The Food and Drug Administration has alerted the public to an increased risk of serious heart-related problems and cancer risk associated with the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR), based on early results from a safety clinical trial comparing tofacitinib and tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA).

The FDA is awaiting further results from the trial, but in a safety communication issued on Feb. 4, the agency advised patients not to discontinue tofacitinib without consulting their health care providers and advised health care professionals to weigh the risks and benefits when prescribing the drug and continue to follow the current prescribing information.

Tofacitinib was approved for treatment of RA in 2012 at a 5-mg dose. After this approval, the FDA required drug manufacturer Pfizer to conduct a safety clinical trial that included the 5-mg twice-daily dose and a 10-mg twice-daily dose that is currently approved only for ulcerative colitis. In addition to RA and ulcerative colitis, tofacitinib is approved for adults with active psoriatic arthritis and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis.

Pfizer announced partial results of the study, known as the ORAL Surveillance trial, in a press release on Jan. 27. The randomized trial included 4,362 RA patients aged 50 years and older who received either 5-mg or 10-mg doses of tofacitinib or a TNF inhibitor (adalimumab or etanercept).

The full results have yet to be released, but based on data from approximately 10,000 person-years for the combined tofacitinib groups and approximately 5,000 person-years for the TNF inhibitor group, the rate of major cardiovascular adverse events was significantly higher in the combined tofacitinib group, compared with the TNF inhibitor group (0.98 vs. 0.73 per 100 person-years; hazard ratio, 1.33). In addition, the rate of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNF inhibitor group (1.13 vs. 0.77 per 100 person-years; HR, 1.48).

In February 2019, the FDA issued a warning stating an increased risk of pulmonary embolism and death associated with the 10-mg twice-daily dose of tofacitinib, following interims results from the safety study.

In July 2019, the FDA added a boxed warning to tofacitinib advising of the increased risk for pulmonary embolism and death associated with the 10-mg twice-daily dose.

The FDA encouraged health care professionals and patients to report any side effects from tofacitinib or other medications through the FDA MedWatch program online or by phone at 1-800-332-1088.
 

Until nuances revealed, no change in practice

The preliminary study findings contain some nuances that are a bit complicated from a statistical standpoint, according to Daniel Furst, MD, professor emeritus of medicine at the University of California, Los Angeles; adjunct professor at the University of Washington, Seattle; and research professor at the University of Florence (Italy).

This is supposed to be a noninferiority study, so something might not be noninferior, “but that doesn’t mean it is inferior,” explained Dr. Furst, who is also a member of the MDedge Rheumatology Editorial Advisory Board.

Dr. Furst said he was surprised by the study findings, because “I didn’t expect there to be any differences, and in fact it is not clear how great the differences are” among the groups in the study, he said.

When the complete findings are released, in one of the instances, “the statistics may show a very small statistical difference that indicates we may have to be more careful in this particularly high-risk group,” Dr. Furst noted.

“When we understand the data more closely, we may find that there are some nuances we need to be careful about,” he said. However, “until those data are out, I would not make any changes in my practice.”

Whether the current study findings represent a class effect is “impossible to say,” since tofacitinib affects three enzymes, while other JAK inhibitors affect only one or two, he noted.

Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech.

The Food and Drug Administration has alerted the public to an increased risk of serious heart-related problems and cancer risk associated with the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR), based on early results from a safety clinical trial comparing tofacitinib and tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA).

The FDA is awaiting further results from the trial, but in a safety communication issued on Feb. 4, the agency advised patients not to discontinue tofacitinib without consulting their health care providers and advised health care professionals to weigh the risks and benefits when prescribing the drug and continue to follow the current prescribing information.

Tofacitinib was approved for treatment of RA in 2012 at a 5-mg dose. After this approval, the FDA required drug manufacturer Pfizer to conduct a safety clinical trial that included the 5-mg twice-daily dose and a 10-mg twice-daily dose that is currently approved only for ulcerative colitis. In addition to RA and ulcerative colitis, tofacitinib is approved for adults with active psoriatic arthritis and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis.

Pfizer announced partial results of the study, known as the ORAL Surveillance trial, in a press release on Jan. 27. The randomized trial included 4,362 RA patients aged 50 years and older who received either 5-mg or 10-mg doses of tofacitinib or a TNF inhibitor (adalimumab or etanercept).

The full results have yet to be released, but based on data from approximately 10,000 person-years for the combined tofacitinib groups and approximately 5,000 person-years for the TNF inhibitor group, the rate of major cardiovascular adverse events was significantly higher in the combined tofacitinib group, compared with the TNF inhibitor group (0.98 vs. 0.73 per 100 person-years; hazard ratio, 1.33). In addition, the rate of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNF inhibitor group (1.13 vs. 0.77 per 100 person-years; HR, 1.48).

In February 2019, the FDA issued a warning stating an increased risk of pulmonary embolism and death associated with the 10-mg twice-daily dose of tofacitinib, following interims results from the safety study.

In July 2019, the FDA added a boxed warning to tofacitinib advising of the increased risk for pulmonary embolism and death associated with the 10-mg twice-daily dose.

The FDA encouraged health care professionals and patients to report any side effects from tofacitinib or other medications through the FDA MedWatch program online or by phone at 1-800-332-1088.
 

Until nuances revealed, no change in practice

The preliminary study findings contain some nuances that are a bit complicated from a statistical standpoint, according to Daniel Furst, MD, professor emeritus of medicine at the University of California, Los Angeles; adjunct professor at the University of Washington, Seattle; and research professor at the University of Florence (Italy).

This is supposed to be a noninferiority study, so something might not be noninferior, “but that doesn’t mean it is inferior,” explained Dr. Furst, who is also a member of the MDedge Rheumatology Editorial Advisory Board.

Dr. Furst said he was surprised by the study findings, because “I didn’t expect there to be any differences, and in fact it is not clear how great the differences are” among the groups in the study, he said.

When the complete findings are released, in one of the instances, “the statistics may show a very small statistical difference that indicates we may have to be more careful in this particularly high-risk group,” Dr. Furst noted.

“When we understand the data more closely, we may find that there are some nuances we need to be careful about,” he said. However, “until those data are out, I would not make any changes in my practice.”

Whether the current study findings represent a class effect is “impossible to say,” since tofacitinib affects three enzymes, while other JAK inhibitors affect only one or two, he noted.

Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech.

The Food and Drug Administration has alerted the public to an increased risk of serious heart-related problems and cancer risk associated with the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR), based on early results from a safety clinical trial comparing tofacitinib and tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA).

The FDA is awaiting further results from the trial, but in a safety communication issued on Feb. 4, the agency advised patients not to discontinue tofacitinib without consulting their health care providers and advised health care professionals to weigh the risks and benefits when prescribing the drug and continue to follow the current prescribing information.

Tofacitinib was approved for treatment of RA in 2012 at a 5-mg dose. After this approval, the FDA required drug manufacturer Pfizer to conduct a safety clinical trial that included the 5-mg twice-daily dose and a 10-mg twice-daily dose that is currently approved only for ulcerative colitis. In addition to RA and ulcerative colitis, tofacitinib is approved for adults with active psoriatic arthritis and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis.

Pfizer announced partial results of the study, known as the ORAL Surveillance trial, in a press release on Jan. 27. The randomized trial included 4,362 RA patients aged 50 years and older who received either 5-mg or 10-mg doses of tofacitinib or a TNF inhibitor (adalimumab or etanercept).

The full results have yet to be released, but based on data from approximately 10,000 person-years for the combined tofacitinib groups and approximately 5,000 person-years for the TNF inhibitor group, the rate of major cardiovascular adverse events was significantly higher in the combined tofacitinib group, compared with the TNF inhibitor group (0.98 vs. 0.73 per 100 person-years; hazard ratio, 1.33). In addition, the rate of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNF inhibitor group (1.13 vs. 0.77 per 100 person-years; HR, 1.48).

In February 2019, the FDA issued a warning stating an increased risk of pulmonary embolism and death associated with the 10-mg twice-daily dose of tofacitinib, following interims results from the safety study.

In July 2019, the FDA added a boxed warning to tofacitinib advising of the increased risk for pulmonary embolism and death associated with the 10-mg twice-daily dose.

The FDA encouraged health care professionals and patients to report any side effects from tofacitinib or other medications through the FDA MedWatch program online or by phone at 1-800-332-1088.
 

Until nuances revealed, no change in practice

The preliminary study findings contain some nuances that are a bit complicated from a statistical standpoint, according to Daniel Furst, MD, professor emeritus of medicine at the University of California, Los Angeles; adjunct professor at the University of Washington, Seattle; and research professor at the University of Florence (Italy).

This is supposed to be a noninferiority study, so something might not be noninferior, “but that doesn’t mean it is inferior,” explained Dr. Furst, who is also a member of the MDedge Rheumatology Editorial Advisory Board.

Dr. Furst said he was surprised by the study findings, because “I didn’t expect there to be any differences, and in fact it is not clear how great the differences are” among the groups in the study, he said.

When the complete findings are released, in one of the instances, “the statistics may show a very small statistical difference that indicates we may have to be more careful in this particularly high-risk group,” Dr. Furst noted.

“When we understand the data more closely, we may find that there are some nuances we need to be careful about,” he said. However, “until those data are out, I would not make any changes in my practice.”

Whether the current study findings represent a class effect is “impossible to say,” since tofacitinib affects three enzymes, while other JAK inhibitors affect only one or two, he noted.

Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech.

The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.

“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.

“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous and will lead to a new stratification option.”
 

Rationale and study details

Dr. Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.

Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.

The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.

Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.

Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.

Phase 2 results

Sotorasib “demonstrated early, deep, and durable responses,” Dr. Li said.

In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.

The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.

“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Dr. Li said.

The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Dr. Li said.

TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.

Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).

“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Dr. Li said.

A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.

The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Dr. Li disclosed relationships with Amgen and many other companies. Dr. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.

“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.

“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous and will lead to a new stratification option.”
 

Rationale and study details

Dr. Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.

Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.

The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.

Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.

Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.

Phase 2 results

Sotorasib “demonstrated early, deep, and durable responses,” Dr. Li said.

In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.

The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.

“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Dr. Li said.

The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Dr. Li said.

TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.

Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).

“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Dr. Li said.

A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.

The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Dr. Li disclosed relationships with Amgen and many other companies. Dr. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.

“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.

“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous and will lead to a new stratification option.”
 

Rationale and study details

Dr. Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.

Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.

The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.

Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.

Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.

Phase 2 results

Sotorasib “demonstrated early, deep, and durable responses,” Dr. Li said.

In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.

The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.

“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Dr. Li said.

The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Dr. Li said.

TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.

Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).

“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Dr. Li said.

A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.

The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Dr. Li disclosed relationships with Amgen and many other companies. Dr. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.

Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.

“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.

Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.

“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.

The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.

“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
 

Meta-analysis of 17 studies examining LT4 discontinuation 

Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.   

With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.

To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.

With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.

The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).

Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.

Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.

Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.

Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.

“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
 

More work needed to determine best way to taper down LT4

The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted

“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.

“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”

In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.

The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
 

Collaborative approach to ‘deprescribing’ suggested

To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.

“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.

When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.

The authors have reported no relevant financial relationships.

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

Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.

Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.

“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.

Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.

“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.

The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.

“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
 

Meta-analysis of 17 studies examining LT4 discontinuation 

Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.   

With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.

To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.

With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.

The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).

Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.

Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.

Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.

Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.

“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
 

More work needed to determine best way to taper down LT4

The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted

“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.

“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”

In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.

The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
 

Collaborative approach to ‘deprescribing’ suggested

To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.

“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.

When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.

The authors have reported no relevant financial relationships.

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

Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.

Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.

“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.

Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.

“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.

The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.

“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
 

Meta-analysis of 17 studies examining LT4 discontinuation 

Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.   

With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.

To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.

With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.

The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).

Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.

Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.

Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.

Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.

“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
 

More work needed to determine best way to taper down LT4

The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted

“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.

“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”

In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.

The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
 

Collaborative approach to ‘deprescribing’ suggested

To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.

“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.

When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.

The authors have reported no relevant financial relationships.

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

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

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

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

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

The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.

The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).

The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.

The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.

The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%. 

“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”

Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.

The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.

Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.

Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.

A postmarketing study to further evaluate the long-term safety will also be required.

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

For decades, opioids have been a mainstay in the management of pain after total joint arthroplasty. In the past 10 years, however, opioid prescribing has come under increased scrutiny due to a rise in rates of opioid abuse, pill diversion, and opioid-related deaths.^1,2 Opioids are associated with adverse effects, including nausea, vomiting, constipation, apathy, and respiratory depression, all of which influence arthroplasty outcomes and affect the patient experience. Although primary care groups account for nearly half of prescriptions written, orthopedic surgeons have the third highest per capita rate of opioid prescribing of all medical specialties.^3,4 This puts orthopedic surgeons, particularly those who perform routine procedures, in an opportune but challenging position to confront this problem through novel pain management strategies.

Approximately 1 million total knee arthroplasties (TKAs) are performed in the US every year, and the US Department of Veterans Affairs (VA) health system performs about 10,000 hip and knee joint replacements.^5,6 There is no standardization of opioid prescribing in the postoperative period following these procedures, and studies have reported a wide variation in prescribing habits even within a single institution for a specific surgery.⁷ Patients who undergo TKA are at particularly high risk of long-term opioid use if they are on continuous opioids at the time of surgery; this is problematic in a VA patient population in which at least 16% of patients are prescribed opioids in a given year.⁸ Furthermore, veterans are twice as likely as nonveterans to die of an accidental overdose.⁹ Despite these risks, opioids remain a cornerstone of postoperative pain management both within and outside of the VA.¹⁰

In 2018, to limit unnecessary prescribing of opioid pain medication, the total joint service at the VA Portland Health Care System (VAPHCS) in Oregon implemented the Minimizing Opioids after Joint Operation (MOJO) postoperative pain protocol. The goal of the protocol was to reduce opioid use following TKA. The objectives were to provide safe, appropriate analgesia while allowing early mobilization and discharge without a concomitant increase in readmissions or emergency department (ED) visits. The purpose of this retrospective chart review was to compare the efficacy of the MOJO protocol with our historical experience and report our preliminary results.

Methods

Institutional review board approval was obtained to retrospectively review the medical records of patients who had undergone TKA surgery during 2018 at VAPHCS. The MOJO protocol was composed of several simultaneous changes. The centerpiece of the new protocol was a drastic decrease in routine prescription of postoperative opioids (Table 1). Other changes included instructing patients to reduce the use of preoperative opioid pain medication 6 weeks before surgery with a goal of no opioid consumption, perform daily sets of preoperative exercises, and attend a preoperative consultation/education session with a nurse coordinator to emphasize early recovery and discharge. In patients with chronic use of opioid pain medication (particularly those for whom the medication had been prescribed for other sources of pain, such as lumbar back pain), the goal was daily opioid use of ≤ 30 morphine equivalent doses (MEDs). During the inpatient stay, we stopped prescribing prophylactic pain medication prior to physical therapy (PT).

We encouraged preoperative optimization of muscle strength by giving instructions for 4 to 8 weeks of daily exercises (Appendix). We introduced perioperative adductor canal blocks (at the discretion of the anesthesia team) and transitioned to surgery without a tourniquet. Patients in both groups received intraoperative antibiotics and IV tranexamic acid (TXA); the MOJO group also received topical TXA.

Further patient care optimization included providing patients with a team-based approach, which consisted of nurse coordinators, physician assistants and nurse practitioners, residents, and the attending surgeon. Our team reviews the planned pain management protocol, perioperative expectations, criteria for discharge, and anticipated surgical outcomes with the patient during their preoperative visits. On postoperative day 1, these members round as a team to encourage patients in their immediate postoperative recovery and rehabilitation. During rounds, the team assesses whether the patient meets the criteria for discharge, adjusting the pain management protocol if necessary.

Results

Forty patients met the inclusion criteria, evenly divided between those undergoing TKA before and after instituting the MOJO protocol (Table 2). A single patient in the MOJO group died and was excluded. A patient who underwent bilateral TKA also was excluded. Both groups reflected the male predominance of the VA patient population. MOJO patients tended to have lower BMIs (34 vs 30, P < .01). All patients indicated for surgery with preoperative opioid use were able to titrate down to their preoperative goal as verified by prescriptions filled at VA pharmacies. Twelve of the patients in the MOJO group received adductor canal blocks.

Results of t tests and χ² tests comparing primary and secondary endpoints are listed in Table 3. Differences between the daily MEDs given in the historical and MOJO groups are shown. There were significant differences between the pre-MOJO and MOJO groups with regard to daily inpatient MEDs (82 mg vs 29 mg, P < .01) and total inpatient MEDs (306 mg vs 32 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 3.9, P < .01), decreased LOS (4.4 days vs 1.2 days, P < .01), a trend toward fewer total ED visits (6 vs 2, P = .24), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). There were no blood transfusions in either group.

Discussion

Our results demonstrate that a multimodal approach to significantly reduce postoperative opioid use in patients with TKA is possible without increasing readmissions or ED visits for pain control. The patients in the MOJO group had a faster recovery, earlier discharge, and less use of postoperative opioid medication. Our approach to postoperative pain management was divided into 2 main categories: patient optimization and surgical optimization.

Patient Selection

Besides the standard evaluation and optimization of patients’ medical conditions, identifying and optimizing at-risk patients before surgery was a critical component of our protocol. Managing postoperative pain in patients with prior opioid use is an intractable challenge in orthopedic surgery. Patients with a history of chronic pain and preoperative use of opioid medications remain at higher risk of postoperative chronic pain and persistent use of opioid medication despite no obvious surgical complications.⁸ In a sample of > 6,000 veterans who underwent TKA at VA hospitals in 2014, 57% of the patients with daily use of opioids in the 90 days before surgery remained on opioids 1 year after surgery (vs 2 % in patients not on long-term opioids).⁸ This relationship between pre- and postoperative opioid use also was dose dependent.¹²

Furthermore, those with high preoperative use may experience worse outcomes relative to the opioid naive population as measured by arthritis-specific pain indices.¹³ In a well-powered retrospective study of patients who underwent elective orthopedic procedures, preoperative opioid abuse or dependence (determined by the International Classification of Diseases, Ninth Revision diagnosis) increased inpatient mortality, aggregate morbidity, surgical site infection, myocardial infarction, and LOS.¹⁴ Preoperative opioid use also has been associated with increased risk of ED visits, readmission, infection, stiffness, and aseptic revision.¹⁵ In patients with TKA in the VA specifically, preoperative opioid use (> 3 months in the prior year) was associated with increased revision rates that were even higher than those for patients with diabetes mellitus.¹⁶

Patient Education

Based on this evidence, we instruct patients to reduce their preoperative opioid dosing to zero (for patients with joint pain) or < 30 MED (for patients using opioids for other reasons). Although preoperative reduction of opioid use has been shown to improve outcomes after TKA, pain subspecialty recommendations for patients with chronic opioid use recommend considering adjunctive therapies, including transcutaneous electrical nerve stimulation, cognitive behavioral therapy, gabapentin, or ketamine.^17,18 Through patient education our team has been successful in decreasing preoperative opioid use without adding other drugs or modalities.

Patient Optimization

Preoperative patient optimization included 4 to 8 weeks of daily sets of physical activity instructions (prehab) to improve the musculoskeletal function. These instructions are given to patients 4 to 8 weeks before surgery and aim to improve the patient’s balance, mobility, and functional ability (Appendix). Meta-analysis has shown that patients who undergo preoperative PT have a small but statistically significant decrease in postoperative pain at 4 weeks, though this does not persist beyond that period.¹⁹

We did note a lower BMI in patients in the MOJO group. Though this has the potential to be a confounder, a study of BMI in > 4,000 patients who underwent joint replacement surgery has shown that BMI is not associated with differences in postoperative pain.²⁰

Surgeon and Surgical-Related Variables

Patients in the MOJO group had increased use of adductor canal blocks. A 2017 meta-analysis of 12,530 patients comparing analgesic modalities found that peripheral nerve blocks targeting multiple nerves (eg, femoral/sciatic) decreased pain at rest, decreased opioid consumption, and improved range of motion postoperatively.²¹ Also, these were found to be superior to single nerve blocks, periarticular infiltration, and epidural blocks.²¹ However, major nerve and epidural blocks affecting the lower extremity may increase the risk of falls and prolong LOS.^22,23 The preferred peripheral block at VAPHCS is a single shot ultrasound-guided adductor canal block before the induction of general or spinal anesthesia. A randomized controlled trial has demonstrated superiority of this block to the femoral nerve block with regard to postoperative quadriceps strength, conferring the theoretical advantage of decreased fall risk and ability to participate in immediate PT.²⁴ Although we are unable to confirm an association between anesthetic modalities and opioid burden, our clinical impression is that blocks were effective at reducing immediate postoperative pain. However, among MOJO patients there were no differences in patients with and without blocks for either pain (4.2 vs 3.8, P = .69) or opioid consumption (28.8 vs 33.0, P = .72) after surgery, though our study was not powered to detect a difference in this restricted subgroup.

Patients who frequently had reported postoperative thigh pain prompted us to make changes in our surgical technique, performing TKA without use of a tourniquet. Tourniquet use has been associated with an increased risk of thigh pain after TKA by multiple authors.^25,26 Postoperative thigh pain also is pressure dependent.²⁷ In addition, its use may be associated with a slightly increased risk of thromboembolic events and delayed functional recovery.^28,29

Because postoperative hemarthrosis is associated with more pain and reduced joint recovery function, we used topical TXA to reduce postoperative surgical site and joint hematoma. TXA (either oral, IV, or topical) during TKA is used to control postoperative bleeding primarily and decrease the need for transfusion without concomitant increase in thromboembolic events.^30,31 Topical TXA may be more effective than IV, particularly in the immediate postoperative period.³² Although pain typically is not an endpoint in studies of TXA, a prospective study of 48 patients showed evidence that its use may be associated with decreased postoperative pain in the first 24 hours after surgery (though not after).³³ Finally, the use of intra-articular injection has evolved in our clinical practice, but literature is lacking with regard to its efficacy; more studies are needed to determine its effect relative to no injection. We have not seen any benefits to using cryotherapy in our practice; considering the costs for equipment and health care provider time, cryotherapy was not included in our new protocol.

Limitations

This is a nonrandomized retrospective single-institution study. Our study population is composed of mostly males with military experience and is not necessarily a representative sample of the general population eligible for joint arthroplasty. Our primary endpoint (reduction of opioid use postoperatively) also was a cornerstone of our intervention. To account for this, we set a very large effect size in our power analysis and evaluated multiple secondary endpoints to determine whether postoperative pain remained well controlled and complications/readmission minimized with our interventions. Because our intervention was multimodal, our study cannot make conclusions about the effect of a particular component of our treatment strategy. We did not measure or compare functional outcomes between both groups, which offers an opportunity for further research.

These limitations are balanced by several strengths. Our cohort was well controlled with respect to the dose and type of drug used. There is staff dedicated to postoperative telephone follow-up after discharge, and veterans are apt to seek care within the VA health care system, which improves case finding for complications and ED visits. No patients were lost to follow-up. Moreover, our drastic reduction in opioid use is promising enough to warrant reporting, while the broader orthopedic literature explores the relative impact of each variable.

Conclusions

The MOJO protocol has been effective for reducing postoperative opioid use after TKA without compromising effective pain management. The drastic reduction in the postoperative use of opioid pain medications and LOS have contributed to a cultural shift within our department, comprehensive team approach, multimodal pain management, and preoperative patient optimization. Further investigations are required to assess the impact of each intervention on observed outcomes. However, the framework and routines are applicable to other institutions and surgical specialties.

Acknowledgments

The authors recognize Derek Bond, MD, for his help in creating the MOJO acronym.

For decades, opioids have been a mainstay in the management of pain after total joint arthroplasty. In the past 10 years, however, opioid prescribing has come under increased scrutiny due to a rise in rates of opioid abuse, pill diversion, and opioid-related deaths.^1,2 Opioids are associated with adverse effects, including nausea, vomiting, constipation, apathy, and respiratory depression, all of which influence arthroplasty outcomes and affect the patient experience. Although primary care groups account for nearly half of prescriptions written, orthopedic surgeons have the third highest per capita rate of opioid prescribing of all medical specialties.^3,4 This puts orthopedic surgeons, particularly those who perform routine procedures, in an opportune but challenging position to confront this problem through novel pain management strategies.

Approximately 1 million total knee arthroplasties (TKAs) are performed in the US every year, and the US Department of Veterans Affairs (VA) health system performs about 10,000 hip and knee joint replacements.^5,6 There is no standardization of opioid prescribing in the postoperative period following these procedures, and studies have reported a wide variation in prescribing habits even within a single institution for a specific surgery.⁷ Patients who undergo TKA are at particularly high risk of long-term opioid use if they are on continuous opioids at the time of surgery; this is problematic in a VA patient population in which at least 16% of patients are prescribed opioids in a given year.⁸ Furthermore, veterans are twice as likely as nonveterans to die of an accidental overdose.⁹ Despite these risks, opioids remain a cornerstone of postoperative pain management both within and outside of the VA.¹⁰

In 2018, to limit unnecessary prescribing of opioid pain medication, the total joint service at the VA Portland Health Care System (VAPHCS) in Oregon implemented the Minimizing Opioids after Joint Operation (MOJO) postoperative pain protocol. The goal of the protocol was to reduce opioid use following TKA. The objectives were to provide safe, appropriate analgesia while allowing early mobilization and discharge without a concomitant increase in readmissions or emergency department (ED) visits. The purpose of this retrospective chart review was to compare the efficacy of the MOJO protocol with our historical experience and report our preliminary results.

Methods

Institutional review board approval was obtained to retrospectively review the medical records of patients who had undergone TKA surgery during 2018 at VAPHCS. The MOJO protocol was composed of several simultaneous changes. The centerpiece of the new protocol was a drastic decrease in routine prescription of postoperative opioids (Table 1). Other changes included instructing patients to reduce the use of preoperative opioid pain medication 6 weeks before surgery with a goal of no opioid consumption, perform daily sets of preoperative exercises, and attend a preoperative consultation/education session with a nurse coordinator to emphasize early recovery and discharge. In patients with chronic use of opioid pain medication (particularly those for whom the medication had been prescribed for other sources of pain, such as lumbar back pain), the goal was daily opioid use of ≤ 30 morphine equivalent doses (MEDs). During the inpatient stay, we stopped prescribing prophylactic pain medication prior to physical therapy (PT).

We encouraged preoperative optimization of muscle strength by giving instructions for 4 to 8 weeks of daily exercises (Appendix). We introduced perioperative adductor canal blocks (at the discretion of the anesthesia team) and transitioned to surgery without a tourniquet. Patients in both groups received intraoperative antibiotics and IV tranexamic acid (TXA); the MOJO group also received topical TXA.

Further patient care optimization included providing patients with a team-based approach, which consisted of nurse coordinators, physician assistants and nurse practitioners, residents, and the attending surgeon. Our team reviews the planned pain management protocol, perioperative expectations, criteria for discharge, and anticipated surgical outcomes with the patient during their preoperative visits. On postoperative day 1, these members round as a team to encourage patients in their immediate postoperative recovery and rehabilitation. During rounds, the team assesses whether the patient meets the criteria for discharge, adjusting the pain management protocol if necessary.

Results

Forty patients met the inclusion criteria, evenly divided between those undergoing TKA before and after instituting the MOJO protocol (Table 2). A single patient in the MOJO group died and was excluded. A patient who underwent bilateral TKA also was excluded. Both groups reflected the male predominance of the VA patient population. MOJO patients tended to have lower BMIs (34 vs 30, P < .01). All patients indicated for surgery with preoperative opioid use were able to titrate down to their preoperative goal as verified by prescriptions filled at VA pharmacies. Twelve of the patients in the MOJO group received adductor canal blocks.

Results of t tests and χ² tests comparing primary and secondary endpoints are listed in Table 3. Differences between the daily MEDs given in the historical and MOJO groups are shown. There were significant differences between the pre-MOJO and MOJO groups with regard to daily inpatient MEDs (82 mg vs 29 mg, P < .01) and total inpatient MEDs (306 mg vs 32 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 3.9, P < .01), decreased LOS (4.4 days vs 1.2 days, P < .01), a trend toward fewer total ED visits (6 vs 2, P = .24), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). There were no blood transfusions in either group.

Discussion

Our results demonstrate that a multimodal approach to significantly reduce postoperative opioid use in patients with TKA is possible without increasing readmissions or ED visits for pain control. The patients in the MOJO group had a faster recovery, earlier discharge, and less use of postoperative opioid medication. Our approach to postoperative pain management was divided into 2 main categories: patient optimization and surgical optimization.

Patient Selection

Besides the standard evaluation and optimization of patients’ medical conditions, identifying and optimizing at-risk patients before surgery was a critical component of our protocol. Managing postoperative pain in patients with prior opioid use is an intractable challenge in orthopedic surgery. Patients with a history of chronic pain and preoperative use of opioid medications remain at higher risk of postoperative chronic pain and persistent use of opioid medication despite no obvious surgical complications.⁸ In a sample of > 6,000 veterans who underwent TKA at VA hospitals in 2014, 57% of the patients with daily use of opioids in the 90 days before surgery remained on opioids 1 year after surgery (vs 2 % in patients not on long-term opioids).⁸ This relationship between pre- and postoperative opioid use also was dose dependent.¹²

Furthermore, those with high preoperative use may experience worse outcomes relative to the opioid naive population as measured by arthritis-specific pain indices.¹³ In a well-powered retrospective study of patients who underwent elective orthopedic procedures, preoperative opioid abuse or dependence (determined by the International Classification of Diseases, Ninth Revision diagnosis) increased inpatient mortality, aggregate morbidity, surgical site infection, myocardial infarction, and LOS.¹⁴ Preoperative opioid use also has been associated with increased risk of ED visits, readmission, infection, stiffness, and aseptic revision.¹⁵ In patients with TKA in the VA specifically, preoperative opioid use (> 3 months in the prior year) was associated with increased revision rates that were even higher than those for patients with diabetes mellitus.¹⁶

Patient Education

Based on this evidence, we instruct patients to reduce their preoperative opioid dosing to zero (for patients with joint pain) or < 30 MED (for patients using opioids for other reasons). Although preoperative reduction of opioid use has been shown to improve outcomes after TKA, pain subspecialty recommendations for patients with chronic opioid use recommend considering adjunctive therapies, including transcutaneous electrical nerve stimulation, cognitive behavioral therapy, gabapentin, or ketamine.^17,18 Through patient education our team has been successful in decreasing preoperative opioid use without adding other drugs or modalities.

Patient Optimization

Preoperative patient optimization included 4 to 8 weeks of daily sets of physical activity instructions (prehab) to improve the musculoskeletal function. These instructions are given to patients 4 to 8 weeks before surgery and aim to improve the patient’s balance, mobility, and functional ability (Appendix). Meta-analysis has shown that patients who undergo preoperative PT have a small but statistically significant decrease in postoperative pain at 4 weeks, though this does not persist beyond that period.¹⁹

We did note a lower BMI in patients in the MOJO group. Though this has the potential to be a confounder, a study of BMI in > 4,000 patients who underwent joint replacement surgery has shown that BMI is not associated with differences in postoperative pain.²⁰

Surgeon and Surgical-Related Variables

Patients in the MOJO group had increased use of adductor canal blocks. A 2017 meta-analysis of 12,530 patients comparing analgesic modalities found that peripheral nerve blocks targeting multiple nerves (eg, femoral/sciatic) decreased pain at rest, decreased opioid consumption, and improved range of motion postoperatively.²¹ Also, these were found to be superior to single nerve blocks, periarticular infiltration, and epidural blocks.²¹ However, major nerve and epidural blocks affecting the lower extremity may increase the risk of falls and prolong LOS.^22,23 The preferred peripheral block at VAPHCS is a single shot ultrasound-guided adductor canal block before the induction of general or spinal anesthesia. A randomized controlled trial has demonstrated superiority of this block to the femoral nerve block with regard to postoperative quadriceps strength, conferring the theoretical advantage of decreased fall risk and ability to participate in immediate PT.²⁴ Although we are unable to confirm an association between anesthetic modalities and opioid burden, our clinical impression is that blocks were effective at reducing immediate postoperative pain. However, among MOJO patients there were no differences in patients with and without blocks for either pain (4.2 vs 3.8, P = .69) or opioid consumption (28.8 vs 33.0, P = .72) after surgery, though our study was not powered to detect a difference in this restricted subgroup.

Patients who frequently had reported postoperative thigh pain prompted us to make changes in our surgical technique, performing TKA without use of a tourniquet. Tourniquet use has been associated with an increased risk of thigh pain after TKA by multiple authors.^25,26 Postoperative thigh pain also is pressure dependent.²⁷ In addition, its use may be associated with a slightly increased risk of thromboembolic events and delayed functional recovery.^28,29

Because postoperative hemarthrosis is associated with more pain and reduced joint recovery function, we used topical TXA to reduce postoperative surgical site and joint hematoma. TXA (either oral, IV, or topical) during TKA is used to control postoperative bleeding primarily and decrease the need for transfusion without concomitant increase in thromboembolic events.^30,31 Topical TXA may be more effective than IV, particularly in the immediate postoperative period.³² Although pain typically is not an endpoint in studies of TXA, a prospective study of 48 patients showed evidence that its use may be associated with decreased postoperative pain in the first 24 hours after surgery (though not after).³³ Finally, the use of intra-articular injection has evolved in our clinical practice, but literature is lacking with regard to its efficacy; more studies are needed to determine its effect relative to no injection. We have not seen any benefits to using cryotherapy in our practice; considering the costs for equipment and health care provider time, cryotherapy was not included in our new protocol.

Limitations

This is a nonrandomized retrospective single-institution study. Our study population is composed of mostly males with military experience and is not necessarily a representative sample of the general population eligible for joint arthroplasty. Our primary endpoint (reduction of opioid use postoperatively) also was a cornerstone of our intervention. To account for this, we set a very large effect size in our power analysis and evaluated multiple secondary endpoints to determine whether postoperative pain remained well controlled and complications/readmission minimized with our interventions. Because our intervention was multimodal, our study cannot make conclusions about the effect of a particular component of our treatment strategy. We did not measure or compare functional outcomes between both groups, which offers an opportunity for further research.

These limitations are balanced by several strengths. Our cohort was well controlled with respect to the dose and type of drug used. There is staff dedicated to postoperative telephone follow-up after discharge, and veterans are apt to seek care within the VA health care system, which improves case finding for complications and ED visits. No patients were lost to follow-up. Moreover, our drastic reduction in opioid use is promising enough to warrant reporting, while the broader orthopedic literature explores the relative impact of each variable.

Conclusions

The MOJO protocol has been effective for reducing postoperative opioid use after TKA without compromising effective pain management. The drastic reduction in the postoperative use of opioid pain medications and LOS have contributed to a cultural shift within our department, comprehensive team approach, multimodal pain management, and preoperative patient optimization. Further investigations are required to assess the impact of each intervention on observed outcomes. However, the framework and routines are applicable to other institutions and surgical specialties.

Acknowledgments

The authors recognize Derek Bond, MD, for his help in creating the MOJO acronym.

For decades, opioids have been a mainstay in the management of pain after total joint arthroplasty. In the past 10 years, however, opioid prescribing has come under increased scrutiny due to a rise in rates of opioid abuse, pill diversion, and opioid-related deaths.^1,2 Opioids are associated with adverse effects, including nausea, vomiting, constipation, apathy, and respiratory depression, all of which influence arthroplasty outcomes and affect the patient experience. Although primary care groups account for nearly half of prescriptions written, orthopedic surgeons have the third highest per capita rate of opioid prescribing of all medical specialties.^3,4 This puts orthopedic surgeons, particularly those who perform routine procedures, in an opportune but challenging position to confront this problem through novel pain management strategies.

Approximately 1 million total knee arthroplasties (TKAs) are performed in the US every year, and the US Department of Veterans Affairs (VA) health system performs about 10,000 hip and knee joint replacements.^5,6 There is no standardization of opioid prescribing in the postoperative period following these procedures, and studies have reported a wide variation in prescribing habits even within a single institution for a specific surgery.⁷ Patients who undergo TKA are at particularly high risk of long-term opioid use if they are on continuous opioids at the time of surgery; this is problematic in a VA patient population in which at least 16% of patients are prescribed opioids in a given year.⁸ Furthermore, veterans are twice as likely as nonveterans to die of an accidental overdose.⁹ Despite these risks, opioids remain a cornerstone of postoperative pain management both within and outside of the VA.¹⁰

In 2018, to limit unnecessary prescribing of opioid pain medication, the total joint service at the VA Portland Health Care System (VAPHCS) in Oregon implemented the Minimizing Opioids after Joint Operation (MOJO) postoperative pain protocol. The goal of the protocol was to reduce opioid use following TKA. The objectives were to provide safe, appropriate analgesia while allowing early mobilization and discharge without a concomitant increase in readmissions or emergency department (ED) visits. The purpose of this retrospective chart review was to compare the efficacy of the MOJO protocol with our historical experience and report our preliminary results.

Methods

Institutional review board approval was obtained to retrospectively review the medical records of patients who had undergone TKA surgery during 2018 at VAPHCS. The MOJO protocol was composed of several simultaneous changes. The centerpiece of the new protocol was a drastic decrease in routine prescription of postoperative opioids (Table 1). Other changes included instructing patients to reduce the use of preoperative opioid pain medication 6 weeks before surgery with a goal of no opioid consumption, perform daily sets of preoperative exercises, and attend a preoperative consultation/education session with a nurse coordinator to emphasize early recovery and discharge. In patients with chronic use of opioid pain medication (particularly those for whom the medication had been prescribed for other sources of pain, such as lumbar back pain), the goal was daily opioid use of ≤ 30 morphine equivalent doses (MEDs). During the inpatient stay, we stopped prescribing prophylactic pain medication prior to physical therapy (PT).

We encouraged preoperative optimization of muscle strength by giving instructions for 4 to 8 weeks of daily exercises (Appendix). We introduced perioperative adductor canal blocks (at the discretion of the anesthesia team) and transitioned to surgery without a tourniquet. Patients in both groups received intraoperative antibiotics and IV tranexamic acid (TXA); the MOJO group also received topical TXA.

Further patient care optimization included providing patients with a team-based approach, which consisted of nurse coordinators, physician assistants and nurse practitioners, residents, and the attending surgeon. Our team reviews the planned pain management protocol, perioperative expectations, criteria for discharge, and anticipated surgical outcomes with the patient during their preoperative visits. On postoperative day 1, these members round as a team to encourage patients in their immediate postoperative recovery and rehabilitation. During rounds, the team assesses whether the patient meets the criteria for discharge, adjusting the pain management protocol if necessary.

Results

Forty patients met the inclusion criteria, evenly divided between those undergoing TKA before and after instituting the MOJO protocol (Table 2). A single patient in the MOJO group died and was excluded. A patient who underwent bilateral TKA also was excluded. Both groups reflected the male predominance of the VA patient population. MOJO patients tended to have lower BMIs (34 vs 30, P < .01). All patients indicated for surgery with preoperative opioid use were able to titrate down to their preoperative goal as verified by prescriptions filled at VA pharmacies. Twelve of the patients in the MOJO group received adductor canal blocks.

Results of t tests and χ² tests comparing primary and secondary endpoints are listed in Table 3. Differences between the daily MEDs given in the historical and MOJO groups are shown. There were significant differences between the pre-MOJO and MOJO groups with regard to daily inpatient MEDs (82 mg vs 29 mg, P < .01) and total inpatient MEDs (306 mg vs 32 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 3.9, P < .01), decreased LOS (4.4 days vs 1.2 days, P < .01), a trend toward fewer total ED visits (6 vs 2, P = .24), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). There were no blood transfusions in either group.

Discussion

Our results demonstrate that a multimodal approach to significantly reduce postoperative opioid use in patients with TKA is possible without increasing readmissions or ED visits for pain control. The patients in the MOJO group had a faster recovery, earlier discharge, and less use of postoperative opioid medication. Our approach to postoperative pain management was divided into 2 main categories: patient optimization and surgical optimization.

Patient Selection

Besides the standard evaluation and optimization of patients’ medical conditions, identifying and optimizing at-risk patients before surgery was a critical component of our protocol. Managing postoperative pain in patients with prior opioid use is an intractable challenge in orthopedic surgery. Patients with a history of chronic pain and preoperative use of opioid medications remain at higher risk of postoperative chronic pain and persistent use of opioid medication despite no obvious surgical complications.⁸ In a sample of > 6,000 veterans who underwent TKA at VA hospitals in 2014, 57% of the patients with daily use of opioids in the 90 days before surgery remained on opioids 1 year after surgery (vs 2 % in patients not on long-term opioids).⁸ This relationship between pre- and postoperative opioid use also was dose dependent.¹²

Furthermore, those with high preoperative use may experience worse outcomes relative to the opioid naive population as measured by arthritis-specific pain indices.¹³ In a well-powered retrospective study of patients who underwent elective orthopedic procedures, preoperative opioid abuse or dependence (determined by the International Classification of Diseases, Ninth Revision diagnosis) increased inpatient mortality, aggregate morbidity, surgical site infection, myocardial infarction, and LOS.¹⁴ Preoperative opioid use also has been associated with increased risk of ED visits, readmission, infection, stiffness, and aseptic revision.¹⁵ In patients with TKA in the VA specifically, preoperative opioid use (> 3 months in the prior year) was associated with increased revision rates that were even higher than those for patients with diabetes mellitus.¹⁶

Patient Education

Based on this evidence, we instruct patients to reduce their preoperative opioid dosing to zero (for patients with joint pain) or < 30 MED (for patients using opioids for other reasons). Although preoperative reduction of opioid use has been shown to improve outcomes after TKA, pain subspecialty recommendations for patients with chronic opioid use recommend considering adjunctive therapies, including transcutaneous electrical nerve stimulation, cognitive behavioral therapy, gabapentin, or ketamine.^17,18 Through patient education our team has been successful in decreasing preoperative opioid use without adding other drugs or modalities.

Patient Optimization

Preoperative patient optimization included 4 to 8 weeks of daily sets of physical activity instructions (prehab) to improve the musculoskeletal function. These instructions are given to patients 4 to 8 weeks before surgery and aim to improve the patient’s balance, mobility, and functional ability (Appendix). Meta-analysis has shown that patients who undergo preoperative PT have a small but statistically significant decrease in postoperative pain at 4 weeks, though this does not persist beyond that period.¹⁹

We did note a lower BMI in patients in the MOJO group. Though this has the potential to be a confounder, a study of BMI in > 4,000 patients who underwent joint replacement surgery has shown that BMI is not associated with differences in postoperative pain.²⁰

Surgeon and Surgical-Related Variables

Patients in the MOJO group had increased use of adductor canal blocks. A 2017 meta-analysis of 12,530 patients comparing analgesic modalities found that peripheral nerve blocks targeting multiple nerves (eg, femoral/sciatic) decreased pain at rest, decreased opioid consumption, and improved range of motion postoperatively.²¹ Also, these were found to be superior to single nerve blocks, periarticular infiltration, and epidural blocks.²¹ However, major nerve and epidural blocks affecting the lower extremity may increase the risk of falls and prolong LOS.^22,23 The preferred peripheral block at VAPHCS is a single shot ultrasound-guided adductor canal block before the induction of general or spinal anesthesia. A randomized controlled trial has demonstrated superiority of this block to the femoral nerve block with regard to postoperative quadriceps strength, conferring the theoretical advantage of decreased fall risk and ability to participate in immediate PT.²⁴ Although we are unable to confirm an association between anesthetic modalities and opioid burden, our clinical impression is that blocks were effective at reducing immediate postoperative pain. However, among MOJO patients there were no differences in patients with and without blocks for either pain (4.2 vs 3.8, P = .69) or opioid consumption (28.8 vs 33.0, P = .72) after surgery, though our study was not powered to detect a difference in this restricted subgroup.

Patients who frequently had reported postoperative thigh pain prompted us to make changes in our surgical technique, performing TKA without use of a tourniquet. Tourniquet use has been associated with an increased risk of thigh pain after TKA by multiple authors.^25,26 Postoperative thigh pain also is pressure dependent.²⁷ In addition, its use may be associated with a slightly increased risk of thromboembolic events and delayed functional recovery.^28,29

Because postoperative hemarthrosis is associated with more pain and reduced joint recovery function, we used topical TXA to reduce postoperative surgical site and joint hematoma. TXA (either oral, IV, or topical) during TKA is used to control postoperative bleeding primarily and decrease the need for transfusion without concomitant increase in thromboembolic events.^30,31 Topical TXA may be more effective than IV, particularly in the immediate postoperative period.³² Although pain typically is not an endpoint in studies of TXA, a prospective study of 48 patients showed evidence that its use may be associated with decreased postoperative pain in the first 24 hours after surgery (though not after).³³ Finally, the use of intra-articular injection has evolved in our clinical practice, but literature is lacking with regard to its efficacy; more studies are needed to determine its effect relative to no injection. We have not seen any benefits to using cryotherapy in our practice; considering the costs for equipment and health care provider time, cryotherapy was not included in our new protocol.

Limitations

This is a nonrandomized retrospective single-institution study. Our study population is composed of mostly males with military experience and is not necessarily a representative sample of the general population eligible for joint arthroplasty. Our primary endpoint (reduction of opioid use postoperatively) also was a cornerstone of our intervention. To account for this, we set a very large effect size in our power analysis and evaluated multiple secondary endpoints to determine whether postoperative pain remained well controlled and complications/readmission minimized with our interventions. Because our intervention was multimodal, our study cannot make conclusions about the effect of a particular component of our treatment strategy. We did not measure or compare functional outcomes between both groups, which offers an opportunity for further research.

These limitations are balanced by several strengths. Our cohort was well controlled with respect to the dose and type of drug used. There is staff dedicated to postoperative telephone follow-up after discharge, and veterans are apt to seek care within the VA health care system, which improves case finding for complications and ED visits. No patients were lost to follow-up. Moreover, our drastic reduction in opioid use is promising enough to warrant reporting, while the broader orthopedic literature explores the relative impact of each variable.

Conclusions

The MOJO protocol has been effective for reducing postoperative opioid use after TKA without compromising effective pain management. The drastic reduction in the postoperative use of opioid pain medications and LOS have contributed to a cultural shift within our department, comprehensive team approach, multimodal pain management, and preoperative patient optimization. Further investigations are required to assess the impact of each intervention on observed outcomes. However, the framework and routines are applicable to other institutions and surgical specialties.

Acknowledgments

The authors recognize Derek Bond, MD, for his help in creating the MOJO acronym.

The Veterans Health Administration (VHA) COVID-19 vaccine allocation plan showcases several lessons for government and health care leaders in planning for future pandemics.¹ Many state governments—underresourced and overwhelmed with other COVID-19 demands—have struggled to get COVID-19 vaccines into the arms of their residents.² In contrast, the VHA was able to mobilize early to identify vaccine allocation guidelines and proactively prepare facilities to vaccinate VHA staff and veterans as soon as vaccines were approved under Emergency Use Authorization by the US Food and Drug Administration.^3,4

In August 2020, VHA formed a COVID-19 Vaccine Integrated Project Team, composed of 6 subgroups: communications, distribution, education, measurement, policy, prioritization, and vaccine safety. The National Center for Ethics in Health Care weighed in on the ethical justification for the developed vaccination risk stratification framework, which was informed by, but not identical to, that recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.⁵

Prioritizing who gets early access to a potentially life-saving vaccine weighs heavily on those leaders charged with making such decisions. The ethics of scarce resource allocation and triage protocols that may be necessary in a pandemic are often in tension with the patient-centered clinical ethics that health care practitioners (HCPs) encounter. HCPs require assistance in appreciating the ethical rationale for this shift in focus from the preference of the individual to the common good. The same is true for the risk stratification criteria required when there is not sufficient vaccine for all those who could benefit from immunization. Decisions must be transparent to ensure widespread acceptance and trust in the vaccination process. The ethical reasoning and values that are the basis for allocation criteria must be clearly, compassionately, and consistently communicated to the public, as outlined below. Ethical questions or concerns involve a conflict between core values: one of the central tasks of ethical analysis is to identify the available ethical options to resolve value conflicts. Several ethical frameworks for vaccine allocation are available—each balances and weighs the primary values of equity, dignity, beneficence, and utility slightly differently.⁶

For example, utilitarian ethics looks to produce the most good and avoid the most harm for the greatest number of people. Within this framework, there can be different notions of “good,” for example, saving the most lives, the most life years, the most quality life years, or the lives of those who have more life “innings” ahead. The approach of the US Department of Veterans Affairs (VA) focuses on saving the most lives in combination with avoiding suffering from serious illness, minimizing contagion, and preserving the essential workforce. Frameworks that give primacy to 1 notion of the good (ie, saving the most lives) may deprioritize other beneficial outcomes, such as allowing earlier return to work, school, and leisure activities that many find integral to human flourishing. Other ethical theories and principles may be used to support various allocation frameworks. For example, a pragmatic ethics approach might emphasize the importance of adapting the approach based on the evolving science and innovation surrounding COVID-19. Having more than 1 ethically defensible approach is common; the goal in ethics work is to be open to diversity of thought and reflect on the strength of one’s reasoning in resolving a core values conflict. We identify 2 central tenets of pandemic ethics that inform vaccine allocation.

1. Pandemic Ethics Requires Proactive Planning and Reevaluation of Continually Evolving Facts

There is an oft quoted saying among bioethicists: “Good ethics begins with good facts.” One obvious challenge during the COVID-19 pandemic has been the difficulty accessing up-to-date facts to inform decision making. If a main goal of a vaccination plan is to minimize the incidence of serious or fatal COVID-19 disease and contagion, myriad data points are needed to identify the best way to do this. For example, if 2 doses of the same vaccine are needed, this impacts the logistics of identifying, inviting, and scheduling eligible individuals and staffing vaccine clinics as well as ensuring that sufficient personal protective equipment and rescue equipment/medication are available to treat allergic reactions. If the adverse effects of vaccines lead to staff absenteeism or vaccine hesitancy, this needs to be factored into logistics.⁷ Tailored messaging is important to reduce appointment no-shows and vaccine nonadopters.⁸ Transportation to vaccination sites is a relevant factor: how a vaccine is stored, thawed, and reconstituted and its shelf life impacts whether it can be transported after thawing and what must be provided on site.

Consideration of the multifaceted factors influencing a successful vaccination campaign requires proactive planning and the readiness to pivot when new information is revealed. For example, vaccine appointment no-shows should be anticipated along with a fair process for allocating unused vaccine that would otherwise be wasted. This is an example of responsible stewardship of a scarce and life-saving resource. A higher than anticipated no-show rate would require revisiting a facility’s approach to ensuring that waste is avoided while the process is perceived to be fair and transparent. Ethical theories and principles cannot do all the work here; mindful attention to detail and proactive, informed planning are critical. Fortunately, the VA is well resourced in this domain, whereas many state health departments floundered in their response, causing unnecessary vaccination delays.⁹

2. Utility: Necessary But Insufficient

Most ethical approaches recognize to some extent that seeking good and minimizing harm is of value. However, a strictly utilitarian approach is insufficient to address the core values in conflict surrounding how best to allocate limited doses of COVID-19 vaccine. For example, some may argue that prioritizing the elderly or those in long-term care facilities like VA’s community living centers because they have the highest COVID-19 mortality rate produces less net benefit than prioritizing younger veterans with comorbidities or certain higher risk essential workers. There are 2 important points to make here.

First, the VHA vaccination plan balances utility with other ethical principles, namely, treating people with equal concern, and addressing health inequities, including a focus on justice and valuing the worth and dignity of each person. Rather than giving everyone an equal chance via lottery, the prioritization plan recognizes that some people have greater need or would stand to better mitigate viral contagion and preserve the essential workforce if they were vaccinated earlier. However, the principle of justice requires that efforts are made to treat like cases the same to avoid perceptions of bias, and to demonstrate respect for the dignity of each individual by way of promoting a fair vaccination process.

This requires transparency, consistency, and delivery of respectful and accurate communication. For example, the VA recognizes that lifetime exposure to social injustice produces health inequities that make Black, Hispanic, and Native American persons more susceptible to contracting COVID-19 and suffering serious or fatal illness. The approach to addressing this inequity is by giving priority to those with higher risk factors. Again, this is an example of blending and balancing ethical principles of utility and justice—that is, recognizing and remedying social injustice is of value both because it will help achieve better outcomes for persons of color and because it is inherently worthwhile to oppose injustice.

However, contrary to some news reports, the VHA approach does not allocate by race/ethnicity alone, as it does by age.^10,11 Doing so would present logistical challenges—for example, race/ethnicity is not an objective classification as is age, and reconciling individuals’ self-reports could create confusion or chaos that is antithetical to a fair, streamlined vaccination program. Putting veterans of color at the front of the vaccination line could backfire by amplifying worries that they are being exposed to vaccine that is not fully tested (a common contributor to vaccine hesitancy, particularly among communities of color familiar with prior exploitation and abuse in the name of science).

Discriminating based on race/ethnicity alone in the spirit of achieving equity would be precedent setting for the VA and would require a strong ethical justification. The decision to prioritize for vaccine based on risk factors strives to achieve this balance of equity and utility, as it encompasses VA staff and veterans of color by way of their status as essential workers or those with comorbidities. However, it is important to address race-based access barriers and vaccine hesitancy to satisfy the equity demands. This effort is underway (eg, engaging community champions and developing tailored educational resources to reach diverse communities).

In addition, pragmatic ethics recognizes that an overly granular, complicated allocation plan would be inefficient to implement. While it might be true that some veterans who are aged < 65 years may be at higher risk from COVID-19 than some elderly veterans, achieving the goals of fairness and transparency requires establishing a vaccine prioritization plan that is both ethically defensible and feasibly implementable (ie, achieves its goal of getting “needles into arms”). For example, veterans aged ≥ 65 years may be invited to schedule their vaccination before younger veterans, but any veteran may be accepted “on-call” for vaccine appointment no-shows via first-come, first-served or by lottery. Flexibility of response is crucial. This played out in adding flexibility around the decision to vaccinate veterans aged ≥ 75 years before those aged 65 to 74 years, after revisiting how this prioritization might affect feasibility and throughput and opting to allow the opportunity to include those aged ≥ 65 years.

There will no doubt be additional modifications to the vaccine allocation plan as more data become available. Since the danger of fueling suspicion and distrust is high (ie, that certain privileged people are jumping the line, as we heard reports of in some non-VA facilities).¹² There is an obvious ethical duty to explain why the chosen approach is ethically defensible. VA facility leaders should be able to answer how their approach achieves the goals of avoiding serious or fatal illness, reducing contagion, and preserving the essential workforce while ensuring a fair, respectful, evidence-based, and transparent process.

The Veterans Health Administration (VHA) COVID-19 vaccine allocation plan showcases several lessons for government and health care leaders in planning for future pandemics.¹ Many state governments—underresourced and overwhelmed with other COVID-19 demands—have struggled to get COVID-19 vaccines into the arms of their residents.² In contrast, the VHA was able to mobilize early to identify vaccine allocation guidelines and proactively prepare facilities to vaccinate VHA staff and veterans as soon as vaccines were approved under Emergency Use Authorization by the US Food and Drug Administration.^3,4

In August 2020, VHA formed a COVID-19 Vaccine Integrated Project Team, composed of 6 subgroups: communications, distribution, education, measurement, policy, prioritization, and vaccine safety. The National Center for Ethics in Health Care weighed in on the ethical justification for the developed vaccination risk stratification framework, which was informed by, but not identical to, that recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.⁵

Prioritizing who gets early access to a potentially life-saving vaccine weighs heavily on those leaders charged with making such decisions. The ethics of scarce resource allocation and triage protocols that may be necessary in a pandemic are often in tension with the patient-centered clinical ethics that health care practitioners (HCPs) encounter. HCPs require assistance in appreciating the ethical rationale for this shift in focus from the preference of the individual to the common good. The same is true for the risk stratification criteria required when there is not sufficient vaccine for all those who could benefit from immunization. Decisions must be transparent to ensure widespread acceptance and trust in the vaccination process. The ethical reasoning and values that are the basis for allocation criteria must be clearly, compassionately, and consistently communicated to the public, as outlined below. Ethical questions or concerns involve a conflict between core values: one of the central tasks of ethical analysis is to identify the available ethical options to resolve value conflicts. Several ethical frameworks for vaccine allocation are available—each balances and weighs the primary values of equity, dignity, beneficence, and utility slightly differently.⁶

For example, utilitarian ethics looks to produce the most good and avoid the most harm for the greatest number of people. Within this framework, there can be different notions of “good,” for example, saving the most lives, the most life years, the most quality life years, or the lives of those who have more life “innings” ahead. The approach of the US Department of Veterans Affairs (VA) focuses on saving the most lives in combination with avoiding suffering from serious illness, minimizing contagion, and preserving the essential workforce. Frameworks that give primacy to 1 notion of the good (ie, saving the most lives) may deprioritize other beneficial outcomes, such as allowing earlier return to work, school, and leisure activities that many find integral to human flourishing. Other ethical theories and principles may be used to support various allocation frameworks. For example, a pragmatic ethics approach might emphasize the importance of adapting the approach based on the evolving science and innovation surrounding COVID-19. Having more than 1 ethically defensible approach is common; the goal in ethics work is to be open to diversity of thought and reflect on the strength of one’s reasoning in resolving a core values conflict. We identify 2 central tenets of pandemic ethics that inform vaccine allocation.

1. Pandemic Ethics Requires Proactive Planning and Reevaluation of Continually Evolving Facts

There is an oft quoted saying among bioethicists: “Good ethics begins with good facts.” One obvious challenge during the COVID-19 pandemic has been the difficulty accessing up-to-date facts to inform decision making. If a main goal of a vaccination plan is to minimize the incidence of serious or fatal COVID-19 disease and contagion, myriad data points are needed to identify the best way to do this. For example, if 2 doses of the same vaccine are needed, this impacts the logistics of identifying, inviting, and scheduling eligible individuals and staffing vaccine clinics as well as ensuring that sufficient personal protective equipment and rescue equipment/medication are available to treat allergic reactions. If the adverse effects of vaccines lead to staff absenteeism or vaccine hesitancy, this needs to be factored into logistics.⁷ Tailored messaging is important to reduce appointment no-shows and vaccine nonadopters.⁸ Transportation to vaccination sites is a relevant factor: how a vaccine is stored, thawed, and reconstituted and its shelf life impacts whether it can be transported after thawing and what must be provided on site.

Consideration of the multifaceted factors influencing a successful vaccination campaign requires proactive planning and the readiness to pivot when new information is revealed. For example, vaccine appointment no-shows should be anticipated along with a fair process for allocating unused vaccine that would otherwise be wasted. This is an example of responsible stewardship of a scarce and life-saving resource. A higher than anticipated no-show rate would require revisiting a facility’s approach to ensuring that waste is avoided while the process is perceived to be fair and transparent. Ethical theories and principles cannot do all the work here; mindful attention to detail and proactive, informed planning are critical. Fortunately, the VA is well resourced in this domain, whereas many state health departments floundered in their response, causing unnecessary vaccination delays.⁹

2. Utility: Necessary But Insufficient

Most ethical approaches recognize to some extent that seeking good and minimizing harm is of value. However, a strictly utilitarian approach is insufficient to address the core values in conflict surrounding how best to allocate limited doses of COVID-19 vaccine. For example, some may argue that prioritizing the elderly or those in long-term care facilities like VA’s community living centers because they have the highest COVID-19 mortality rate produces less net benefit than prioritizing younger veterans with comorbidities or certain higher risk essential workers. There are 2 important points to make here.

First, the VHA vaccination plan balances utility with other ethical principles, namely, treating people with equal concern, and addressing health inequities, including a focus on justice and valuing the worth and dignity of each person. Rather than giving everyone an equal chance via lottery, the prioritization plan recognizes that some people have greater need or would stand to better mitigate viral contagion and preserve the essential workforce if they were vaccinated earlier. However, the principle of justice requires that efforts are made to treat like cases the same to avoid perceptions of bias, and to demonstrate respect for the dignity of each individual by way of promoting a fair vaccination process.

This requires transparency, consistency, and delivery of respectful and accurate communication. For example, the VA recognizes that lifetime exposure to social injustice produces health inequities that make Black, Hispanic, and Native American persons more susceptible to contracting COVID-19 and suffering serious or fatal illness. The approach to addressing this inequity is by giving priority to those with higher risk factors. Again, this is an example of blending and balancing ethical principles of utility and justice—that is, recognizing and remedying social injustice is of value both because it will help achieve better outcomes for persons of color and because it is inherently worthwhile to oppose injustice.

However, contrary to some news reports, the VHA approach does not allocate by race/ethnicity alone, as it does by age.^10,11 Doing so would present logistical challenges—for example, race/ethnicity is not an objective classification as is age, and reconciling individuals’ self-reports could create confusion or chaos that is antithetical to a fair, streamlined vaccination program. Putting veterans of color at the front of the vaccination line could backfire by amplifying worries that they are being exposed to vaccine that is not fully tested (a common contributor to vaccine hesitancy, particularly among communities of color familiar with prior exploitation and abuse in the name of science).

Discriminating based on race/ethnicity alone in the spirit of achieving equity would be precedent setting for the VA and would require a strong ethical justification. The decision to prioritize for vaccine based on risk factors strives to achieve this balance of equity and utility, as it encompasses VA staff and veterans of color by way of their status as essential workers or those with comorbidities. However, it is important to address race-based access barriers and vaccine hesitancy to satisfy the equity demands. This effort is underway (eg, engaging community champions and developing tailored educational resources to reach diverse communities).

In addition, pragmatic ethics recognizes that an overly granular, complicated allocation plan would be inefficient to implement. While it might be true that some veterans who are aged < 65 years may be at higher risk from COVID-19 than some elderly veterans, achieving the goals of fairness and transparency requires establishing a vaccine prioritization plan that is both ethically defensible and feasibly implementable (ie, achieves its goal of getting “needles into arms”). For example, veterans aged ≥ 65 years may be invited to schedule their vaccination before younger veterans, but any veteran may be accepted “on-call” for vaccine appointment no-shows via first-come, first-served or by lottery. Flexibility of response is crucial. This played out in adding flexibility around the decision to vaccinate veterans aged ≥ 75 years before those aged 65 to 74 years, after revisiting how this prioritization might affect feasibility and throughput and opting to allow the opportunity to include those aged ≥ 65 years.

There will no doubt be additional modifications to the vaccine allocation plan as more data become available. Since the danger of fueling suspicion and distrust is high (ie, that certain privileged people are jumping the line, as we heard reports of in some non-VA facilities).¹² There is an obvious ethical duty to explain why the chosen approach is ethically defensible. VA facility leaders should be able to answer how their approach achieves the goals of avoiding serious or fatal illness, reducing contagion, and preserving the essential workforce while ensuring a fair, respectful, evidence-based, and transparent process.

The Veterans Health Administration (VHA) COVID-19 vaccine allocation plan showcases several lessons for government and health care leaders in planning for future pandemics.¹ Many state governments—underresourced and overwhelmed with other COVID-19 demands—have struggled to get COVID-19 vaccines into the arms of their residents.² In contrast, the VHA was able to mobilize early to identify vaccine allocation guidelines and proactively prepare facilities to vaccinate VHA staff and veterans as soon as vaccines were approved under Emergency Use Authorization by the US Food and Drug Administration.^3,4

In August 2020, VHA formed a COVID-19 Vaccine Integrated Project Team, composed of 6 subgroups: communications, distribution, education, measurement, policy, prioritization, and vaccine safety. The National Center for Ethics in Health Care weighed in on the ethical justification for the developed vaccination risk stratification framework, which was informed by, but not identical to, that recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.⁵

Prioritizing who gets early access to a potentially life-saving vaccine weighs heavily on those leaders charged with making such decisions. The ethics of scarce resource allocation and triage protocols that may be necessary in a pandemic are often in tension with the patient-centered clinical ethics that health care practitioners (HCPs) encounter. HCPs require assistance in appreciating the ethical rationale for this shift in focus from the preference of the individual to the common good. The same is true for the risk stratification criteria required when there is not sufficient vaccine for all those who could benefit from immunization. Decisions must be transparent to ensure widespread acceptance and trust in the vaccination process. The ethical reasoning and values that are the basis for allocation criteria must be clearly, compassionately, and consistently communicated to the public, as outlined below. Ethical questions or concerns involve a conflict between core values: one of the central tasks of ethical analysis is to identify the available ethical options to resolve value conflicts. Several ethical frameworks for vaccine allocation are available—each balances and weighs the primary values of equity, dignity, beneficence, and utility slightly differently.⁶

For example, utilitarian ethics looks to produce the most good and avoid the most harm for the greatest number of people. Within this framework, there can be different notions of “good,” for example, saving the most lives, the most life years, the most quality life years, or the lives of those who have more life “innings” ahead. The approach of the US Department of Veterans Affairs (VA) focuses on saving the most lives in combination with avoiding suffering from serious illness, minimizing contagion, and preserving the essential workforce. Frameworks that give primacy to 1 notion of the good (ie, saving the most lives) may deprioritize other beneficial outcomes, such as allowing earlier return to work, school, and leisure activities that many find integral to human flourishing. Other ethical theories and principles may be used to support various allocation frameworks. For example, a pragmatic ethics approach might emphasize the importance of adapting the approach based on the evolving science and innovation surrounding COVID-19. Having more than 1 ethically defensible approach is common; the goal in ethics work is to be open to diversity of thought and reflect on the strength of one’s reasoning in resolving a core values conflict. We identify 2 central tenets of pandemic ethics that inform vaccine allocation.

1. Pandemic Ethics Requires Proactive Planning and Reevaluation of Continually Evolving Facts

There is an oft quoted saying among bioethicists: “Good ethics begins with good facts.” One obvious challenge during the COVID-19 pandemic has been the difficulty accessing up-to-date facts to inform decision making. If a main goal of a vaccination plan is to minimize the incidence of serious or fatal COVID-19 disease and contagion, myriad data points are needed to identify the best way to do this. For example, if 2 doses of the same vaccine are needed, this impacts the logistics of identifying, inviting, and scheduling eligible individuals and staffing vaccine clinics as well as ensuring that sufficient personal protective equipment and rescue equipment/medication are available to treat allergic reactions. If the adverse effects of vaccines lead to staff absenteeism or vaccine hesitancy, this needs to be factored into logistics.⁷ Tailored messaging is important to reduce appointment no-shows and vaccine nonadopters.⁸ Transportation to vaccination sites is a relevant factor: how a vaccine is stored, thawed, and reconstituted and its shelf life impacts whether it can be transported after thawing and what must be provided on site.

Consideration of the multifaceted factors influencing a successful vaccination campaign requires proactive planning and the readiness to pivot when new information is revealed. For example, vaccine appointment no-shows should be anticipated along with a fair process for allocating unused vaccine that would otherwise be wasted. This is an example of responsible stewardship of a scarce and life-saving resource. A higher than anticipated no-show rate would require revisiting a facility’s approach to ensuring that waste is avoided while the process is perceived to be fair and transparent. Ethical theories and principles cannot do all the work here; mindful attention to detail and proactive, informed planning are critical. Fortunately, the VA is well resourced in this domain, whereas many state health departments floundered in their response, causing unnecessary vaccination delays.⁹

2. Utility: Necessary But Insufficient

Most ethical approaches recognize to some extent that seeking good and minimizing harm is of value. However, a strictly utilitarian approach is insufficient to address the core values in conflict surrounding how best to allocate limited doses of COVID-19 vaccine. For example, some may argue that prioritizing the elderly or those in long-term care facilities like VA’s community living centers because they have the highest COVID-19 mortality rate produces less net benefit than prioritizing younger veterans with comorbidities or certain higher risk essential workers. There are 2 important points to make here.

First, the VHA vaccination plan balances utility with other ethical principles, namely, treating people with equal concern, and addressing health inequities, including a focus on justice and valuing the worth and dignity of each person. Rather than giving everyone an equal chance via lottery, the prioritization plan recognizes that some people have greater need or would stand to better mitigate viral contagion and preserve the essential workforce if they were vaccinated earlier. However, the principle of justice requires that efforts are made to treat like cases the same to avoid perceptions of bias, and to demonstrate respect for the dignity of each individual by way of promoting a fair vaccination process.

This requires transparency, consistency, and delivery of respectful and accurate communication. For example, the VA recognizes that lifetime exposure to social injustice produces health inequities that make Black, Hispanic, and Native American persons more susceptible to contracting COVID-19 and suffering serious or fatal illness. The approach to addressing this inequity is by giving priority to those with higher risk factors. Again, this is an example of blending and balancing ethical principles of utility and justice—that is, recognizing and remedying social injustice is of value both because it will help achieve better outcomes for persons of color and because it is inherently worthwhile to oppose injustice.

However, contrary to some news reports, the VHA approach does not allocate by race/ethnicity alone, as it does by age.^10,11 Doing so would present logistical challenges—for example, race/ethnicity is not an objective classification as is age, and reconciling individuals’ self-reports could create confusion or chaos that is antithetical to a fair, streamlined vaccination program. Putting veterans of color at the front of the vaccination line could backfire by amplifying worries that they are being exposed to vaccine that is not fully tested (a common contributor to vaccine hesitancy, particularly among communities of color familiar with prior exploitation and abuse in the name of science).

Discriminating based on race/ethnicity alone in the spirit of achieving equity would be precedent setting for the VA and would require a strong ethical justification. The decision to prioritize for vaccine based on risk factors strives to achieve this balance of equity and utility, as it encompasses VA staff and veterans of color by way of their status as essential workers or those with comorbidities. However, it is important to address race-based access barriers and vaccine hesitancy to satisfy the equity demands. This effort is underway (eg, engaging community champions and developing tailored educational resources to reach diverse communities).

In addition, pragmatic ethics recognizes that an overly granular, complicated allocation plan would be inefficient to implement. While it might be true that some veterans who are aged < 65 years may be at higher risk from COVID-19 than some elderly veterans, achieving the goals of fairness and transparency requires establishing a vaccine prioritization plan that is both ethically defensible and feasibly implementable (ie, achieves its goal of getting “needles into arms”). For example, veterans aged ≥ 65 years may be invited to schedule their vaccination before younger veterans, but any veteran may be accepted “on-call” for vaccine appointment no-shows via first-come, first-served or by lottery. Flexibility of response is crucial. This played out in adding flexibility around the decision to vaccinate veterans aged ≥ 75 years before those aged 65 to 74 years, after revisiting how this prioritization might affect feasibility and throughput and opting to allow the opportunity to include those aged ≥ 65 years.

There will no doubt be additional modifications to the vaccine allocation plan as more data become available. Since the danger of fueling suspicion and distrust is high (ie, that certain privileged people are jumping the line, as we heard reports of in some non-VA facilities).¹² There is an obvious ethical duty to explain why the chosen approach is ethically defensible. VA facility leaders should be able to answer how their approach achieves the goals of avoiding serious or fatal illness, reducing contagion, and preserving the essential workforce while ensuring a fair, respectful, evidence-based, and transparent process.

New details confirm an increased risk of developing intracranial meningiomas after prolonged use of the hormonal product cyproterone acetate.

Cyproterone acetate is a synthetic progestogen and potent antiandrogen that has been used in the treatment of hirsutism, alopecia, early puberty, amenorrhea, acne, and prostate cancer, and has also been combined with an estrogen in hormone replacement therapy.

The new findings were published online in the BMJ. The primary analysis showed that, among women using cyproterone acetate, the rate of meningiomas was 23.8 per 100,000 person years vs. 4.5 per 100,000 in the control group. After adjusting for confounders, cyproterone acetate was associated with a sevenfold increased risk of meningioma.

These were young women – the mean age of participants was 29.4 years, and more than 40% of the cohort were younger than 25 years. The initial prescriber was a gynecologist for more than half (56.7%) of the participants, and 31.6% of prescriptions could correspond to the treatment of acne without hirsutism; 13.1% of prescriptions were compatible with management of hirsutism.

“Our study provides confirmation of the risk but also the measurement of the dose-effect relationship, the decrease in the risk after stopping use, and the preferential anatomical localization of meningiomas,” said lead author Alain Weill, MD, EPI-PHARE Scientific Interest Group, Saint-Denis, France.

“A large proportion of meningiomas involve the skull base, which is of considerable importance because skull base meningioma surgery is one of the most challenging forms of surgery and is associated with a much higher risk than surgery for convexity meningiomas,” he said in an interview.

Cyproterone acetate products have been available in Europe since the 1970s under various trade names and dose strengths (1, 2, 10, 50, and 100 mg), and marketed for various indications. These products are also marketed in many other industrialized nations, but not in the United States or Japan.

The link between cyproterone acetate and an increased risk of meningioma has been known for the past decade, and information on the risk of meningioma is already included in the prescribing information for cyproterone products.

Last year, the European Medicines Agency strengthened the warnings that were already in place and recommended that cyproterone products with daily doses of 10 mg or more be restricted because of the risk of developing meningioma.

“The recommendation from the EMA is a direct consequence of our study, that was sent to the EMA in summary form in 2018 and followed up with a very detailed with a report in summer 2019,” said Dr. Weill. “In light of this report, the European Medicines Agency recommended in February 2020 that drugs containing 10 mg or more of cyproterone acetate should only be used for hirsutism, androgenic alopecia, and acne and seborrhea once other treatment options have failed, including treatment with lower doses.”

Dr. Weill pointed out that two other epidemiologic studies have assessed the link between cyproterone acetate use and meningioma and showed an association. “Those studies and our own study are complementary and provide a coherent set of epidemiological evidence,” he said in the interview. “They show a documented risk for high-dose cyproterone acetate in men, women, and transgender people, and the absence of any observed risk for low-dose cyproterone acetate use in women.”
 

Strong dose-effect relationship

For their study, Dr. Weill and colleagues used data from the French administrative health care database. Between 2007 and 2014, 253,777 girls and women aged 7-70 years had begun using cyproterone acetate during that time period.

All participants had received at least one prescription for high-dose cyproterone acetate and did not have a history of meningioma, benign brain tumors, or long-term disease. They were considered to be exposed if they had received a cumulative dose of at least 3 g during the first 6 months (139,222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114,555 participants).

Overall, a total of 69 meningiomas were diagnosed in the exposed group (during 289,544 person years of follow-up) and 20 meningiomas in the control group (during 439,949 person years of follow-up). All were treated by surgery or radiotherapy.

When the analysis was done according to the cumulative dose, it showed a dose-effect relation, with a higher risk associated with a higher cumulative dose. The hazard ratio was not significant for exposure to less than 12 g of cyproterone acetate, but it jumped rapidly jumped as the dose climbed: The hazard ratio was 11.3 for 36-60 g and was 21.7 for 60 g or higher.

In a secondary analysis, the authors looked at the cohort who were already using cyproterone acetate in 2006 (n = 123,997). Women with long-term exposure were also taking estrogens more often (55.5% vs. 31.9%), and the incidence of meningioma in the exposed group was 141 per 100,000 person years, which was a risk greater than 20-fold (adjusted hazard ratio 21.2.) They also observed a strong dose-effect relationship, with adjusted hazard ratio ranging from 5.0 to 31.1.

However, the risk of meningioma decreased noticeably after treatment was stopped. At 1 year after discontinuing treatment, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group.

Dr. Weill noted the clinical implications of these findings: clinicians need to inform patients who have used high-dose cyproterone acetate for at least 3-5 years about the increased risk of intracranial meningioma, he said.  

“The indication of cyproterone acetate should be clearly defined and the lowest possible daily dose used,” he said. “In the context of prolonged use of high-dose cyproterone acetate, magnetic resonance imaging screening for meningioma should be considered.”

“In patients with a documented meningioma, cyproterone acetate should be discontinued because the meningioma might regress in response to treatment discontinuation and invasive treatment could be avoided,” Dr. Weill added.
 

Use only when necessary

Weighing in on the research, Adilia Hormigo, MD, PhD, director of neuro-oncology at The Tisch Cancer Institute at Mount Sinai Health System in New York, noted that, “it is well known that there are sex differences in the incidence of meningiomas, as they are more frequent in women than men, and there is an association between breast cancer and the occurrence of meningiomas.”

Progesterone and androgen receptors have been found in meningiomas, she said in an interview, and there is no consensus regarding estrogen receptors. “In addition, hormonal therapy to inhibit estrogen or progesterone receptors has not produced any decrease in meningiomas’ growth,” she said.

The current study revealed an association between prolonged use of cyproterone acetate with an increased incidence of meningiomas, and the sphenoid-orbital meningioma location was specific for the drug use. “It is unclear from the study if all the meningiomas were benign,” she said. “Even if they are benign, they can cause severe morbidity, including seizures.”

Dr. Hormigo recommended that an MRI be performed on any patient who is taking a long course of cyproterone acetate in order to evaluate the development of meningiomas or meningioma progression. “And the drug should only be used when necessary,” she added.

This research was funded by the French National Health Insurance Fund and the Health Product Epidemiology Scientific Interest Group. Dr. Weill is an employee of the French National Health Insurance Fund, as are several other coauthors. The other authors have disclosed no relevant financial relationships. Dr. Hormigo has disclosed no relevant financial relationships.

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

New details confirm an increased risk of developing intracranial meningiomas after prolonged use of the hormonal product cyproterone acetate.

Cyproterone acetate is a synthetic progestogen and potent antiandrogen that has been used in the treatment of hirsutism, alopecia, early puberty, amenorrhea, acne, and prostate cancer, and has also been combined with an estrogen in hormone replacement therapy.

The new findings were published online in the BMJ. The primary analysis showed that, among women using cyproterone acetate, the rate of meningiomas was 23.8 per 100,000 person years vs. 4.5 per 100,000 in the control group. After adjusting for confounders, cyproterone acetate was associated with a sevenfold increased risk of meningioma.

These were young women – the mean age of participants was 29.4 years, and more than 40% of the cohort were younger than 25 years. The initial prescriber was a gynecologist for more than half (56.7%) of the participants, and 31.6% of prescriptions could correspond to the treatment of acne without hirsutism; 13.1% of prescriptions were compatible with management of hirsutism.

“Our study provides confirmation of the risk but also the measurement of the dose-effect relationship, the decrease in the risk after stopping use, and the preferential anatomical localization of meningiomas,” said lead author Alain Weill, MD, EPI-PHARE Scientific Interest Group, Saint-Denis, France.

“A large proportion of meningiomas involve the skull base, which is of considerable importance because skull base meningioma surgery is one of the most challenging forms of surgery and is associated with a much higher risk than surgery for convexity meningiomas,” he said in an interview.

Cyproterone acetate products have been available in Europe since the 1970s under various trade names and dose strengths (1, 2, 10, 50, and 100 mg), and marketed for various indications. These products are also marketed in many other industrialized nations, but not in the United States or Japan.

The link between cyproterone acetate and an increased risk of meningioma has been known for the past decade, and information on the risk of meningioma is already included in the prescribing information for cyproterone products.

Last year, the European Medicines Agency strengthened the warnings that were already in place and recommended that cyproterone products with daily doses of 10 mg or more be restricted because of the risk of developing meningioma.

“The recommendation from the EMA is a direct consequence of our study, that was sent to the EMA in summary form in 2018 and followed up with a very detailed with a report in summer 2019,” said Dr. Weill. “In light of this report, the European Medicines Agency recommended in February 2020 that drugs containing 10 mg or more of cyproterone acetate should only be used for hirsutism, androgenic alopecia, and acne and seborrhea once other treatment options have failed, including treatment with lower doses.”

Dr. Weill pointed out that two other epidemiologic studies have assessed the link between cyproterone acetate use and meningioma and showed an association. “Those studies and our own study are complementary and provide a coherent set of epidemiological evidence,” he said in the interview. “They show a documented risk for high-dose cyproterone acetate in men, women, and transgender people, and the absence of any observed risk for low-dose cyproterone acetate use in women.”
 

Strong dose-effect relationship

For their study, Dr. Weill and colleagues used data from the French administrative health care database. Between 2007 and 2014, 253,777 girls and women aged 7-70 years had begun using cyproterone acetate during that time period.

All participants had received at least one prescription for high-dose cyproterone acetate and did not have a history of meningioma, benign brain tumors, or long-term disease. They were considered to be exposed if they had received a cumulative dose of at least 3 g during the first 6 months (139,222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114,555 participants).

Overall, a total of 69 meningiomas were diagnosed in the exposed group (during 289,544 person years of follow-up) and 20 meningiomas in the control group (during 439,949 person years of follow-up). All were treated by surgery or radiotherapy.

When the analysis was done according to the cumulative dose, it showed a dose-effect relation, with a higher risk associated with a higher cumulative dose. The hazard ratio was not significant for exposure to less than 12 g of cyproterone acetate, but it jumped rapidly jumped as the dose climbed: The hazard ratio was 11.3 for 36-60 g and was 21.7 for 60 g or higher.

In a secondary analysis, the authors looked at the cohort who were already using cyproterone acetate in 2006 (n = 123,997). Women with long-term exposure were also taking estrogens more often (55.5% vs. 31.9%), and the incidence of meningioma in the exposed group was 141 per 100,000 person years, which was a risk greater than 20-fold (adjusted hazard ratio 21.2.) They also observed a strong dose-effect relationship, with adjusted hazard ratio ranging from 5.0 to 31.1.

However, the risk of meningioma decreased noticeably after treatment was stopped. At 1 year after discontinuing treatment, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group.

Dr. Weill noted the clinical implications of these findings: clinicians need to inform patients who have used high-dose cyproterone acetate for at least 3-5 years about the increased risk of intracranial meningioma, he said.  

“The indication of cyproterone acetate should be clearly defined and the lowest possible daily dose used,” he said. “In the context of prolonged use of high-dose cyproterone acetate, magnetic resonance imaging screening for meningioma should be considered.”

“In patients with a documented meningioma, cyproterone acetate should be discontinued because the meningioma might regress in response to treatment discontinuation and invasive treatment could be avoided,” Dr. Weill added.
 

Use only when necessary

Weighing in on the research, Adilia Hormigo, MD, PhD, director of neuro-oncology at The Tisch Cancer Institute at Mount Sinai Health System in New York, noted that, “it is well known that there are sex differences in the incidence of meningiomas, as they are more frequent in women than men, and there is an association between breast cancer and the occurrence of meningiomas.”

Progesterone and androgen receptors have been found in meningiomas, she said in an interview, and there is no consensus regarding estrogen receptors. “In addition, hormonal therapy to inhibit estrogen or progesterone receptors has not produced any decrease in meningiomas’ growth,” she said.

The current study revealed an association between prolonged use of cyproterone acetate with an increased incidence of meningiomas, and the sphenoid-orbital meningioma location was specific for the drug use. “It is unclear from the study if all the meningiomas were benign,” she said. “Even if they are benign, they can cause severe morbidity, including seizures.”

Dr. Hormigo recommended that an MRI be performed on any patient who is taking a long course of cyproterone acetate in order to evaluate the development of meningiomas or meningioma progression. “And the drug should only be used when necessary,” she added.

This research was funded by the French National Health Insurance Fund and the Health Product Epidemiology Scientific Interest Group. Dr. Weill is an employee of the French National Health Insurance Fund, as are several other coauthors. The other authors have disclosed no relevant financial relationships. Dr. Hormigo has disclosed no relevant financial relationships.

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

New details confirm an increased risk of developing intracranial meningiomas after prolonged use of the hormonal product cyproterone acetate.

Cyproterone acetate is a synthetic progestogen and potent antiandrogen that has been used in the treatment of hirsutism, alopecia, early puberty, amenorrhea, acne, and prostate cancer, and has also been combined with an estrogen in hormone replacement therapy.

The new findings were published online in the BMJ. The primary analysis showed that, among women using cyproterone acetate, the rate of meningiomas was 23.8 per 100,000 person years vs. 4.5 per 100,000 in the control group. After adjusting for confounders, cyproterone acetate was associated with a sevenfold increased risk of meningioma.

These were young women – the mean age of participants was 29.4 years, and more than 40% of the cohort were younger than 25 years. The initial prescriber was a gynecologist for more than half (56.7%) of the participants, and 31.6% of prescriptions could correspond to the treatment of acne without hirsutism; 13.1% of prescriptions were compatible with management of hirsutism.

“Our study provides confirmation of the risk but also the measurement of the dose-effect relationship, the decrease in the risk after stopping use, and the preferential anatomical localization of meningiomas,” said lead author Alain Weill, MD, EPI-PHARE Scientific Interest Group, Saint-Denis, France.

“A large proportion of meningiomas involve the skull base, which is of considerable importance because skull base meningioma surgery is one of the most challenging forms of surgery and is associated with a much higher risk than surgery for convexity meningiomas,” he said in an interview.

Cyproterone acetate products have been available in Europe since the 1970s under various trade names and dose strengths (1, 2, 10, 50, and 100 mg), and marketed for various indications. These products are also marketed in many other industrialized nations, but not in the United States or Japan.

The link between cyproterone acetate and an increased risk of meningioma has been known for the past decade, and information on the risk of meningioma is already included in the prescribing information for cyproterone products.

Last year, the European Medicines Agency strengthened the warnings that were already in place and recommended that cyproterone products with daily doses of 10 mg or more be restricted because of the risk of developing meningioma.

“The recommendation from the EMA is a direct consequence of our study, that was sent to the EMA in summary form in 2018 and followed up with a very detailed with a report in summer 2019,” said Dr. Weill. “In light of this report, the European Medicines Agency recommended in February 2020 that drugs containing 10 mg or more of cyproterone acetate should only be used for hirsutism, androgenic alopecia, and acne and seborrhea once other treatment options have failed, including treatment with lower doses.”

Dr. Weill pointed out that two other epidemiologic studies have assessed the link between cyproterone acetate use and meningioma and showed an association. “Those studies and our own study are complementary and provide a coherent set of epidemiological evidence,” he said in the interview. “They show a documented risk for high-dose cyproterone acetate in men, women, and transgender people, and the absence of any observed risk for low-dose cyproterone acetate use in women.”
 

Strong dose-effect relationship

For their study, Dr. Weill and colleagues used data from the French administrative health care database. Between 2007 and 2014, 253,777 girls and women aged 7-70 years had begun using cyproterone acetate during that time period.

All participants had received at least one prescription for high-dose cyproterone acetate and did not have a history of meningioma, benign brain tumors, or long-term disease. They were considered to be exposed if they had received a cumulative dose of at least 3 g during the first 6 months (139,222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114,555 participants).

Overall, a total of 69 meningiomas were diagnosed in the exposed group (during 289,544 person years of follow-up) and 20 meningiomas in the control group (during 439,949 person years of follow-up). All were treated by surgery or radiotherapy.

When the analysis was done according to the cumulative dose, it showed a dose-effect relation, with a higher risk associated with a higher cumulative dose. The hazard ratio was not significant for exposure to less than 12 g of cyproterone acetate, but it jumped rapidly jumped as the dose climbed: The hazard ratio was 11.3 for 36-60 g and was 21.7 for 60 g or higher.

In a secondary analysis, the authors looked at the cohort who were already using cyproterone acetate in 2006 (n = 123,997). Women with long-term exposure were also taking estrogens more often (55.5% vs. 31.9%), and the incidence of meningioma in the exposed group was 141 per 100,000 person years, which was a risk greater than 20-fold (adjusted hazard ratio 21.2.) They also observed a strong dose-effect relationship, with adjusted hazard ratio ranging from 5.0 to 31.1.

However, the risk of meningioma decreased noticeably after treatment was stopped. At 1 year after discontinuing treatment, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group.

Dr. Weill noted the clinical implications of these findings: clinicians need to inform patients who have used high-dose cyproterone acetate for at least 3-5 years about the increased risk of intracranial meningioma, he said.  

“The indication of cyproterone acetate should be clearly defined and the lowest possible daily dose used,” he said. “In the context of prolonged use of high-dose cyproterone acetate, magnetic resonance imaging screening for meningioma should be considered.”

“In patients with a documented meningioma, cyproterone acetate should be discontinued because the meningioma might regress in response to treatment discontinuation and invasive treatment could be avoided,” Dr. Weill added.
 

Use only when necessary

Weighing in on the research, Adilia Hormigo, MD, PhD, director of neuro-oncology at The Tisch Cancer Institute at Mount Sinai Health System in New York, noted that, “it is well known that there are sex differences in the incidence of meningiomas, as they are more frequent in women than men, and there is an association between breast cancer and the occurrence of meningiomas.”

Progesterone and androgen receptors have been found in meningiomas, she said in an interview, and there is no consensus regarding estrogen receptors. “In addition, hormonal therapy to inhibit estrogen or progesterone receptors has not produced any decrease in meningiomas’ growth,” she said.

The current study revealed an association between prolonged use of cyproterone acetate with an increased incidence of meningiomas, and the sphenoid-orbital meningioma location was specific for the drug use. “It is unclear from the study if all the meningiomas were benign,” she said. “Even if they are benign, they can cause severe morbidity, including seizures.”

Dr. Hormigo recommended that an MRI be performed on any patient who is taking a long course of cyproterone acetate in order to evaluate the development of meningiomas or meningioma progression. “And the drug should only be used when necessary,” she added.

This research was funded by the French National Health Insurance Fund and the Health Product Epidemiology Scientific Interest Group. Dr. Weill is an employee of the French National Health Insurance Fund, as are several other coauthors. The other authors have disclosed no relevant financial relationships. Dr. Hormigo has disclosed no relevant financial relationships.

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

Little has been known about children sick enough with COVID-19 to require intensive care because such patients are relatively few, but preliminary data analyzed from a nationwide registry indicate that they are more likely to be older, to be Black, and to have asthma.

Gastrointestinal distress is also more common in children with severe COVID-19, according to research by Sandeep Tripathi, MD. Dr. Tripathi, a pediatric intensivist and associate professor at the University of Illinois at Peoria, presented the findings on Feb. 3 at the Society for Critical Care Medicine (SCCM) 2021 Critical Care Congress.
 

Registry data gathered from 49 sites

Results from the SCCM’s VIRUS: COVID-19 Registry, which involved data from 49 sites, included 181 children admitted to an intensive care unit between February and July 2020. Those in the ICU were older than patients who did not receive care in the ICU (10 years vs. 3.67 years; P < .01) and were more likely to be Black (28.8% vs. 17.8%; P = .02).

More of the patients who required intensive care had preexisting conditions (58.2% vs. 44.3%; P = .01), the most common of which was asthma.

For both the ICU patients and the non-ICU group, the most common presenting symptom was fever.

Symptoms that were more common among children needing ICU care included nausea/vomiting (38.4% vs. 22.1%; P < .01), dyspnea (31.8% vs. 17.7%; P < .01), and abdominal pain (25.2% vs. 14.1%; P < .01).

Significantly higher proportions of ICU patients had multisystem inflammatory syndrome of childhood (MIS-C) (44.2% vs. 6.8%; P < .01) and acute kidney injury (9.34% vs. 1.7%; P < .01).

“The children who presented with MIS-C tended to be much sicker than children who present with just COVID,” Dr. Tripathi said in an interview.

In this analysis, among children in ICUs with COVID, the mortality rate was 4%, Dr. Tripathi said.

He said he hopes the information, which will be periodically published with updated data, will raise awareness of which children might be likely to experience progression to severe disease.

“The information may help physicians be more mindful of deterioration in those patients and be more aggressive in their management,” he said. When children are brought to the emergency department with the features this analysis highlights, he said, “physicians should have a low threshold for treating or admitting the patients.”

Another study that was presented on Feb. 3 in parallel with the registry study described patterns of illness among 68 children hospitalized with COVID-19 in a tertiary-care pediatric center.

In that analysis, Meghana Nadiger, MD, a critical care fellow with Nicklaus Children’s Hospital in Miami, found that all patients admitted to the pediatric ICU (n = 17) had either MIS-C or severe illness and COVID-19-related Kawasaki-like disease.

The investigators also found that the patients with serious illness were more commonly adolescents with elevated body mass index (73%). In this study, 83.8% of the hospitalized children were Hispanic. They also found that 88.8% of the children older than 2 years who had been hospitalized with COVID-19 were overweight or obese, with a BMI >25 kg/m².

Jerry Zimmerman, MD, PhD, SCCM’s immediate past president, said in an interview that he found it interesting that in the Nadiger study, “All of the children with severe illness had MIS-C as compared to adults, who typically are critically ill with severe acute respiratory distress syndrome.” Dr. Zimmerman was not involved in either study.

He said that although the high percentage of Hispanic patients in the hospitalized population may reflect the high percentage of Hispanic children in the Miami area, it may also reflect challenges of controlling the disease in the Hispanic community. Such challenges might include shortages of personal protective equipment, poorer access to health care, and difficulty in social distancing.

Dr. Zimmerman pointed out that obesity is an important risk factor for COVID-19 and that according to the Centers for Disease Control and Prevention, childhood obesity is much more common among Hispanics (25.8%) and non-Hispanic Blacks persons (22.0%) compared with non-Hispanic White persons (14.1%).

The VIRUS registry is funded in part by the Gordon and Betty Moore Foundation and Janssen Research and Development. Dr. Tripathi, Dr. Nadiger, and Dr. Zimmerman have disclosed no relevant financial relationships.

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

Little has been known about children sick enough with COVID-19 to require intensive care because such patients are relatively few, but preliminary data analyzed from a nationwide registry indicate that they are more likely to be older, to be Black, and to have asthma.

Gastrointestinal distress is also more common in children with severe COVID-19, according to research by Sandeep Tripathi, MD. Dr. Tripathi, a pediatric intensivist and associate professor at the University of Illinois at Peoria, presented the findings on Feb. 3 at the Society for Critical Care Medicine (SCCM) 2021 Critical Care Congress.
 

Registry data gathered from 49 sites

Results from the SCCM’s VIRUS: COVID-19 Registry, which involved data from 49 sites, included 181 children admitted to an intensive care unit between February and July 2020. Those in the ICU were older than patients who did not receive care in the ICU (10 years vs. 3.67 years; P < .01) and were more likely to be Black (28.8% vs. 17.8%; P = .02).

More of the patients who required intensive care had preexisting conditions (58.2% vs. 44.3%; P = .01), the most common of which was asthma.

For both the ICU patients and the non-ICU group, the most common presenting symptom was fever.

Symptoms that were more common among children needing ICU care included nausea/vomiting (38.4% vs. 22.1%; P < .01), dyspnea (31.8% vs. 17.7%; P < .01), and abdominal pain (25.2% vs. 14.1%; P < .01).

Significantly higher proportions of ICU patients had multisystem inflammatory syndrome of childhood (MIS-C) (44.2% vs. 6.8%; P < .01) and acute kidney injury (9.34% vs. 1.7%; P < .01).

“The children who presented with MIS-C tended to be much sicker than children who present with just COVID,” Dr. Tripathi said in an interview.

In this analysis, among children in ICUs with COVID, the mortality rate was 4%, Dr. Tripathi said.

He said he hopes the information, which will be periodically published with updated data, will raise awareness of which children might be likely to experience progression to severe disease.

“The information may help physicians be more mindful of deterioration in those patients and be more aggressive in their management,” he said. When children are brought to the emergency department with the features this analysis highlights, he said, “physicians should have a low threshold for treating or admitting the patients.”

Another study that was presented on Feb. 3 in parallel with the registry study described patterns of illness among 68 children hospitalized with COVID-19 in a tertiary-care pediatric center.

In that analysis, Meghana Nadiger, MD, a critical care fellow with Nicklaus Children’s Hospital in Miami, found that all patients admitted to the pediatric ICU (n = 17) had either MIS-C or severe illness and COVID-19-related Kawasaki-like disease.

The investigators also found that the patients with serious illness were more commonly adolescents with elevated body mass index (73%). In this study, 83.8% of the hospitalized children were Hispanic. They also found that 88.8% of the children older than 2 years who had been hospitalized with COVID-19 were overweight or obese, with a BMI >25 kg/m².

Jerry Zimmerman, MD, PhD, SCCM’s immediate past president, said in an interview that he found it interesting that in the Nadiger study, “All of the children with severe illness had MIS-C as compared to adults, who typically are critically ill with severe acute respiratory distress syndrome.” Dr. Zimmerman was not involved in either study.

He said that although the high percentage of Hispanic patients in the hospitalized population may reflect the high percentage of Hispanic children in the Miami area, it may also reflect challenges of controlling the disease in the Hispanic community. Such challenges might include shortages of personal protective equipment, poorer access to health care, and difficulty in social distancing.

Dr. Zimmerman pointed out that obesity is an important risk factor for COVID-19 and that according to the Centers for Disease Control and Prevention, childhood obesity is much more common among Hispanics (25.8%) and non-Hispanic Blacks persons (22.0%) compared with non-Hispanic White persons (14.1%).

The VIRUS registry is funded in part by the Gordon and Betty Moore Foundation and Janssen Research and Development. Dr. Tripathi, Dr. Nadiger, and Dr. Zimmerman have disclosed no relevant financial relationships.

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

Little has been known about children sick enough with COVID-19 to require intensive care because such patients are relatively few, but preliminary data analyzed from a nationwide registry indicate that they are more likely to be older, to be Black, and to have asthma.

Gastrointestinal distress is also more common in children with severe COVID-19, according to research by Sandeep Tripathi, MD. Dr. Tripathi, a pediatric intensivist and associate professor at the University of Illinois at Peoria, presented the findings on Feb. 3 at the Society for Critical Care Medicine (SCCM) 2021 Critical Care Congress.
 

Registry data gathered from 49 sites

Results from the SCCM’s VIRUS: COVID-19 Registry, which involved data from 49 sites, included 181 children admitted to an intensive care unit between February and July 2020. Those in the ICU were older than patients who did not receive care in the ICU (10 years vs. 3.67 years; P < .01) and were more likely to be Black (28.8% vs. 17.8%; P = .02).

More of the patients who required intensive care had preexisting conditions (58.2% vs. 44.3%; P = .01), the most common of which was asthma.

For both the ICU patients and the non-ICU group, the most common presenting symptom was fever.

Symptoms that were more common among children needing ICU care included nausea/vomiting (38.4% vs. 22.1%; P < .01), dyspnea (31.8% vs. 17.7%; P < .01), and abdominal pain (25.2% vs. 14.1%; P < .01).

Significantly higher proportions of ICU patients had multisystem inflammatory syndrome of childhood (MIS-C) (44.2% vs. 6.8%; P < .01) and acute kidney injury (9.34% vs. 1.7%; P < .01).

“The children who presented with MIS-C tended to be much sicker than children who present with just COVID,” Dr. Tripathi said in an interview.

In this analysis, among children in ICUs with COVID, the mortality rate was 4%, Dr. Tripathi said.

He said he hopes the information, which will be periodically published with updated data, will raise awareness of which children might be likely to experience progression to severe disease.

“The information may help physicians be more mindful of deterioration in those patients and be more aggressive in their management,” he said. When children are brought to the emergency department with the features this analysis highlights, he said, “physicians should have a low threshold for treating or admitting the patients.”

Another study that was presented on Feb. 3 in parallel with the registry study described patterns of illness among 68 children hospitalized with COVID-19 in a tertiary-care pediatric center.

In that analysis, Meghana Nadiger, MD, a critical care fellow with Nicklaus Children’s Hospital in Miami, found that all patients admitted to the pediatric ICU (n = 17) had either MIS-C or severe illness and COVID-19-related Kawasaki-like disease.

The investigators also found that the patients with serious illness were more commonly adolescents with elevated body mass index (73%). In this study, 83.8% of the hospitalized children were Hispanic. They also found that 88.8% of the children older than 2 years who had been hospitalized with COVID-19 were overweight or obese, with a BMI >25 kg/m².

Jerry Zimmerman, MD, PhD, SCCM’s immediate past president, said in an interview that he found it interesting that in the Nadiger study, “All of the children with severe illness had MIS-C as compared to adults, who typically are critically ill with severe acute respiratory distress syndrome.” Dr. Zimmerman was not involved in either study.

He said that although the high percentage of Hispanic patients in the hospitalized population may reflect the high percentage of Hispanic children in the Miami area, it may also reflect challenges of controlling the disease in the Hispanic community. Such challenges might include shortages of personal protective equipment, poorer access to health care, and difficulty in social distancing.

Dr. Zimmerman pointed out that obesity is an important risk factor for COVID-19 and that according to the Centers for Disease Control and Prevention, childhood obesity is much more common among Hispanics (25.8%) and non-Hispanic Blacks persons (22.0%) compared with non-Hispanic White persons (14.1%).

The VIRUS registry is funded in part by the Gordon and Betty Moore Foundation and Janssen Research and Development. Dr. Tripathi, Dr. Nadiger, and Dr. Zimmerman have disclosed no relevant financial relationships.

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

Researchers say women with type 2 diabetes treated with metformin had a reduced rate of the most common type of breast cancer, estrogen receptor (ER)–positive tumors, during a median follow-up of nearly 9 years in a prospective study of more than 44,000 individuals in the United States.

Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.

“Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer – but not other types of breast cancer – is biologically plausible and supported by our results, even though some [endpoints] are not statistically significant,” senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., said in an interview.

“Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk,” Dr. Sandler added.

The results were published online Jan. 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.

Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York, who was not involved with the study, said: “Certainly, metformin helps with weight loss, which is linked with estrogen-driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer.”
 

A tangled web ... with no clear conclusions yet

But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that, while this is “a large, well-designed prospective cohort study,” it tells a complicated story.

“The report by Park adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk, but definitive conclusions regarding these associations are not yet possible,” they observe.

The “largely negative” results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Dr. Lohmann, of London Health Sciences Centre, University of Western Ontario, and Dr. Goodwin, of Mount Sinai Hospital, Toronto.

“Clearly, this is an important area, and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment, and breast cancer risk,” they write.

Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3,500 women with hormone receptor–positive early-stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.
 

Study followed women whose sisters had breast cancer 

The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 U.S. states and Puerto Rico in 2003-2009.

The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.

Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.

During a median follow-up of 8.6 years, 2,678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.

In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99, compared with women without diabetes.

But, said Dr. Sandler, “there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this.”
 

Association of metformin and breast cancer

Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer, compared with women with diabetes not taking metformin, a nonsignificant association.

Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer, compared with those who did not take it, was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.

In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.

The editorialists note, however, that “the number of patients who were found to have triple-negative breast cancer was small [so] we cannot draw any practice-changing conclusions from it.”

In conclusion, Dr. Park and colleagues reiterate: “Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes.”

The study received no commercial funding. Dr. Sandler, Dr. Park, Dr. Lohmann, Dr. Goodwin, and Dr. Cate have reported no relevant financial relationships.

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

Researchers say women with type 2 diabetes treated with metformin had a reduced rate of the most common type of breast cancer, estrogen receptor (ER)–positive tumors, during a median follow-up of nearly 9 years in a prospective study of more than 44,000 individuals in the United States.

Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.

“Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer – but not other types of breast cancer – is biologically plausible and supported by our results, even though some [endpoints] are not statistically significant,” senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., said in an interview.

“Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk,” Dr. Sandler added.

The results were published online Jan. 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.

Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York, who was not involved with the study, said: “Certainly, metformin helps with weight loss, which is linked with estrogen-driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer.”
 

A tangled web ... with no clear conclusions yet

But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that, while this is “a large, well-designed prospective cohort study,” it tells a complicated story.

“The report by Park adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk, but definitive conclusions regarding these associations are not yet possible,” they observe.

The “largely negative” results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Dr. Lohmann, of London Health Sciences Centre, University of Western Ontario, and Dr. Goodwin, of Mount Sinai Hospital, Toronto.

“Clearly, this is an important area, and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment, and breast cancer risk,” they write.

Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3,500 women with hormone receptor–positive early-stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.
 

Study followed women whose sisters had breast cancer 

The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 U.S. states and Puerto Rico in 2003-2009.

The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.

Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.

During a median follow-up of 8.6 years, 2,678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.

In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99, compared with women without diabetes.

But, said Dr. Sandler, “there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this.”
 

Association of metformin and breast cancer

Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer, compared with women with diabetes not taking metformin, a nonsignificant association.

Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer, compared with those who did not take it, was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.

In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.

The editorialists note, however, that “the number of patients who were found to have triple-negative breast cancer was small [so] we cannot draw any practice-changing conclusions from it.”

In conclusion, Dr. Park and colleagues reiterate: “Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes.”

The study received no commercial funding. Dr. Sandler, Dr. Park, Dr. Lohmann, Dr. Goodwin, and Dr. Cate have reported no relevant financial relationships.

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

Researchers say women with type 2 diabetes treated with metformin had a reduced rate of the most common type of breast cancer, estrogen receptor (ER)–positive tumors, during a median follow-up of nearly 9 years in a prospective study of more than 44,000 individuals in the United States.

Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.

“Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer – but not other types of breast cancer – is biologically plausible and supported by our results, even though some [endpoints] are not statistically significant,” senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., said in an interview.

“Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk,” Dr. Sandler added.

The results were published online Jan. 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.

Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York, who was not involved with the study, said: “Certainly, metformin helps with weight loss, which is linked with estrogen-driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer.”
 

A tangled web ... with no clear conclusions yet

But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that, while this is “a large, well-designed prospective cohort study,” it tells a complicated story.

“The report by Park adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk, but definitive conclusions regarding these associations are not yet possible,” they observe.

The “largely negative” results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Dr. Lohmann, of London Health Sciences Centre, University of Western Ontario, and Dr. Goodwin, of Mount Sinai Hospital, Toronto.

“Clearly, this is an important area, and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment, and breast cancer risk,” they write.

Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3,500 women with hormone receptor–positive early-stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.
 

Study followed women whose sisters had breast cancer 

The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 U.S. states and Puerto Rico in 2003-2009.

The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.

Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.

During a median follow-up of 8.6 years, 2,678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.

In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99, compared with women without diabetes.

But, said Dr. Sandler, “there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this.”
 

Association of metformin and breast cancer

Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer, compared with women with diabetes not taking metformin, a nonsignificant association.

Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer, compared with those who did not take it, was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.

In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.

The editorialists note, however, that “the number of patients who were found to have triple-negative breast cancer was small [so] we cannot draw any practice-changing conclusions from it.”

In conclusion, Dr. Park and colleagues reiterate: “Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes.”

The study received no commercial funding. Dr. Sandler, Dr. Park, Dr. Lohmann, Dr. Goodwin, and Dr. Cate have reported no relevant financial relationships.

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

The Food and Drug Administration has revised its emergency use authorization for COVID-19 convalescent plasma on the basis of the latest available data.

The revision states that only high-titer COVID-19 convalescent plasma can be used and only in hospitalized patients who are early in the disease course and those with impaired humoral immunity who cannot produce an adequate antibody response.

The revisions stem from new clinical trial data analyzed or reported since the original EUA was issued in August 2020. The original EUA did not have these restrictions.

“This and other changes to the EUA represent important updates to the use of convalescent plasma for the treatment of COVID-19 patients,” Peter Marks, MD, PhD, director, FDA Center for Biologics Evaluation and Research, said in a statement announcing the revisions.

“COVID-19 convalescent plasma used according to the revised EUA may have efficacy, and its known and potential benefits outweigh its known and potential risks,” the FDA said.

The agency said it revoked use of low-titer COVID-19 convalescent plasma on the basis of new data from clinical trials, including randomized, controlled trials, that have failed to demonstrate that low-titer convalescent plasma may be effective in the treatment of hospitalized patients with COVID-19.

The FDA’s updated fact sheet for health care providers on the use of COVID-19 convalescent plasma also notes that transfusion of COVID-19 convalescent plasma late in the disease course, following respiratory failure requiring intubation and mechanical ventilation, hasn’t been found to have clinical benefit.

The revised EUA also includes several additional tests that can be used to manufacture COVID-19 convalescent plasma.

“With this update, nine tests are now included in the EUA for testing plasma donations for anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release,” the FDA said.

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

The Food and Drug Administration has revised its emergency use authorization for COVID-19 convalescent plasma on the basis of the latest available data.

The revision states that only high-titer COVID-19 convalescent plasma can be used and only in hospitalized patients who are early in the disease course and those with impaired humoral immunity who cannot produce an adequate antibody response.

The revisions stem from new clinical trial data analyzed or reported since the original EUA was issued in August 2020. The original EUA did not have these restrictions.

“This and other changes to the EUA represent important updates to the use of convalescent plasma for the treatment of COVID-19 patients,” Peter Marks, MD, PhD, director, FDA Center for Biologics Evaluation and Research, said in a statement announcing the revisions.

“COVID-19 convalescent plasma used according to the revised EUA may have efficacy, and its known and potential benefits outweigh its known and potential risks,” the FDA said.

The agency said it revoked use of low-titer COVID-19 convalescent plasma on the basis of new data from clinical trials, including randomized, controlled trials, that have failed to demonstrate that low-titer convalescent plasma may be effective in the treatment of hospitalized patients with COVID-19.

The FDA’s updated fact sheet for health care providers on the use of COVID-19 convalescent plasma also notes that transfusion of COVID-19 convalescent plasma late in the disease course, following respiratory failure requiring intubation and mechanical ventilation, hasn’t been found to have clinical benefit.

The revised EUA also includes several additional tests that can be used to manufacture COVID-19 convalescent plasma.

“With this update, nine tests are now included in the EUA for testing plasma donations for anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release,” the FDA said.

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

The Food and Drug Administration has revised its emergency use authorization for COVID-19 convalescent plasma on the basis of the latest available data.

The revision states that only high-titer COVID-19 convalescent plasma can be used and only in hospitalized patients who are early in the disease course and those with impaired humoral immunity who cannot produce an adequate antibody response.

The revisions stem from new clinical trial data analyzed or reported since the original EUA was issued in August 2020. The original EUA did not have these restrictions.

“This and other changes to the EUA represent important updates to the use of convalescent plasma for the treatment of COVID-19 patients,” Peter Marks, MD, PhD, director, FDA Center for Biologics Evaluation and Research, said in a statement announcing the revisions.

“COVID-19 convalescent plasma used according to the revised EUA may have efficacy, and its known and potential benefits outweigh its known and potential risks,” the FDA said.

The agency said it revoked use of low-titer COVID-19 convalescent plasma on the basis of new data from clinical trials, including randomized, controlled trials, that have failed to demonstrate that low-titer convalescent plasma may be effective in the treatment of hospitalized patients with COVID-19.

The FDA’s updated fact sheet for health care providers on the use of COVID-19 convalescent plasma also notes that transfusion of COVID-19 convalescent plasma late in the disease course, following respiratory failure requiring intubation and mechanical ventilation, hasn’t been found to have clinical benefit.

The revised EUA also includes several additional tests that can be used to manufacture COVID-19 convalescent plasma.

“With this update, nine tests are now included in the EUA for testing plasma donations for anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release,” the FDA said.

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