That’s going to be a challenge for distribution, I think.”
 

Good news, but…

In the press release, BioNTech SE’s cofounder and CEO, Ugur Sahin, MD, characterized the findings as “a victory for innovation, science and a global collaborative effort. When we embarked on this journey 10 months ago this is what we aspired to achieve. Especially today, while we are all in the midst of a second wave and many of us in lockdown, we appreciate even more how important this milestone is on our path towards ending this pandemic and for all of us to regain a sense of normality.”

President-elect Joe Biden also weighed in, calling the results “excellent news” in a news release.

“At the same time, it is also important to understand that the end of the battle against COVID-19 is still months away,” he said. “This news follows a previously announced timeline by industry officials that forecast vaccine approval by late November. Even if that is achieved, and some Americans are vaccinated later this year, it will be many more months before there is widespread vaccination in this country.

“Today’s news does not change this urgent reality. Americans will have to rely on masking, distancing, contact tracing, hand washing, and other measures to keep themselves safe well into next year,” Biden added.
 

This article first appeared on Medscape.com.

A new proposed rule from the Centers for Medicare & Medicaid Services (CMS) would expand coverage for continuous glucose monitors (CGMs) under Medicare to include devices that aren’t approved for making treatment decisions.

Getty

If accepted, the proposed rule would classify all approved CGMs as durable medical equipment under Medicare Part B and establish payment amounts for all related supplies. The move primarily affects Medtronic’s Guardian Connect System, which has not been approved by the U.S. Food and Drug Administration to replace the need for fingersticks in determining insulin or other glucose-lowering medication dosing.

Two other CGM systems, the Dexcom G6 and Abbott Libre, have “therapeutic” indications and are, therefore, already covered under Medicare, as is the combined insulin pump–CGM Tandem Diabetes Care Control-IQ Technology system.

According to a CMS statement, “CGMs that are not approved for use in making diabetes treatment decisions can be used to alert beneficiaries about potentially dangerous glucose levels while they sleep and that they should further test their glucose levels using a blood glucose monitor. ... This proposal would give Medicare beneficiaries and their physicians a wider range of technology and devices to choose from in managing diabetes.”

Sean Salmon, executive vice president and president of the Diabetes Group at Medtronic said in an interview that the company is “very encouraged” by the proposal. “Importantly, the proposed rule would enable continuity of therapy for people on Medtronic insulin pumps aging into Medicare – including Medtronic hybrid closed loop systems, which automatically adjust insulin delivery based on readings from the integrated CGM.”

The type 1 diabetes research and advocacy organization JDRF also applauded the proposed rule, noting in a statement, “CGM technology can be an integral component of artificial pancreas systems and important on its own to significantly improve diabetes management and enable users to avoid potential crises and risks for long-term complications. JDRF is heartened by this proposed change as it has long advocated for coverage, affordability and choice of all therapies to help ensure people with T1D have what they need to survive.”

The proposal is part of a broader set of proposed changes to Medicare Durable Medical Equipment, Prosthetics, Orthotic Devices and Supplies (DMEPOS) coverage and payment policies. Comments on the entire document can be submitted through Jan. 4, 2021 to the Federal Register.

A new proposed rule from the Centers for Medicare & Medicaid Services (CMS) would expand coverage for continuous glucose monitors (CGMs) under Medicare to include devices that aren’t approved for making treatment decisions.

Getty

If accepted, the proposed rule would classify all approved CGMs as durable medical equipment under Medicare Part B and establish payment amounts for all related supplies. The move primarily affects Medtronic’s Guardian Connect System, which has not been approved by the U.S. Food and Drug Administration to replace the need for fingersticks in determining insulin or other glucose-lowering medication dosing.

Two other CGM systems, the Dexcom G6 and Abbott Libre, have “therapeutic” indications and are, therefore, already covered under Medicare, as is the combined insulin pump–CGM Tandem Diabetes Care Control-IQ Technology system.

According to a CMS statement, “CGMs that are not approved for use in making diabetes treatment decisions can be used to alert beneficiaries about potentially dangerous glucose levels while they sleep and that they should further test their glucose levels using a blood glucose monitor. ... This proposal would give Medicare beneficiaries and their physicians a wider range of technology and devices to choose from in managing diabetes.”

Sean Salmon, executive vice president and president of the Diabetes Group at Medtronic said in an interview that the company is “very encouraged” by the proposal. “Importantly, the proposed rule would enable continuity of therapy for people on Medtronic insulin pumps aging into Medicare – including Medtronic hybrid closed loop systems, which automatically adjust insulin delivery based on readings from the integrated CGM.”

The type 1 diabetes research and advocacy organization JDRF also applauded the proposed rule, noting in a statement, “CGM technology can be an integral component of artificial pancreas systems and important on its own to significantly improve diabetes management and enable users to avoid potential crises and risks for long-term complications. JDRF is heartened by this proposed change as it has long advocated for coverage, affordability and choice of all therapies to help ensure people with T1D have what they need to survive.”

The proposal is part of a broader set of proposed changes to Medicare Durable Medical Equipment, Prosthetics, Orthotic Devices and Supplies (DMEPOS) coverage and payment policies. Comments on the entire document can be submitted through Jan. 4, 2021 to the Federal Register.

A new proposed rule from the Centers for Medicare & Medicaid Services (CMS) would expand coverage for continuous glucose monitors (CGMs) under Medicare to include devices that aren’t approved for making treatment decisions.

Getty

If accepted, the proposed rule would classify all approved CGMs as durable medical equipment under Medicare Part B and establish payment amounts for all related supplies. The move primarily affects Medtronic’s Guardian Connect System, which has not been approved by the U.S. Food and Drug Administration to replace the need for fingersticks in determining insulin or other glucose-lowering medication dosing.

Two other CGM systems, the Dexcom G6 and Abbott Libre, have “therapeutic” indications and are, therefore, already covered under Medicare, as is the combined insulin pump–CGM Tandem Diabetes Care Control-IQ Technology system.

According to a CMS statement, “CGMs that are not approved for use in making diabetes treatment decisions can be used to alert beneficiaries about potentially dangerous glucose levels while they sleep and that they should further test their glucose levels using a blood glucose monitor. ... This proposal would give Medicare beneficiaries and their physicians a wider range of technology and devices to choose from in managing diabetes.”

Sean Salmon, executive vice president and president of the Diabetes Group at Medtronic said in an interview that the company is “very encouraged” by the proposal. “Importantly, the proposed rule would enable continuity of therapy for people on Medtronic insulin pumps aging into Medicare – including Medtronic hybrid closed loop systems, which automatically adjust insulin delivery based on readings from the integrated CGM.”

The type 1 diabetes research and advocacy organization JDRF also applauded the proposed rule, noting in a statement, “CGM technology can be an integral component of artificial pancreas systems and important on its own to significantly improve diabetes management and enable users to avoid potential crises and risks for long-term complications. JDRF is heartened by this proposed change as it has long advocated for coverage, affordability and choice of all therapies to help ensure people with T1D have what they need to survive.”

The proposal is part of a broader set of proposed changes to Medicare Durable Medical Equipment, Prosthetics, Orthotic Devices and Supplies (DMEPOS) coverage and payment policies. Comments on the entire document can be submitted through Jan. 4, 2021 to the Federal Register.

Denosumab boosted bone mineral density (BMD) over 12 months to a greater extent than did alendronate in a randomized, 12-month study. The investigator-initiated research compared BMD at the lumbar spine and elsewhere among people with systemic lupus erythematosus (SLE) and other autoimmune conditions. Long-term glucocorticoid therapy places some people in this group at higher risk for adverse effects of bone density loss.

“Glucocorticoids remain the mainstay of treatment of rheumatic diseases, but [they are] a major risk factor for osteoporosis and fracture,” study author Chi Chiu Mok, MD, said in an interview.

Compared with baseline, adults randomly assigned to denosumab had a 3.5% increase in lumbar spine BMD at 12 months, compared with 2.5% among those taking alendronate, a significant difference. Dr. Mok, a consultant and honorary associate professor in the department of medicine and nuclear medicine at Tuen Mun Hospital in Hong Kong, presented the study results at the virtual annual meeting of the American College of Rheumatology.

“Given the knowledge that denosumab is more effective than alendronate in raising spinal BMD in chronic users of GCs without increasing adverse events, this drug may be considered as an alternative first-line therapy in higher-risk patients and in those who are contraindicated for the oral bisphosphonates,” he said.
 

Cost considerations

Denosumab is a human monoclonal antibody administered as a subcutaneous injection, available under the brand names Prolia and Xgeva. Alendronate is an oral agent available as both generic and brand name formulations.

“Yes, denosumab is more expensive, more costly than oral alendronate, but our study shows efficacy is better for steroid users,” Dr. Mok said in answer to a question about cost disparity between the two agents during his presentation at the meeting. “For patients who are contraindicated or have low compliance for bisphosphonate, or are high-risk patients, I recommend first-line use of denosumab.”

Researchers previously studied these agents, including a smaller study by Dr. Mok and colleagues that showed a BMD benefit after switching people on an oral bisphosphonate to denosumab. However, he said, “There is a paucity of data regarding comparative efficacy of denosumab and the bisphosphonates in long-term steroid users.”

To explore any differences in a larger patient population, the investigators randomly assigned adults with SLE and other autoimmune conditions to the two treatments: denosumab 60 mg subcutaneoulsy every 6 months or oral alendronate 70 mg/week. All patients also received 3,000 mg calcium and 1,000 IU vitamin D₃ (cholecalciferol) each day.

After three discontinuations in denosumab cohort and four in the alendronate group, the researchers evaluated 69 people taking denosumab and 70 others taking alendronate. The discontinuations were caused by noncompliance, Dr. Mok said, not by adverse events.

Adverse events were reported, but the rate did not differ significantly between groups. Dr. Mok highlighted some notable differences, including more minor infections and arthralgias reported in the denosumab cohort. Chest discomfort was reported in one denosumab recipient versus no patients in the alendronate group. Dyspepsia/upper GI symptoms and dizziness/vertigo occurred more often in the alendronate group.

Women were 96% of the study population, and mean age was 50 years. A majority, 81%, had underlying SLE. Other diagnoses included rheumatoid arthritis, myositis, antineutrophil cytoplasmic antibody–associated vasculitis, and polymyalgia rheumatica. The mean dose of prednisolone at study entry was 5.1 mg/day.
 

Key BMD and biomarker findings

BMD increased significantly in the spine, hip, and femoral neck in both treatment groups by 12 months. However, after adjustment for baseline BMD and covariates including age, menopause, and history of fracture, the gains in the denosumab group were significantly higher.

The increase in lumbar spine BMD at 12 months of 3.5% in the denosumab group versus 2.5% in the alendronate group was statistically significant (P = .045). Less significant was a 0.9% increase at the hip in the denosumab patients versus 1.6% in the alendronate group (P = .10), as well as femoral neck BMD gains of 1% in the denosumab group versus 1.5% in the alendronate group (P = .86).

Furthermore, “denosumab was more potent in suppressing the bone markers at 12 months,” Dr. Mok said.

Specifically, the percentage decrease in serum PINP (procollagen type I N-terminal propeptide) levels in the denosumab group was significantly greater than in the alendronate group (P = .001). Likewise, the decrease in CTX (C-terminal telopeptide of type I collagen) was significantly greater in the denosumab cohort versus the alendronate cohort (P < .001).

“Dr. Mok’s study was a well-controlled investigation. The superiority of denosumab was impressive, especially given the small group sizes of 69 and 70,” session comoderator Gregg Silverman, MD, professor in the department of internal medicine and the department of pathology at New York University, said when asked for comment.

“However, bone density measurements may not tell the whole story. These results support a bigger and much larger-scale study to confirm that rates of fracture on denosumab are also reduced.”

No new symptomatic fractures occurred in either group during the study. The investigators are evaluating for any new radiologic fractures, with results pending.

Dr. Mok said “results of our study in Asian patients are largely confirmatory” of a previous 2018 comparison study and a 2019 comparison study, each sponsored by Amgen.

A small sample size, short duration of treatment, and the open-label design were limitations of the study.

The trial was an investigator-initiated study. Dr. Mok and colleagues had no relevant financial disclosures. Dr. Silverman had no relevant financial disclosures.

SOURCE: Mok CC et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract 1442.

Denosumab boosted bone mineral density (BMD) over 12 months to a greater extent than did alendronate in a randomized, 12-month study. The investigator-initiated research compared BMD at the lumbar spine and elsewhere among people with systemic lupus erythematosus (SLE) and other autoimmune conditions. Long-term glucocorticoid therapy places some people in this group at higher risk for adverse effects of bone density loss.

“Glucocorticoids remain the mainstay of treatment of rheumatic diseases, but [they are] a major risk factor for osteoporosis and fracture,” study author Chi Chiu Mok, MD, said in an interview.

Compared with baseline, adults randomly assigned to denosumab had a 3.5% increase in lumbar spine BMD at 12 months, compared with 2.5% among those taking alendronate, a significant difference. Dr. Mok, a consultant and honorary associate professor in the department of medicine and nuclear medicine at Tuen Mun Hospital in Hong Kong, presented the study results at the virtual annual meeting of the American College of Rheumatology.

“Given the knowledge that denosumab is more effective than alendronate in raising spinal BMD in chronic users of GCs without increasing adverse events, this drug may be considered as an alternative first-line therapy in higher-risk patients and in those who are contraindicated for the oral bisphosphonates,” he said.
 

Cost considerations

Denosumab is a human monoclonal antibody administered as a subcutaneous injection, available under the brand names Prolia and Xgeva. Alendronate is an oral agent available as both generic and brand name formulations.

“Yes, denosumab is more expensive, more costly than oral alendronate, but our study shows efficacy is better for steroid users,” Dr. Mok said in answer to a question about cost disparity between the two agents during his presentation at the meeting. “For patients who are contraindicated or have low compliance for bisphosphonate, or are high-risk patients, I recommend first-line use of denosumab.”

Researchers previously studied these agents, including a smaller study by Dr. Mok and colleagues that showed a BMD benefit after switching people on an oral bisphosphonate to denosumab. However, he said, “There is a paucity of data regarding comparative efficacy of denosumab and the bisphosphonates in long-term steroid users.”

To explore any differences in a larger patient population, the investigators randomly assigned adults with SLE and other autoimmune conditions to the two treatments: denosumab 60 mg subcutaneoulsy every 6 months or oral alendronate 70 mg/week. All patients also received 3,000 mg calcium and 1,000 IU vitamin D₃ (cholecalciferol) each day.

After three discontinuations in denosumab cohort and four in the alendronate group, the researchers evaluated 69 people taking denosumab and 70 others taking alendronate. The discontinuations were caused by noncompliance, Dr. Mok said, not by adverse events.

Adverse events were reported, but the rate did not differ significantly between groups. Dr. Mok highlighted some notable differences, including more minor infections and arthralgias reported in the denosumab cohort. Chest discomfort was reported in one denosumab recipient versus no patients in the alendronate group. Dyspepsia/upper GI symptoms and dizziness/vertigo occurred more often in the alendronate group.

Women were 96% of the study population, and mean age was 50 years. A majority, 81%, had underlying SLE. Other diagnoses included rheumatoid arthritis, myositis, antineutrophil cytoplasmic antibody–associated vasculitis, and polymyalgia rheumatica. The mean dose of prednisolone at study entry was 5.1 mg/day.
 

Key BMD and biomarker findings

BMD increased significantly in the spine, hip, and femoral neck in both treatment groups by 12 months. However, after adjustment for baseline BMD and covariates including age, menopause, and history of fracture, the gains in the denosumab group were significantly higher.

The increase in lumbar spine BMD at 12 months of 3.5% in the denosumab group versus 2.5% in the alendronate group was statistically significant (P = .045). Less significant was a 0.9% increase at the hip in the denosumab patients versus 1.6% in the alendronate group (P = .10), as well as femoral neck BMD gains of 1% in the denosumab group versus 1.5% in the alendronate group (P = .86).

Furthermore, “denosumab was more potent in suppressing the bone markers at 12 months,” Dr. Mok said.

Specifically, the percentage decrease in serum PINP (procollagen type I N-terminal propeptide) levels in the denosumab group was significantly greater than in the alendronate group (P = .001). Likewise, the decrease in CTX (C-terminal telopeptide of type I collagen) was significantly greater in the denosumab cohort versus the alendronate cohort (P < .001).

“Dr. Mok’s study was a well-controlled investigation. The superiority of denosumab was impressive, especially given the small group sizes of 69 and 70,” session comoderator Gregg Silverman, MD, professor in the department of internal medicine and the department of pathology at New York University, said when asked for comment.

“However, bone density measurements may not tell the whole story. These results support a bigger and much larger-scale study to confirm that rates of fracture on denosumab are also reduced.”

No new symptomatic fractures occurred in either group during the study. The investigators are evaluating for any new radiologic fractures, with results pending.

Dr. Mok said “results of our study in Asian patients are largely confirmatory” of a previous 2018 comparison study and a 2019 comparison study, each sponsored by Amgen.

A small sample size, short duration of treatment, and the open-label design were limitations of the study.

The trial was an investigator-initiated study. Dr. Mok and colleagues had no relevant financial disclosures. Dr. Silverman had no relevant financial disclosures.

SOURCE: Mok CC et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract 1442.

Denosumab boosted bone mineral density (BMD) over 12 months to a greater extent than did alendronate in a randomized, 12-month study. The investigator-initiated research compared BMD at the lumbar spine and elsewhere among people with systemic lupus erythematosus (SLE) and other autoimmune conditions. Long-term glucocorticoid therapy places some people in this group at higher risk for adverse effects of bone density loss.

“Glucocorticoids remain the mainstay of treatment of rheumatic diseases, but [they are] a major risk factor for osteoporosis and fracture,” study author Chi Chiu Mok, MD, said in an interview.

Compared with baseline, adults randomly assigned to denosumab had a 3.5% increase in lumbar spine BMD at 12 months, compared with 2.5% among those taking alendronate, a significant difference. Dr. Mok, a consultant and honorary associate professor in the department of medicine and nuclear medicine at Tuen Mun Hospital in Hong Kong, presented the study results at the virtual annual meeting of the American College of Rheumatology.

“Given the knowledge that denosumab is more effective than alendronate in raising spinal BMD in chronic users of GCs without increasing adverse events, this drug may be considered as an alternative first-line therapy in higher-risk patients and in those who are contraindicated for the oral bisphosphonates,” he said.
 

Cost considerations

Denosumab is a human monoclonal antibody administered as a subcutaneous injection, available under the brand names Prolia and Xgeva. Alendronate is an oral agent available as both generic and brand name formulations.

“Yes, denosumab is more expensive, more costly than oral alendronate, but our study shows efficacy is better for steroid users,” Dr. Mok said in answer to a question about cost disparity between the two agents during his presentation at the meeting. “For patients who are contraindicated or have low compliance for bisphosphonate, or are high-risk patients, I recommend first-line use of denosumab.”

Researchers previously studied these agents, including a smaller study by Dr. Mok and colleagues that showed a BMD benefit after switching people on an oral bisphosphonate to denosumab. However, he said, “There is a paucity of data regarding comparative efficacy of denosumab and the bisphosphonates in long-term steroid users.”

To explore any differences in a larger patient population, the investigators randomly assigned adults with SLE and other autoimmune conditions to the two treatments: denosumab 60 mg subcutaneoulsy every 6 months or oral alendronate 70 mg/week. All patients also received 3,000 mg calcium and 1,000 IU vitamin D₃ (cholecalciferol) each day.

After three discontinuations in denosumab cohort and four in the alendronate group, the researchers evaluated 69 people taking denosumab and 70 others taking alendronate. The discontinuations were caused by noncompliance, Dr. Mok said, not by adverse events.

Adverse events were reported, but the rate did not differ significantly between groups. Dr. Mok highlighted some notable differences, including more minor infections and arthralgias reported in the denosumab cohort. Chest discomfort was reported in one denosumab recipient versus no patients in the alendronate group. Dyspepsia/upper GI symptoms and dizziness/vertigo occurred more often in the alendronate group.

Women were 96% of the study population, and mean age was 50 years. A majority, 81%, had underlying SLE. Other diagnoses included rheumatoid arthritis, myositis, antineutrophil cytoplasmic antibody–associated vasculitis, and polymyalgia rheumatica. The mean dose of prednisolone at study entry was 5.1 mg/day.
 

Key BMD and biomarker findings

BMD increased significantly in the spine, hip, and femoral neck in both treatment groups by 12 months. However, after adjustment for baseline BMD and covariates including age, menopause, and history of fracture, the gains in the denosumab group were significantly higher.

The increase in lumbar spine BMD at 12 months of 3.5% in the denosumab group versus 2.5% in the alendronate group was statistically significant (P = .045). Less significant was a 0.9% increase at the hip in the denosumab patients versus 1.6% in the alendronate group (P = .10), as well as femoral neck BMD gains of 1% in the denosumab group versus 1.5% in the alendronate group (P = .86).

Furthermore, “denosumab was more potent in suppressing the bone markers at 12 months,” Dr. Mok said.

Specifically, the percentage decrease in serum PINP (procollagen type I N-terminal propeptide) levels in the denosumab group was significantly greater than in the alendronate group (P = .001). Likewise, the decrease in CTX (C-terminal telopeptide of type I collagen) was significantly greater in the denosumab cohort versus the alendronate cohort (P < .001).

“Dr. Mok’s study was a well-controlled investigation. The superiority of denosumab was impressive, especially given the small group sizes of 69 and 70,” session comoderator Gregg Silverman, MD, professor in the department of internal medicine and the department of pathology at New York University, said when asked for comment.

“However, bone density measurements may not tell the whole story. These results support a bigger and much larger-scale study to confirm that rates of fracture on denosumab are also reduced.”

No new symptomatic fractures occurred in either group during the study. The investigators are evaluating for any new radiologic fractures, with results pending.

Dr. Mok said “results of our study in Asian patients are largely confirmatory” of a previous 2018 comparison study and a 2019 comparison study, each sponsored by Amgen.

A small sample size, short duration of treatment, and the open-label design were limitations of the study.

The trial was an investigator-initiated study. Dr. Mok and colleagues had no relevant financial disclosures. Dr. Silverman had no relevant financial disclosures.

SOURCE: Mok CC et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract 1442.

The Department of Veterans Affairs is recruiting 8,000 volunteers for the Phase 3 clinical trials of at least four COVID-19 vaccine candidates at 20 federal medical facilities across the United States, according to officials with the VA and Operation Warp Speed, the Trump administration’s initiative to fast-track a coronavirus vaccine.

The largely unpublicized effort follows a Department of Defense announcement in September that it has partnered with AstraZeneca to recruit volunteers at five of its medical facilities, which are separate from the VA system. DOD is also is in talks with developers of other vaccine candidates, although officials won’t say which ones.

Both federal departments have long experience in medical research and diverse populations – a crucial component of effective clinical trials, said J. Stephen Morrison, senior vice president and director of global health policy at the Center for Strategic and International Studies, a bipartisan think tank in Washington.

Since active troops are essential to national security, and veterans are extremely vulnerable to COVID-19, both departments have a vested interest in supporting the development of safe, effective vaccines, Mr. Morrison said.

“On the DOD active servicemen and -women side, it’s a question of making sure they’re ready, they are protected,” Mr. Morrison said. “With VA, their population, all elderly and infirm with underlying conditions, they could really be suffering if we don’t get a vaccine.”

According to a VA website, of its 20 medical centers involved, 17 would be part of the Johnson & Johnson vaccine trial, while the three others are recruiting – or have completed recruitment – for advanced-stage trials for Moderna, AstraZeneca, and Pfizer vaccines.

Matthew Hepburn, MD, head of vaccine development at Operation Warp Speed, said the VA effort lets veterans contribute to the overall well-being of the country.

“This is another way they can continue to serve in this way, fighting the pandemic as a volunteer,” Dr. Hepburn said during a discussion of vaccine and therapeutics development hosted by the Heritage Foundation on Oct. 27.

It’s not unusual for the military to participate in multicenter trials for treatments of ailments as diverse as cancer and trauma. Historically, many vaccines have been tested first by the military.

In the general population, clinicians often have difficulty recruiting African Americans and other minorities for medical research, and “the military provides a rich opportunity to find volunteers for those groups,” said retired Rear Adm. Thomas Cullison, MD, a doctor and former deputy surgeon general for the Navy.

Military health facilities are held to the same standards as private research facilities, he said.

No service members will be required to participate in the COVID vaccine trials. All volunteers will be paid by the developer.

Support for routine vaccinations runs high in the military, but some have expressed concerns about new vaccines and mandatory inoculations, especially for anthrax. In a 2002 federal study, 85% of those who received that vaccine reported an adverse reaction, with just under half noticing minor redness at the injection site. But nearly a quarter of the side effects reported were more systemic, including fevers, chills, fatigue and joint pain.

That survey of a small group of National Guard and Reserve members found that, while 73% said they believe immunizations are effective, two-thirds said they did not support the mandatory anthrax program, and 6 in 10 said they were not satisfied with the information they were given on the vaccines.

To quell concerns over the military’s role in supporting COVID vaccine development, the Pentagon has reiterated that troops or their dependents interested in participating in the research must provide voluntary written consent, and they will be allowed to take part only if they will be in the same location for the length of the research, expected to last at least 2 years.

In addition, active-duty members such as new recruits and boot camp participants will not be allowed to volunteer because they are “considered vulnerable from an ethical and regulatory standpoint,” an official said.

At the VA, officials are seeking to recruit healthy veterans aged 18-65 years old who are not pregnant and may be at risk for exposure. As with trials conducted in civilian facilities, participants will be paid by the developer, VA spokesperson Christina Noel said.

Also, VA nurses and caseworkers also are being asked to identify their sickest, highest-risk patients to determine who should be at the top of the list once a vaccine is approved, according to a VA nurse and other health officials who asked not to be identified because they were not authorized to speak with the press.

The U.S. military has a long history of contributing to research on vaccines, including a key role in developing inoculations against yellow fever and adenovirus, and the Walter Reed Army Institute of Research is developing its own vaccine against the coronavirus.

Some segments of the population remain skeptical of federal medical experiments. A survey by AP-NORC in May found that Black people are particularly reluctant to get the coronavirus vaccine. Many have concerns about federal research in part because of associations with the infamous Tuskegee Institute syphilis experiments, in which U.S. Public Health Service officials intentionally withheld a cure from Black men infected with the disease.

But Mr. Morrison, of the Center for Strategic and International Studies, said the Defense Department and VA are a “natural fit” for the COVID vaccine trials.

“DOD has lots of expertise. They know how to vaccinate; they know how to reach communities. They have a whole science infrastructure and research-and-development infrastructure. And when you are thinking what the mission of VA is, [VA] sees this is part of their mission,” Mr. Morrison said.

The Defense Department announced its agreement with AstraZeneca in September, shortly before the drugmaker’s vaccine trial was put on hold to study a serious medical condition that one participant reported. That research was approved by the Food and Drug Administration to begin again Oct. 23. The military plans to restart its efforts to recruit 3,000 volunteers.

The Pentagon has also signed an agreement with another vaccine developer, the head of the Defense Health Agency, Army Lt. Gen. Ronald Place, told reporters Oct. 8. He wouldn’t provide the company’s name.

Senator Elizabeth Warren (D-Mass.) and Senator Mazie Hirono (D-Hawaii) have called, unsuccessfully, for the Senate Armed Services Committee to investigate what they say is a lack of Pentagon transparency on its role in vaccine development and distribution. The Defense Department has awarded more than $6 billion in Operation Warp Speed contracts through an intermediary, Advanced Technology International, and the two senators want more information about those contracts.

“There may well be a valuable role for DoD officials in [Operation Warp Speed] – particularly given the department’s logistical capacity,” they wrote to the committee chair and ranking member. “But it is important that Congress conduct appropriate oversight of, and understand, DoD’s activities in this area.”

Neither department has disclosed the financial arrangements they have made with developers to support the vaccine research.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

The Department of Veterans Affairs is recruiting 8,000 volunteers for the Phase 3 clinical trials of at least four COVID-19 vaccine candidates at 20 federal medical facilities across the United States, according to officials with the VA and Operation Warp Speed, the Trump administration’s initiative to fast-track a coronavirus vaccine.

The largely unpublicized effort follows a Department of Defense announcement in September that it has partnered with AstraZeneca to recruit volunteers at five of its medical facilities, which are separate from the VA system. DOD is also is in talks with developers of other vaccine candidates, although officials won’t say which ones.

Both federal departments have long experience in medical research and diverse populations – a crucial component of effective clinical trials, said J. Stephen Morrison, senior vice president and director of global health policy at the Center for Strategic and International Studies, a bipartisan think tank in Washington.

Since active troops are essential to national security, and veterans are extremely vulnerable to COVID-19, both departments have a vested interest in supporting the development of safe, effective vaccines, Mr. Morrison said.

“On the DOD active servicemen and -women side, it’s a question of making sure they’re ready, they are protected,” Mr. Morrison said. “With VA, their population, all elderly and infirm with underlying conditions, they could really be suffering if we don’t get a vaccine.”

According to a VA website, of its 20 medical centers involved, 17 would be part of the Johnson & Johnson vaccine trial, while the three others are recruiting – or have completed recruitment – for advanced-stage trials for Moderna, AstraZeneca, and Pfizer vaccines.

Matthew Hepburn, MD, head of vaccine development at Operation Warp Speed, said the VA effort lets veterans contribute to the overall well-being of the country.

“This is another way they can continue to serve in this way, fighting the pandemic as a volunteer,” Dr. Hepburn said during a discussion of vaccine and therapeutics development hosted by the Heritage Foundation on Oct. 27.

It’s not unusual for the military to participate in multicenter trials for treatments of ailments as diverse as cancer and trauma. Historically, many vaccines have been tested first by the military.

In the general population, clinicians often have difficulty recruiting African Americans and other minorities for medical research, and “the military provides a rich opportunity to find volunteers for those groups,” said retired Rear Adm. Thomas Cullison, MD, a doctor and former deputy surgeon general for the Navy.

Military health facilities are held to the same standards as private research facilities, he said.

No service members will be required to participate in the COVID vaccine trials. All volunteers will be paid by the developer.

Support for routine vaccinations runs high in the military, but some have expressed concerns about new vaccines and mandatory inoculations, especially for anthrax. In a 2002 federal study, 85% of those who received that vaccine reported an adverse reaction, with just under half noticing minor redness at the injection site. But nearly a quarter of the side effects reported were more systemic, including fevers, chills, fatigue and joint pain.

That survey of a small group of National Guard and Reserve members found that, while 73% said they believe immunizations are effective, two-thirds said they did not support the mandatory anthrax program, and 6 in 10 said they were not satisfied with the information they were given on the vaccines.

To quell concerns over the military’s role in supporting COVID vaccine development, the Pentagon has reiterated that troops or their dependents interested in participating in the research must provide voluntary written consent, and they will be allowed to take part only if they will be in the same location for the length of the research, expected to last at least 2 years.

In addition, active-duty members such as new recruits and boot camp participants will not be allowed to volunteer because they are “considered vulnerable from an ethical and regulatory standpoint,” an official said.

At the VA, officials are seeking to recruit healthy veterans aged 18-65 years old who are not pregnant and may be at risk for exposure. As with trials conducted in civilian facilities, participants will be paid by the developer, VA spokesperson Christina Noel said.

Also, VA nurses and caseworkers also are being asked to identify their sickest, highest-risk patients to determine who should be at the top of the list once a vaccine is approved, according to a VA nurse and other health officials who asked not to be identified because they were not authorized to speak with the press.

The U.S. military has a long history of contributing to research on vaccines, including a key role in developing inoculations against yellow fever and adenovirus, and the Walter Reed Army Institute of Research is developing its own vaccine against the coronavirus.

Some segments of the population remain skeptical of federal medical experiments. A survey by AP-NORC in May found that Black people are particularly reluctant to get the coronavirus vaccine. Many have concerns about federal research in part because of associations with the infamous Tuskegee Institute syphilis experiments, in which U.S. Public Health Service officials intentionally withheld a cure from Black men infected with the disease.

But Mr. Morrison, of the Center for Strategic and International Studies, said the Defense Department and VA are a “natural fit” for the COVID vaccine trials.

“DOD has lots of expertise. They know how to vaccinate; they know how to reach communities. They have a whole science infrastructure and research-and-development infrastructure. And when you are thinking what the mission of VA is, [VA] sees this is part of their mission,” Mr. Morrison said.

The Defense Department announced its agreement with AstraZeneca in September, shortly before the drugmaker’s vaccine trial was put on hold to study a serious medical condition that one participant reported. That research was approved by the Food and Drug Administration to begin again Oct. 23. The military plans to restart its efforts to recruit 3,000 volunteers.

The Pentagon has also signed an agreement with another vaccine developer, the head of the Defense Health Agency, Army Lt. Gen. Ronald Place, told reporters Oct. 8. He wouldn’t provide the company’s name.

Senator Elizabeth Warren (D-Mass.) and Senator Mazie Hirono (D-Hawaii) have called, unsuccessfully, for the Senate Armed Services Committee to investigate what they say is a lack of Pentagon transparency on its role in vaccine development and distribution. The Defense Department has awarded more than $6 billion in Operation Warp Speed contracts through an intermediary, Advanced Technology International, and the two senators want more information about those contracts.

“There may well be a valuable role for DoD officials in [Operation Warp Speed] – particularly given the department’s logistical capacity,” they wrote to the committee chair and ranking member. “But it is important that Congress conduct appropriate oversight of, and understand, DoD’s activities in this area.”

Neither department has disclosed the financial arrangements they have made with developers to support the vaccine research.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

The Department of Veterans Affairs is recruiting 8,000 volunteers for the Phase 3 clinical trials of at least four COVID-19 vaccine candidates at 20 federal medical facilities across the United States, according to officials with the VA and Operation Warp Speed, the Trump administration’s initiative to fast-track a coronavirus vaccine.

The largely unpublicized effort follows a Department of Defense announcement in September that it has partnered with AstraZeneca to recruit volunteers at five of its medical facilities, which are separate from the VA system. DOD is also is in talks with developers of other vaccine candidates, although officials won’t say which ones.

Both federal departments have long experience in medical research and diverse populations – a crucial component of effective clinical trials, said J. Stephen Morrison, senior vice president and director of global health policy at the Center for Strategic and International Studies, a bipartisan think tank in Washington.

Since active troops are essential to national security, and veterans are extremely vulnerable to COVID-19, both departments have a vested interest in supporting the development of safe, effective vaccines, Mr. Morrison said.

“On the DOD active servicemen and -women side, it’s a question of making sure they’re ready, they are protected,” Mr. Morrison said. “With VA, their population, all elderly and infirm with underlying conditions, they could really be suffering if we don’t get a vaccine.”

According to a VA website, of its 20 medical centers involved, 17 would be part of the Johnson & Johnson vaccine trial, while the three others are recruiting – or have completed recruitment – for advanced-stage trials for Moderna, AstraZeneca, and Pfizer vaccines.

Matthew Hepburn, MD, head of vaccine development at Operation Warp Speed, said the VA effort lets veterans contribute to the overall well-being of the country.

“This is another way they can continue to serve in this way, fighting the pandemic as a volunteer,” Dr. Hepburn said during a discussion of vaccine and therapeutics development hosted by the Heritage Foundation on Oct. 27.

It’s not unusual for the military to participate in multicenter trials for treatments of ailments as diverse as cancer and trauma. Historically, many vaccines have been tested first by the military.

In the general population, clinicians often have difficulty recruiting African Americans and other minorities for medical research, and “the military provides a rich opportunity to find volunteers for those groups,” said retired Rear Adm. Thomas Cullison, MD, a doctor and former deputy surgeon general for the Navy.

Military health facilities are held to the same standards as private research facilities, he said.

No service members will be required to participate in the COVID vaccine trials. All volunteers will be paid by the developer.

Support for routine vaccinations runs high in the military, but some have expressed concerns about new vaccines and mandatory inoculations, especially for anthrax. In a 2002 federal study, 85% of those who received that vaccine reported an adverse reaction, with just under half noticing minor redness at the injection site. But nearly a quarter of the side effects reported were more systemic, including fevers, chills, fatigue and joint pain.

That survey of a small group of National Guard and Reserve members found that, while 73% said they believe immunizations are effective, two-thirds said they did not support the mandatory anthrax program, and 6 in 10 said they were not satisfied with the information they were given on the vaccines.

To quell concerns over the military’s role in supporting COVID vaccine development, the Pentagon has reiterated that troops or their dependents interested in participating in the research must provide voluntary written consent, and they will be allowed to take part only if they will be in the same location for the length of the research, expected to last at least 2 years.

In addition, active-duty members such as new recruits and boot camp participants will not be allowed to volunteer because they are “considered vulnerable from an ethical and regulatory standpoint,” an official said.

At the VA, officials are seeking to recruit healthy veterans aged 18-65 years old who are not pregnant and may be at risk for exposure. As with trials conducted in civilian facilities, participants will be paid by the developer, VA spokesperson Christina Noel said.

Also, VA nurses and caseworkers also are being asked to identify their sickest, highest-risk patients to determine who should be at the top of the list once a vaccine is approved, according to a VA nurse and other health officials who asked not to be identified because they were not authorized to speak with the press.

The U.S. military has a long history of contributing to research on vaccines, including a key role in developing inoculations against yellow fever and adenovirus, and the Walter Reed Army Institute of Research is developing its own vaccine against the coronavirus.

Some segments of the population remain skeptical of federal medical experiments. A survey by AP-NORC in May found that Black people are particularly reluctant to get the coronavirus vaccine. Many have concerns about federal research in part because of associations with the infamous Tuskegee Institute syphilis experiments, in which U.S. Public Health Service officials intentionally withheld a cure from Black men infected with the disease.

But Mr. Morrison, of the Center for Strategic and International Studies, said the Defense Department and VA are a “natural fit” for the COVID vaccine trials.

“DOD has lots of expertise. They know how to vaccinate; they know how to reach communities. They have a whole science infrastructure and research-and-development infrastructure. And when you are thinking what the mission of VA is, [VA] sees this is part of their mission,” Mr. Morrison said.

The Defense Department announced its agreement with AstraZeneca in September, shortly before the drugmaker’s vaccine trial was put on hold to study a serious medical condition that one participant reported. That research was approved by the Food and Drug Administration to begin again Oct. 23. The military plans to restart its efforts to recruit 3,000 volunteers.

The Pentagon has also signed an agreement with another vaccine developer, the head of the Defense Health Agency, Army Lt. Gen. Ronald Place, told reporters Oct. 8. He wouldn’t provide the company’s name.

Senator Elizabeth Warren (D-Mass.) and Senator Mazie Hirono (D-Hawaii) have called, unsuccessfully, for the Senate Armed Services Committee to investigate what they say is a lack of Pentagon transparency on its role in vaccine development and distribution. The Defense Department has awarded more than $6 billion in Operation Warp Speed contracts through an intermediary, Advanced Technology International, and the two senators want more information about those contracts.

“There may well be a valuable role for DoD officials in [Operation Warp Speed] – particularly given the department’s logistical capacity,” they wrote to the committee chair and ranking member. “But it is important that Congress conduct appropriate oversight of, and understand, DoD’s activities in this area.”

Neither department has disclosed the financial arrangements they have made with developers to support the vaccine research.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

The Supreme Court on Tuesday will hear oral arguments in a case that, for the third time in eight years, could result in the justices striking down the Affordable Care Act.

ETIENJones/thinkstockphotos

The case, California v. Texas, is the result of a change to the health law made by Congress in 2017. As part of a major tax bill, Congress reduced to zero the penalty for not having health insurance. But it was that penalty – a tax – that the high court ruled made the law constitutional in a 2012 decision, argues a group of Republican state attorneys general. Without the tax, they say in their suit, the rest of the law must fall, too.

After originally contending that the entire law should not be struck down when the suit was filed in 2018, the Trump administration changed course in 2019 and joined the GOP officials who brought the case.

Here are some key questions and answers about the case.
 

What are the possibilities for how the court could rule?

There is a long list of ways this could play out.

The justices could declare the entire law unconstitutional – which is what a federal district judge in Texas ruled in December 2018. But legal experts say that’s not the most likely outcome of this case.

First, the court may avoid deciding the case on its merits entirely by ruling that the plaintiffs do not have “standing” to sue. The central issue in the case is whether the requirement in the law to have insurance – which remains even though Congress eliminated the penalty or tax – is constitutional. But states are not subject to the so-called individual mandate, so some analysts suggest the Republican officials have no standing. In addition, questions have been raised about the individual plaintiffs in the case, two consultants from Texas who argue that they felt compelled to buy insurance even without a possible penalty.

The court could also rule that, by eliminating the penalty but not the rest of the mandate (which Congress could not do in that 2017 tax bill for procedural reasons), lawmakers “didn’t mean to coerce anyone to do anything, and so there’s no constitutional problem,” University of Michigan law professor Nicholas Bagley said in a recent webinar for the NIHCM Foundation, the Commonwealth Fund, and the University of Southern California’s Center for Health Journalism.

Or, said Bagley, the court could rule that, without the tax, the requirement to have health insurance is unconstitutional, but the rest of the law is not. In that case, the justices might strike the mandate only, which would have basically no impact.

It gets more complicated if the court decides that, as the plaintiffs argue, the individual mandate language without the penalty is unconstitutional and so closely tied to other parts of the law that some of them must fall as well.

Even there the court has choices. One option would be, as the Trump administration originally argued, to strike down the mandate and just the pieces of the law most closely related to it – which happen to include the insurance protections for people with preexisting conditions, an extremely popular provision of the law. The two parts are connected because the original purpose of the mandate was to make sure enough healthy people sign up for insurance to offset the added costs to insurers of sicker people.

Another option, of course, would be for the court to follow the lead of the Texas judge and strike down the entire law.

While that’s not the most likely outcome, said Bagley, if it happens it could be “a hot mess” for the nation’s entire health care system. As just one example, he said, “every hospital is getting paid pursuant to changes made by the ACA. How do you even go about making payments if the thing that you are looking to guide what those payments ought to be is itself invalid?”
 

What impact will new Justice Amy Coney Barrett have?

Perhaps a lot. Before the death of Justice Ruth Bader Ginsburg, most court observers thought the case was highly unlikely to result in the entire law being struck down. That’s because Chief Justice John Roberts voted to uphold the law in 2012, and again when it was challenged in a less sweeping way in 2015.

But with Barrett replacing Ginsburg, even if Roberts joined the court’s remaining three liberals they could still be outvoted by the other five conservatives. Barrett was coy about her views on the Affordable Care Act during her confirmation hearings in October, but she has written that she thinks Roberts was wrong to uphold the law in 2012.
 

Could a new president and Congress make the case go away?

Many have suggested that, if Joe Biden assumes the presidency, his Justice Department could simply drop the case. But the administration did not bring the case; the GOP state officials did. And while normally the Justice Department’s job is to defend existing laws in court, in this case the ACA is being defended by a group of Democratic state attorneys general. A new administration could change that position, but that’s not the same as dropping the case.

Congress, on the other hand, could easily make the case moot. It could add back even a nominal financial penalty for not having insurance. It could eliminate the mandate altogether, although that would require 60 votes in the Senate under current rules. Congress could also pass a “severability” provision saying that, if any portion of the law is struck down, the rest should remain.

“The problem is not technical,” said Bagley. “It’s political.”
 

What is the timeline for a decision? Could the court delay implementation of its ruling?

The court usually hears oral arguments in a case months before it issues a decision. Unless the decision is unanimous or turns out to be very simple, Bagley said, he would expect to see an opinion “sometime in the spring.”

As to whether the court could find some or all of the law unconstitutional but delay when its decision takes effect, Bagley said that happened from time to time as recently as the 1970s. “That practice has been more or less abandoned,” he said, but in the case of a law so large, “you could imagine the Supreme Court using its discretion to say the decision wouldn’t take effect immediately.”

If the court does invalidate the entire ACA, Congress could act to fix things, but it’s unclear if it will be able to, especially if Republicans still control the Senate. If the justices strike the law, Bagley said, “I honestly think the likeliest outcome is that Congress runs around like a chicken with its head cut off, doesn’t come to a deal, and we’re back to where we were before 2010” when the ACA passed.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

The Supreme Court on Tuesday will hear oral arguments in a case that, for the third time in eight years, could result in the justices striking down the Affordable Care Act.

ETIENJones/thinkstockphotos

The case, California v. Texas, is the result of a change to the health law made by Congress in 2017. As part of a major tax bill, Congress reduced to zero the penalty for not having health insurance. But it was that penalty – a tax – that the high court ruled made the law constitutional in a 2012 decision, argues a group of Republican state attorneys general. Without the tax, they say in their suit, the rest of the law must fall, too.

After originally contending that the entire law should not be struck down when the suit was filed in 2018, the Trump administration changed course in 2019 and joined the GOP officials who brought the case.

Here are some key questions and answers about the case.
 

What are the possibilities for how the court could rule?

There is a long list of ways this could play out.

The justices could declare the entire law unconstitutional – which is what a federal district judge in Texas ruled in December 2018. But legal experts say that’s not the most likely outcome of this case.

First, the court may avoid deciding the case on its merits entirely by ruling that the plaintiffs do not have “standing” to sue. The central issue in the case is whether the requirement in the law to have insurance – which remains even though Congress eliminated the penalty or tax – is constitutional. But states are not subject to the so-called individual mandate, so some analysts suggest the Republican officials have no standing. In addition, questions have been raised about the individual plaintiffs in the case, two consultants from Texas who argue that they felt compelled to buy insurance even without a possible penalty.

The court could also rule that, by eliminating the penalty but not the rest of the mandate (which Congress could not do in that 2017 tax bill for procedural reasons), lawmakers “didn’t mean to coerce anyone to do anything, and so there’s no constitutional problem,” University of Michigan law professor Nicholas Bagley said in a recent webinar for the NIHCM Foundation, the Commonwealth Fund, and the University of Southern California’s Center for Health Journalism.

Or, said Bagley, the court could rule that, without the tax, the requirement to have health insurance is unconstitutional, but the rest of the law is not. In that case, the justices might strike the mandate only, which would have basically no impact.

It gets more complicated if the court decides that, as the plaintiffs argue, the individual mandate language without the penalty is unconstitutional and so closely tied to other parts of the law that some of them must fall as well.

Even there the court has choices. One option would be, as the Trump administration originally argued, to strike down the mandate and just the pieces of the law most closely related to it – which happen to include the insurance protections for people with preexisting conditions, an extremely popular provision of the law. The two parts are connected because the original purpose of the mandate was to make sure enough healthy people sign up for insurance to offset the added costs to insurers of sicker people.

Another option, of course, would be for the court to follow the lead of the Texas judge and strike down the entire law.

While that’s not the most likely outcome, said Bagley, if it happens it could be “a hot mess” for the nation’s entire health care system. As just one example, he said, “every hospital is getting paid pursuant to changes made by the ACA. How do you even go about making payments if the thing that you are looking to guide what those payments ought to be is itself invalid?”
 

What impact will new Justice Amy Coney Barrett have?

Perhaps a lot. Before the death of Justice Ruth Bader Ginsburg, most court observers thought the case was highly unlikely to result in the entire law being struck down. That’s because Chief Justice John Roberts voted to uphold the law in 2012, and again when it was challenged in a less sweeping way in 2015.

But with Barrett replacing Ginsburg, even if Roberts joined the court’s remaining three liberals they could still be outvoted by the other five conservatives. Barrett was coy about her views on the Affordable Care Act during her confirmation hearings in October, but she has written that she thinks Roberts was wrong to uphold the law in 2012.
 

Could a new president and Congress make the case go away?

Many have suggested that, if Joe Biden assumes the presidency, his Justice Department could simply drop the case. But the administration did not bring the case; the GOP state officials did. And while normally the Justice Department’s job is to defend existing laws in court, in this case the ACA is being defended by a group of Democratic state attorneys general. A new administration could change that position, but that’s not the same as dropping the case.

Congress, on the other hand, could easily make the case moot. It could add back even a nominal financial penalty for not having insurance. It could eliminate the mandate altogether, although that would require 60 votes in the Senate under current rules. Congress could also pass a “severability” provision saying that, if any portion of the law is struck down, the rest should remain.

“The problem is not technical,” said Bagley. “It’s political.”
 

What is the timeline for a decision? Could the court delay implementation of its ruling?

The court usually hears oral arguments in a case months before it issues a decision. Unless the decision is unanimous or turns out to be very simple, Bagley said, he would expect to see an opinion “sometime in the spring.”

As to whether the court could find some or all of the law unconstitutional but delay when its decision takes effect, Bagley said that happened from time to time as recently as the 1970s. “That practice has been more or less abandoned,” he said, but in the case of a law so large, “you could imagine the Supreme Court using its discretion to say the decision wouldn’t take effect immediately.”

If the court does invalidate the entire ACA, Congress could act to fix things, but it’s unclear if it will be able to, especially if Republicans still control the Senate. If the justices strike the law, Bagley said, “I honestly think the likeliest outcome is that Congress runs around like a chicken with its head cut off, doesn’t come to a deal, and we’re back to where we were before 2010” when the ACA passed.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

The Supreme Court on Tuesday will hear oral arguments in a case that, for the third time in eight years, could result in the justices striking down the Affordable Care Act.

ETIENJones/thinkstockphotos

The case, California v. Texas, is the result of a change to the health law made by Congress in 2017. As part of a major tax bill, Congress reduced to zero the penalty for not having health insurance. But it was that penalty – a tax – that the high court ruled made the law constitutional in a 2012 decision, argues a group of Republican state attorneys general. Without the tax, they say in their suit, the rest of the law must fall, too.

After originally contending that the entire law should not be struck down when the suit was filed in 2018, the Trump administration changed course in 2019 and joined the GOP officials who brought the case.

Here are some key questions and answers about the case.
 

What are the possibilities for how the court could rule?

There is a long list of ways this could play out.

The justices could declare the entire law unconstitutional – which is what a federal district judge in Texas ruled in December 2018. But legal experts say that’s not the most likely outcome of this case.

First, the court may avoid deciding the case on its merits entirely by ruling that the plaintiffs do not have “standing” to sue. The central issue in the case is whether the requirement in the law to have insurance – which remains even though Congress eliminated the penalty or tax – is constitutional. But states are not subject to the so-called individual mandate, so some analysts suggest the Republican officials have no standing. In addition, questions have been raised about the individual plaintiffs in the case, two consultants from Texas who argue that they felt compelled to buy insurance even without a possible penalty.

The court could also rule that, by eliminating the penalty but not the rest of the mandate (which Congress could not do in that 2017 tax bill for procedural reasons), lawmakers “didn’t mean to coerce anyone to do anything, and so there’s no constitutional problem,” University of Michigan law professor Nicholas Bagley said in a recent webinar for the NIHCM Foundation, the Commonwealth Fund, and the University of Southern California’s Center for Health Journalism.

Or, said Bagley, the court could rule that, without the tax, the requirement to have health insurance is unconstitutional, but the rest of the law is not. In that case, the justices might strike the mandate only, which would have basically no impact.

It gets more complicated if the court decides that, as the plaintiffs argue, the individual mandate language without the penalty is unconstitutional and so closely tied to other parts of the law that some of them must fall as well.

Even there the court has choices. One option would be, as the Trump administration originally argued, to strike down the mandate and just the pieces of the law most closely related to it – which happen to include the insurance protections for people with preexisting conditions, an extremely popular provision of the law. The two parts are connected because the original purpose of the mandate was to make sure enough healthy people sign up for insurance to offset the added costs to insurers of sicker people.

Another option, of course, would be for the court to follow the lead of the Texas judge and strike down the entire law.

While that’s not the most likely outcome, said Bagley, if it happens it could be “a hot mess” for the nation’s entire health care system. As just one example, he said, “every hospital is getting paid pursuant to changes made by the ACA. How do you even go about making payments if the thing that you are looking to guide what those payments ought to be is itself invalid?”
 

What impact will new Justice Amy Coney Barrett have?

Perhaps a lot. Before the death of Justice Ruth Bader Ginsburg, most court observers thought the case was highly unlikely to result in the entire law being struck down. That’s because Chief Justice John Roberts voted to uphold the law in 2012, and again when it was challenged in a less sweeping way in 2015.

But with Barrett replacing Ginsburg, even if Roberts joined the court’s remaining three liberals they could still be outvoted by the other five conservatives. Barrett was coy about her views on the Affordable Care Act during her confirmation hearings in October, but she has written that she thinks Roberts was wrong to uphold the law in 2012.
 

Could a new president and Congress make the case go away?

Many have suggested that, if Joe Biden assumes the presidency, his Justice Department could simply drop the case. But the administration did not bring the case; the GOP state officials did. And while normally the Justice Department’s job is to defend existing laws in court, in this case the ACA is being defended by a group of Democratic state attorneys general. A new administration could change that position, but that’s not the same as dropping the case.

Congress, on the other hand, could easily make the case moot. It could add back even a nominal financial penalty for not having insurance. It could eliminate the mandate altogether, although that would require 60 votes in the Senate under current rules. Congress could also pass a “severability” provision saying that, if any portion of the law is struck down, the rest should remain.

“The problem is not technical,” said Bagley. “It’s political.”
 

What is the timeline for a decision? Could the court delay implementation of its ruling?

The court usually hears oral arguments in a case months before it issues a decision. Unless the decision is unanimous or turns out to be very simple, Bagley said, he would expect to see an opinion “sometime in the spring.”

As to whether the court could find some or all of the law unconstitutional but delay when its decision takes effect, Bagley said that happened from time to time as recently as the 1970s. “That practice has been more or less abandoned,” he said, but in the case of a law so large, “you could imagine the Supreme Court using its discretion to say the decision wouldn’t take effect immediately.”

If the court does invalidate the entire ACA, Congress could act to fix things, but it’s unclear if it will be able to, especially if Republicans still control the Senate. If the justices strike the law, Bagley said, “I honestly think the likeliest outcome is that Congress runs around like a chicken with its head cut off, doesn’t come to a deal, and we’re back to where we were before 2010” when the ACA passed.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

Osteoporosis is frequently underdiagnosed and undertreated in men before and even after they have experienced a fracture, according to research presented at the virtual annual meeting of the American College of Rheumatology.

“This is an important public health concern,” as fractures contribute significantly to morbidity and mortality, said Jeffrey Curtis, MD, MS, MPH, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

Men are often overlooked, he said, “because it’s misconstrued as a disease that mainly, if not only, affects Caucasian women,” despite the fact that 20%-25% of fractures occur in men.

Emerging evidence suggests that men who have bone fractures have worse outcomes than women, Dr. Curtis said.
 

Guidelines lacking

Consistent guidelines for osteoporosis screening among men are also lacking, leading to ambiguity and increased disease burden.

Researchers studied records for a 5% random sample of male Medicare fee-for-service beneficiaries (n = 9,876) aged at least 65 years with a closed fragility fracture between January 2010 and September 2014. Average age for the men with fractures was 77.9 years, and the most common sites of the fracture were the spine, hip, and ankle.

They looked back to see whether these men had been effectively screened and treated.

Very few had.

“We found that 92.8% of them did not have any diagnosis or treatment of osteoporosis at baseline,” Curtis said. On top of that, less than 6% of men had undergone any dual-energy x-ray absorptiometry (DEXA) or bone mineral testing in the 2 years prior to their fracture.

Even men who had high-risk factors for falls, such as those using beta-blockers, mobility impairment, or a history of opioid use, were unlikely to be screened, he said.

Dr. Curtis’s data show there was actually a decline in DEXA scans from 2012 to 2014, and that decline was particularly high in men aged 75 years and older who are more likely to be at risk for fracture.

In addition to underscreening and undertreating before the fracture, Dr. Curtis said, “The treatment patterns after the fracture were not much better.” In the year after the fracture, “only about 10% of these men had BMD [bone mineral density] testing. Only 9% were treated with an osteoporosis medication.”

“Importantly, about 7% of the men in this large cohort went on to have one or more fractures in the next year,” he added.

Reasons for undertreatment

Reasons for the poor rates of diagnosis and treatment may begin with patients not having symptoms. Therefore, they aren’t coming into doctors’ offices asking to be screened. “Even if they break bones, they may not know enough to ask how to prevent the next fracture,” Dr. Curtis said.

There’s a financial obstacle as well, Dr. Curtis explained. “U.S. legislation that provides population screening for Medicare patients really, for men, is quite dissimilar to the near-universal coverage for women. So many clinicians worry they won’t get reimbursed if they order DEXA in men for screening.”

Additionally, postfracture quality-of-care guidelines that are reimbursed as part of the Medicare Access and CHIP Reauthorization Act of 2015 and the Merit-based Incentive Payment System program specifically exclude men, he noted.

Better management of male osteoporosis, including early identification of at-risk individuals is clearly warranted, he said, so they can be screened and put on effective therapy.

Sonali Khandelwal, MD, a rheumatologist with Rush University Medical Center, Chicago, who was not part of the research, agreed.

She said in an interview that part of the problem is that diagnosis and treatment could come from a variety of specialists – endocrinologists, rheumatologists, orthopedists, and primary care physicians – and each may think it falls in another’s realm.

At Rush and some other sites nationally, she said, an alert is registered in electronic medical records flagging any patient who may need bone density screening based on age, medications, or history.

Rush University also has a fracture liaison service under which everyone hospitalized there who may have had a history of a fracture or is admitted with a fracture gets followed up with screening and treatment, “to capture those patients who may not have come through the system otherwise.”

She said guidelines have called for DEXA screening for men at age 70, but she said clinical screening should start younger – as young as 50 – for patients with conditions such as lupus, rheumatoid arthritis, hypogonadism, or those on chronic steroids.

Dr. Khandelwal said that, even when an insurance company doesn›t typically cover bone density screening for men, physicians can often make a case for reimbursement if the patient has a history of falls or fractures.

“In the long run, preventing a fracture is saving so much more money than when you get a fracture and end up in a hospital and have to go to a nursing home,” she said.

Dr. Curtis reported relationships with AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Gilead Sciences, and Sanofi. Dr. Khandelwal reported no relevant financial relationships.

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

Osteoporosis is frequently underdiagnosed and undertreated in men before and even after they have experienced a fracture, according to research presented at the virtual annual meeting of the American College of Rheumatology.

“This is an important public health concern,” as fractures contribute significantly to morbidity and mortality, said Jeffrey Curtis, MD, MS, MPH, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

Men are often overlooked, he said, “because it’s misconstrued as a disease that mainly, if not only, affects Caucasian women,” despite the fact that 20%-25% of fractures occur in men.

Emerging evidence suggests that men who have bone fractures have worse outcomes than women, Dr. Curtis said.
 

Guidelines lacking

Consistent guidelines for osteoporosis screening among men are also lacking, leading to ambiguity and increased disease burden.

Researchers studied records for a 5% random sample of male Medicare fee-for-service beneficiaries (n = 9,876) aged at least 65 years with a closed fragility fracture between January 2010 and September 2014. Average age for the men with fractures was 77.9 years, and the most common sites of the fracture were the spine, hip, and ankle.

They looked back to see whether these men had been effectively screened and treated.

Very few had.

“We found that 92.8% of them did not have any diagnosis or treatment of osteoporosis at baseline,” Curtis said. On top of that, less than 6% of men had undergone any dual-energy x-ray absorptiometry (DEXA) or bone mineral testing in the 2 years prior to their fracture.

Even men who had high-risk factors for falls, such as those using beta-blockers, mobility impairment, or a history of opioid use, were unlikely to be screened, he said.

Dr. Curtis’s data show there was actually a decline in DEXA scans from 2012 to 2014, and that decline was particularly high in men aged 75 years and older who are more likely to be at risk for fracture.

In addition to underscreening and undertreating before the fracture, Dr. Curtis said, “The treatment patterns after the fracture were not much better.” In the year after the fracture, “only about 10% of these men had BMD [bone mineral density] testing. Only 9% were treated with an osteoporosis medication.”

“Importantly, about 7% of the men in this large cohort went on to have one or more fractures in the next year,” he added.

Reasons for undertreatment

Reasons for the poor rates of diagnosis and treatment may begin with patients not having symptoms. Therefore, they aren’t coming into doctors’ offices asking to be screened. “Even if they break bones, they may not know enough to ask how to prevent the next fracture,” Dr. Curtis said.

There’s a financial obstacle as well, Dr. Curtis explained. “U.S. legislation that provides population screening for Medicare patients really, for men, is quite dissimilar to the near-universal coverage for women. So many clinicians worry they won’t get reimbursed if they order DEXA in men for screening.”

Additionally, postfracture quality-of-care guidelines that are reimbursed as part of the Medicare Access and CHIP Reauthorization Act of 2015 and the Merit-based Incentive Payment System program specifically exclude men, he noted.

Better management of male osteoporosis, including early identification of at-risk individuals is clearly warranted, he said, so they can be screened and put on effective therapy.

Sonali Khandelwal, MD, a rheumatologist with Rush University Medical Center, Chicago, who was not part of the research, agreed.

She said in an interview that part of the problem is that diagnosis and treatment could come from a variety of specialists – endocrinologists, rheumatologists, orthopedists, and primary care physicians – and each may think it falls in another’s realm.

At Rush and some other sites nationally, she said, an alert is registered in electronic medical records flagging any patient who may need bone density screening based on age, medications, or history.

Rush University also has a fracture liaison service under which everyone hospitalized there who may have had a history of a fracture or is admitted with a fracture gets followed up with screening and treatment, “to capture those patients who may not have come through the system otherwise.”

She said guidelines have called for DEXA screening for men at age 70, but she said clinical screening should start younger – as young as 50 – for patients with conditions such as lupus, rheumatoid arthritis, hypogonadism, or those on chronic steroids.

Dr. Khandelwal said that, even when an insurance company doesn›t typically cover bone density screening for men, physicians can often make a case for reimbursement if the patient has a history of falls or fractures.

“In the long run, preventing a fracture is saving so much more money than when you get a fracture and end up in a hospital and have to go to a nursing home,” she said.

Dr. Curtis reported relationships with AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Gilead Sciences, and Sanofi. Dr. Khandelwal reported no relevant financial relationships.

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

Osteoporosis is frequently underdiagnosed and undertreated in men before and even after they have experienced a fracture, according to research presented at the virtual annual meeting of the American College of Rheumatology.

“This is an important public health concern,” as fractures contribute significantly to morbidity and mortality, said Jeffrey Curtis, MD, MS, MPH, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

Men are often overlooked, he said, “because it’s misconstrued as a disease that mainly, if not only, affects Caucasian women,” despite the fact that 20%-25% of fractures occur in men.

Emerging evidence suggests that men who have bone fractures have worse outcomes than women, Dr. Curtis said.
 

Guidelines lacking

Consistent guidelines for osteoporosis screening among men are also lacking, leading to ambiguity and increased disease burden.

Researchers studied records for a 5% random sample of male Medicare fee-for-service beneficiaries (n = 9,876) aged at least 65 years with a closed fragility fracture between January 2010 and September 2014. Average age for the men with fractures was 77.9 years, and the most common sites of the fracture were the spine, hip, and ankle.

They looked back to see whether these men had been effectively screened and treated.

Very few had.

“We found that 92.8% of them did not have any diagnosis or treatment of osteoporosis at baseline,” Curtis said. On top of that, less than 6% of men had undergone any dual-energy x-ray absorptiometry (DEXA) or bone mineral testing in the 2 years prior to their fracture.

Even men who had high-risk factors for falls, such as those using beta-blockers, mobility impairment, or a history of opioid use, were unlikely to be screened, he said.

Dr. Curtis’s data show there was actually a decline in DEXA scans from 2012 to 2014, and that decline was particularly high in men aged 75 years and older who are more likely to be at risk for fracture.

In addition to underscreening and undertreating before the fracture, Dr. Curtis said, “The treatment patterns after the fracture were not much better.” In the year after the fracture, “only about 10% of these men had BMD [bone mineral density] testing. Only 9% were treated with an osteoporosis medication.”

“Importantly, about 7% of the men in this large cohort went on to have one or more fractures in the next year,” he added.

Reasons for undertreatment

Reasons for the poor rates of diagnosis and treatment may begin with patients not having symptoms. Therefore, they aren’t coming into doctors’ offices asking to be screened. “Even if they break bones, they may not know enough to ask how to prevent the next fracture,” Dr. Curtis said.

There’s a financial obstacle as well, Dr. Curtis explained. “U.S. legislation that provides population screening for Medicare patients really, for men, is quite dissimilar to the near-universal coverage for women. So many clinicians worry they won’t get reimbursed if they order DEXA in men for screening.”

Additionally, postfracture quality-of-care guidelines that are reimbursed as part of the Medicare Access and CHIP Reauthorization Act of 2015 and the Merit-based Incentive Payment System program specifically exclude men, he noted.

Better management of male osteoporosis, including early identification of at-risk individuals is clearly warranted, he said, so they can be screened and put on effective therapy.

Sonali Khandelwal, MD, a rheumatologist with Rush University Medical Center, Chicago, who was not part of the research, agreed.

She said in an interview that part of the problem is that diagnosis and treatment could come from a variety of specialists – endocrinologists, rheumatologists, orthopedists, and primary care physicians – and each may think it falls in another’s realm.

At Rush and some other sites nationally, she said, an alert is registered in electronic medical records flagging any patient who may need bone density screening based on age, medications, or history.

Rush University also has a fracture liaison service under which everyone hospitalized there who may have had a history of a fracture or is admitted with a fracture gets followed up with screening and treatment, “to capture those patients who may not have come through the system otherwise.”

She said guidelines have called for DEXA screening for men at age 70, but she said clinical screening should start younger – as young as 50 – for patients with conditions such as lupus, rheumatoid arthritis, hypogonadism, or those on chronic steroids.

Dr. Khandelwal said that, even when an insurance company doesn›t typically cover bone density screening for men, physicians can often make a case for reimbursement if the patient has a history of falls or fractures.

“In the long run, preventing a fracture is saving so much more money than when you get a fracture and end up in a hospital and have to go to a nursing home,” she said.

Dr. Curtis reported relationships with AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Gilead Sciences, and Sanofi. Dr. Khandelwal reported no relevant financial relationships.

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

Timing is everything when it comes to the use of the anabolic agent romosozumab (Evenity) for the treatment of advanced osteoporosis, a review of clinical trials suggests.

In four studies with treatment sequences in which romosozumab was administered either before or following the use of an antiresorptive agent, initial treatment with 1 year of romosozumab produced substantial bone mineral density (BMD) gains in the total hip and lumbar spine.

Transition from romosozumab to a potent resorptive agent, either alendronate or denosumab (Prolia) augmented the initial gains, reported Felicia Cosman, MD, professor of clinical medicine at Columbia University, New York.

Romosozumab was the third approved agent in its class, following teriparatide in 2002, and abaloparatide (Tymlos) in 2017, both of which have been shown to produce rapid reductions in fracture risk and large improvements in BMD when they were administered up front, followed by an antiresorptive agent.

“But since romosozumab has a very different mechanism of action compared to both teriparatide and abaloparatide, we didn’t know if treatment sequence would be as important for this agent as it was for teriparatide,” she said during a press briefing prior to her presentation of the data in an oral abstract session at the virtual annual meeting of the American College of Rheumatology.

Two-for-one

Romosozumab is unique in that it both increases bone formation and decreases bone resorption, and has been shown in treatment-naive postmenopausal women with osteoporosis to significantly improve BMD and reduce fracture risk, compared with either placebo or alendronate. Romosozumab has also been studied as sequential therapy in patients treated initially with either alendronate or denosumab.

To see whether treatment sequence could have differential effects on clinical outcomes for patients with osteoporosis, Dr. Cosman and colleagues looked at results from four clinical trials, using levels of bone turnover markers (procollagen type I N-terminal propeptide [PINP] and beta-isomer of the C-terminal telopeptide of type I collagen [beta-CTX]) and BMD gains in the total hip and spine as outcomes.

The two trials of romosozumab in treatment-naive women were the ARCH trial comparing romosozumab with alendronate in a double-blind phase for 1 year, followed by 1 year of open-label alendronate, and the FRAME trial, in which romosozumab was compared with placebo in a 1-year double-blind phase, followed by 1-year of open-label denosumab.

The two trials of romosozumab in women treated initially with antiresorptive agents were the STRUCTURE trial in which patients on oral bisphosphonates for at least 3 years or alendronate 70 mg weekly for 1 year were randomized to receive either romosozumab or teriparatide, and a phase 2 trial (NCT00896532) that included a 24-month romosozumab or placebo treatment phase followed by rerandomization to a 12-month extension phase with denosumab or placebo, followed by a 12-month retreatment phase with romosozumab, followed by a 24-month follow-on phase with zoledronic acid or no intervention.

Total hip BMD gains

In the ARCH trial, total hip BMD increased 6.2% with 1 year of romosozumab, and a cumulative total of 7.1% with the 2-year romosozumab/alendronate sequence. In the FRAME trial, patients gained 6.8% in total hip BMD after 1 year of romosozumab and a total of 8.8% after 2 years of romosozumab followed by denosumab.

In contrast, in the STRUCTURE trial, patients treated for 1 year or longer with alendronate and then with 1 year of romosozumab had a 2.9% BMD gain in the total hip. In the phase 2 trial, 1 year of romosozumab following 1 year of denosumab yielded a 0.9% BMD gain, for a total gain of 3.8% with the denosumab sequence.
 

Lumbar spine BMD gains

In ARCH, lumbar spine BMD increased 13.7% with 1 year of romosozumab, and a total of 15.2% with the 2-year sequence of romosozumab followed by alendronate. Similarly, in FRAME, patients gained 13.3% in BMD after a year of romosozumab, and total of 17.6% by the end of the 2-year romosozumab/denosumab sequence.

In contrast, in STRUCTURE, patients who had previously been on alendronate for at least 1 year had a gain of 9.8% after 1 year of romosozumab, and in the phase 2 study, patients who had been on denosumab for 1 year had an increase in lumbar spine BMD of 5.3% after 1 year on romosozumab, and a total gain of 11.5% at the end of the 2-year sequence.
 

Serum PINP and beta-CTX

Looking at the markers of bone turnover, the investigators saw that, in both ARCH and FRAME, PINP peaked at over 80% of baseline at 1 month, and then continued to steadily decline past 1 year. The beta-CTX nadir was 40%-50% below baseline at 1 year.

At the end of year 2, the PINP nadir was –67% with follow-on alendronate, and –69% with denosumab, and the beta-CTX nadir was –72% and –92%, respectively.

In the two trials where romosozumab was the follow-on therapy, however, the trends were distinctly different. In STRUCTURE, for example, PINP peaked at 141% of baseline at 1 month, and then returned toward baseline, whereas beta-CTX remained largely unchanged.

In the phase 2 trial, PINP peaked at 28% above baseline at 9 months, and then only slightly declined, and beta-CTX peaked at 211% at the end of 1 year of romosozumab.

Best used up front

“This study is important, because it suggests that for the three bone-building drugs that the best effects will really be attained on bone strength if the agents are used as initial therapy in very-high-risk patients. Those are people who have sustained fractures within the preceding 2 years, who had multiple fractures at any point in their adulthood, and who present with very low BMD, particularly if they have any associated clinical risk factors such as family history or other underlying diseases or medications that have detrimental effects on bone,” Dr. Cosman said at the briefing.

Marcy Bolster, MD, from the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston, and associate professor of medicine at Harvard Medical School in Boston, who was not involved in the study, commented that the study provides important information for clinicians who treat patients with osteoporosis.

“We have an increasing number of medications available for use in the treatment of patients with osteoporosis, and as we consider the importance of reducing fracture risk, the duration of therapy, the timing of a bisphosphonate holiday, it is essential that we consider any advantages to the order or sequence of our medications,” she said when asked for comment.

“This study provides evidence supporting the concept of the ‘anabolic window’ in which there is a demonstrated advantage in treating patients with an anabolic agent prior to treatment with an antiresorptive agent, and while gains in bone mineral density were achieved with either order of medication use, the gains were more dramatic with treatment with romosozumab as the first agent,” she added.

Dr. Bolster also noted it will be important to demonstrate reduction in fracture risk as well as gain in BMD.

The study was sponsored by Amgen, Astellas, and UCB. Dr. Cosman disclosed grants/research support from Amgen, and consulting fees and speaker activities for Amgen and Radius Health. Dr. Bolster disclosed relationships with AbbVie, Corbus, Cumberland, Gilead, Johnson & Johnson, and Pfizer.

SOURCE: Cosman F et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 1973.

Timing is everything when it comes to the use of the anabolic agent romosozumab (Evenity) for the treatment of advanced osteoporosis, a review of clinical trials suggests.

In four studies with treatment sequences in which romosozumab was administered either before or following the use of an antiresorptive agent, initial treatment with 1 year of romosozumab produced substantial bone mineral density (BMD) gains in the total hip and lumbar spine.

Transition from romosozumab to a potent resorptive agent, either alendronate or denosumab (Prolia) augmented the initial gains, reported Felicia Cosman, MD, professor of clinical medicine at Columbia University, New York.

Romosozumab was the third approved agent in its class, following teriparatide in 2002, and abaloparatide (Tymlos) in 2017, both of which have been shown to produce rapid reductions in fracture risk and large improvements in BMD when they were administered up front, followed by an antiresorptive agent.

“But since romosozumab has a very different mechanism of action compared to both teriparatide and abaloparatide, we didn’t know if treatment sequence would be as important for this agent as it was for teriparatide,” she said during a press briefing prior to her presentation of the data in an oral abstract session at the virtual annual meeting of the American College of Rheumatology.

Two-for-one

Romosozumab is unique in that it both increases bone formation and decreases bone resorption, and has been shown in treatment-naive postmenopausal women with osteoporosis to significantly improve BMD and reduce fracture risk, compared with either placebo or alendronate. Romosozumab has also been studied as sequential therapy in patients treated initially with either alendronate or denosumab.

To see whether treatment sequence could have differential effects on clinical outcomes for patients with osteoporosis, Dr. Cosman and colleagues looked at results from four clinical trials, using levels of bone turnover markers (procollagen type I N-terminal propeptide [PINP] and beta-isomer of the C-terminal telopeptide of type I collagen [beta-CTX]) and BMD gains in the total hip and spine as outcomes.

The two trials of romosozumab in treatment-naive women were the ARCH trial comparing romosozumab with alendronate in a double-blind phase for 1 year, followed by 1 year of open-label alendronate, and the FRAME trial, in which romosozumab was compared with placebo in a 1-year double-blind phase, followed by 1-year of open-label denosumab.

The two trials of romosozumab in women treated initially with antiresorptive agents were the STRUCTURE trial in which patients on oral bisphosphonates for at least 3 years or alendronate 70 mg weekly for 1 year were randomized to receive either romosozumab or teriparatide, and a phase 2 trial (NCT00896532) that included a 24-month romosozumab or placebo treatment phase followed by rerandomization to a 12-month extension phase with denosumab or placebo, followed by a 12-month retreatment phase with romosozumab, followed by a 24-month follow-on phase with zoledronic acid or no intervention.

Total hip BMD gains

In the ARCH trial, total hip BMD increased 6.2% with 1 year of romosozumab, and a cumulative total of 7.1% with the 2-year romosozumab/alendronate sequence. In the FRAME trial, patients gained 6.8% in total hip BMD after 1 year of romosozumab and a total of 8.8% after 2 years of romosozumab followed by denosumab.

In contrast, in the STRUCTURE trial, patients treated for 1 year or longer with alendronate and then with 1 year of romosozumab had a 2.9% BMD gain in the total hip. In the phase 2 trial, 1 year of romosozumab following 1 year of denosumab yielded a 0.9% BMD gain, for a total gain of 3.8% with the denosumab sequence.
 

Lumbar spine BMD gains

In ARCH, lumbar spine BMD increased 13.7% with 1 year of romosozumab, and a total of 15.2% with the 2-year sequence of romosozumab followed by alendronate. Similarly, in FRAME, patients gained 13.3% in BMD after a year of romosozumab, and total of 17.6% by the end of the 2-year romosozumab/denosumab sequence.

In contrast, in STRUCTURE, patients who had previously been on alendronate for at least 1 year had a gain of 9.8% after 1 year of romosozumab, and in the phase 2 study, patients who had been on denosumab for 1 year had an increase in lumbar spine BMD of 5.3% after 1 year on romosozumab, and a total gain of 11.5% at the end of the 2-year sequence.
 

Serum PINP and beta-CTX

Looking at the markers of bone turnover, the investigators saw that, in both ARCH and FRAME, PINP peaked at over 80% of baseline at 1 month, and then continued to steadily decline past 1 year. The beta-CTX nadir was 40%-50% below baseline at 1 year.

At the end of year 2, the PINP nadir was –67% with follow-on alendronate, and –69% with denosumab, and the beta-CTX nadir was –72% and –92%, respectively.

In the two trials where romosozumab was the follow-on therapy, however, the trends were distinctly different. In STRUCTURE, for example, PINP peaked at 141% of baseline at 1 month, and then returned toward baseline, whereas beta-CTX remained largely unchanged.

In the phase 2 trial, PINP peaked at 28% above baseline at 9 months, and then only slightly declined, and beta-CTX peaked at 211% at the end of 1 year of romosozumab.

Best used up front

“This study is important, because it suggests that for the three bone-building drugs that the best effects will really be attained on bone strength if the agents are used as initial therapy in very-high-risk patients. Those are people who have sustained fractures within the preceding 2 years, who had multiple fractures at any point in their adulthood, and who present with very low BMD, particularly if they have any associated clinical risk factors such as family history or other underlying diseases or medications that have detrimental effects on bone,” Dr. Cosman said at the briefing.

Marcy Bolster, MD, from the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston, and associate professor of medicine at Harvard Medical School in Boston, who was not involved in the study, commented that the study provides important information for clinicians who treat patients with osteoporosis.

“We have an increasing number of medications available for use in the treatment of patients with osteoporosis, and as we consider the importance of reducing fracture risk, the duration of therapy, the timing of a bisphosphonate holiday, it is essential that we consider any advantages to the order or sequence of our medications,” she said when asked for comment.

“This study provides evidence supporting the concept of the ‘anabolic window’ in which there is a demonstrated advantage in treating patients with an anabolic agent prior to treatment with an antiresorptive agent, and while gains in bone mineral density were achieved with either order of medication use, the gains were more dramatic with treatment with romosozumab as the first agent,” she added.

Dr. Bolster also noted it will be important to demonstrate reduction in fracture risk as well as gain in BMD.

The study was sponsored by Amgen, Astellas, and UCB. Dr. Cosman disclosed grants/research support from Amgen, and consulting fees and speaker activities for Amgen and Radius Health. Dr. Bolster disclosed relationships with AbbVie, Corbus, Cumberland, Gilead, Johnson & Johnson, and Pfizer.

SOURCE: Cosman F et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 1973.

Timing is everything when it comes to the use of the anabolic agent romosozumab (Evenity) for the treatment of advanced osteoporosis, a review of clinical trials suggests.

In four studies with treatment sequences in which romosozumab was administered either before or following the use of an antiresorptive agent, initial treatment with 1 year of romosozumab produced substantial bone mineral density (BMD) gains in the total hip and lumbar spine.

Transition from romosozumab to a potent resorptive agent, either alendronate or denosumab (Prolia) augmented the initial gains, reported Felicia Cosman, MD, professor of clinical medicine at Columbia University, New York.

Romosozumab was the third approved agent in its class, following teriparatide in 2002, and abaloparatide (Tymlos) in 2017, both of which have been shown to produce rapid reductions in fracture risk and large improvements in BMD when they were administered up front, followed by an antiresorptive agent.

“But since romosozumab has a very different mechanism of action compared to both teriparatide and abaloparatide, we didn’t know if treatment sequence would be as important for this agent as it was for teriparatide,” she said during a press briefing prior to her presentation of the data in an oral abstract session at the virtual annual meeting of the American College of Rheumatology.

Two-for-one

Romosozumab is unique in that it both increases bone formation and decreases bone resorption, and has been shown in treatment-naive postmenopausal women with osteoporosis to significantly improve BMD and reduce fracture risk, compared with either placebo or alendronate. Romosozumab has also been studied as sequential therapy in patients treated initially with either alendronate or denosumab.

To see whether treatment sequence could have differential effects on clinical outcomes for patients with osteoporosis, Dr. Cosman and colleagues looked at results from four clinical trials, using levels of bone turnover markers (procollagen type I N-terminal propeptide [PINP] and beta-isomer of the C-terminal telopeptide of type I collagen [beta-CTX]) and BMD gains in the total hip and spine as outcomes.

The two trials of romosozumab in treatment-naive women were the ARCH trial comparing romosozumab with alendronate in a double-blind phase for 1 year, followed by 1 year of open-label alendronate, and the FRAME trial, in which romosozumab was compared with placebo in a 1-year double-blind phase, followed by 1-year of open-label denosumab.

The two trials of romosozumab in women treated initially with antiresorptive agents were the STRUCTURE trial in which patients on oral bisphosphonates for at least 3 years or alendronate 70 mg weekly for 1 year were randomized to receive either romosozumab or teriparatide, and a phase 2 trial (NCT00896532) that included a 24-month romosozumab or placebo treatment phase followed by rerandomization to a 12-month extension phase with denosumab or placebo, followed by a 12-month retreatment phase with romosozumab, followed by a 24-month follow-on phase with zoledronic acid or no intervention.

Total hip BMD gains

In the ARCH trial, total hip BMD increased 6.2% with 1 year of romosozumab, and a cumulative total of 7.1% with the 2-year romosozumab/alendronate sequence. In the FRAME trial, patients gained 6.8% in total hip BMD after 1 year of romosozumab and a total of 8.8% after 2 years of romosozumab followed by denosumab.

In contrast, in the STRUCTURE trial, patients treated for 1 year or longer with alendronate and then with 1 year of romosozumab had a 2.9% BMD gain in the total hip. In the phase 2 trial, 1 year of romosozumab following 1 year of denosumab yielded a 0.9% BMD gain, for a total gain of 3.8% with the denosumab sequence.
 

Lumbar spine BMD gains

In ARCH, lumbar spine BMD increased 13.7% with 1 year of romosozumab, and a total of 15.2% with the 2-year sequence of romosozumab followed by alendronate. Similarly, in FRAME, patients gained 13.3% in BMD after a year of romosozumab, and total of 17.6% by the end of the 2-year romosozumab/denosumab sequence.

In contrast, in STRUCTURE, patients who had previously been on alendronate for at least 1 year had a gain of 9.8% after 1 year of romosozumab, and in the phase 2 study, patients who had been on denosumab for 1 year had an increase in lumbar spine BMD of 5.3% after 1 year on romosozumab, and a total gain of 11.5% at the end of the 2-year sequence.
 

Serum PINP and beta-CTX

Looking at the markers of bone turnover, the investigators saw that, in both ARCH and FRAME, PINP peaked at over 80% of baseline at 1 month, and then continued to steadily decline past 1 year. The beta-CTX nadir was 40%-50% below baseline at 1 year.

At the end of year 2, the PINP nadir was –67% with follow-on alendronate, and –69% with denosumab, and the beta-CTX nadir was –72% and –92%, respectively.

In the two trials where romosozumab was the follow-on therapy, however, the trends were distinctly different. In STRUCTURE, for example, PINP peaked at 141% of baseline at 1 month, and then returned toward baseline, whereas beta-CTX remained largely unchanged.

In the phase 2 trial, PINP peaked at 28% above baseline at 9 months, and then only slightly declined, and beta-CTX peaked at 211% at the end of 1 year of romosozumab.

Best used up front

“This study is important, because it suggests that for the three bone-building drugs that the best effects will really be attained on bone strength if the agents are used as initial therapy in very-high-risk patients. Those are people who have sustained fractures within the preceding 2 years, who had multiple fractures at any point in their adulthood, and who present with very low BMD, particularly if they have any associated clinical risk factors such as family history or other underlying diseases or medications that have detrimental effects on bone,” Dr. Cosman said at the briefing.

Marcy Bolster, MD, from the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston, and associate professor of medicine at Harvard Medical School in Boston, who was not involved in the study, commented that the study provides important information for clinicians who treat patients with osteoporosis.

“We have an increasing number of medications available for use in the treatment of patients with osteoporosis, and as we consider the importance of reducing fracture risk, the duration of therapy, the timing of a bisphosphonate holiday, it is essential that we consider any advantages to the order or sequence of our medications,” she said when asked for comment.

“This study provides evidence supporting the concept of the ‘anabolic window’ in which there is a demonstrated advantage in treating patients with an anabolic agent prior to treatment with an antiresorptive agent, and while gains in bone mineral density were achieved with either order of medication use, the gains were more dramatic with treatment with romosozumab as the first agent,” she added.

Dr. Bolster also noted it will be important to demonstrate reduction in fracture risk as well as gain in BMD.

The study was sponsored by Amgen, Astellas, and UCB. Dr. Cosman disclosed grants/research support from Amgen, and consulting fees and speaker activities for Amgen and Radius Health. Dr. Bolster disclosed relationships with AbbVie, Corbus, Cumberland, Gilead, Johnson & Johnson, and Pfizer.

SOURCE: Cosman F et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 1973.