High out-of-pocket costs for medications remain a barrier for patients with psoriasis or psoriatic arthritis on Medicare, according to findings from a cross-sectional analysis of the Centers for Medicare & Medicaid Services Prescription Drug Plan Formulary Data from the fourth quarter of 2020.

Mathier/Thinkstock

Although biologics have demonstrated safety and effectiveness for psoriasis and psoriatic arthritis, their costs have risen, which has led patients to switch or discontinue biologics and consequently incur greater health care costs, wrote Sarah P. Pourali and colleagues at Vanderbilt University, Nashville, Tenn.

The authors also noted that Medicare patients in particular experience a financial burden if they have no limits on out-of-pocket spending, and while patient assistance programs may offset some out-of-pocket spending for specialty drugs, not all patients are aware of or qualify for them. Ineligibility for low-income subsidies also serves as a barrier and is associated with lower adherence to treatment.

In a study published in JAMA Dermatology, the researchers identified 5,011 formularies using the CMS data. The medications were etanercept, adalimumab, golimumab, ustekinumab, certolizumab pegol, apremilast, secukinumab, abatacept, ixekizumab, brodalumab, tofacitinib, tofacitinib XR, guselkumab, tildrakizumab, and risankizumab.

Overall, coverage for those 15 specialty medications ranged from 10.0% to 99.8% across products and Part D plans. The most commonly covered medications were adalimumab and ustekinumab (99.8% for both) and the least covered were brodalumab and tildrakizumab (10.9% and 10.0%, respectively).

Prior authorization was required by 90.5%-100% of the plans when medications were covered, and plans with limits on the quantity of medications covered ranged from 1.0% of plans (for guselkumab) to 78% of plans (for tofacitinib).

Copays were relatively rare; 2.4%-5.5% of the plans offered copays on any of the 15 medications.

The standard Medicare benefit for 2021 included a $445 deductible, 25% coinsurance for initial drug spending, and 5% coinsurance for drug spending in the catastrophic phase of coverage, the researchers noted. Overall, apremilast had the lowest estimated out-of-pocket costs for initial fills, under the catastrophic coverage phase, and annual cost, and ustekinumab had the highest. The estimated out-of-pocket costs for an initial fill ranged from $1,234 for apremilast to $3,426 for ustekinumab. Out-of-pocket costs for medications under the catastrophic phase ranged from $181 for apremilast to $1,175 for ustekinumab. Estimated out-of-pocket costs for a year of treatment ranged from $4,423 for apremilast to $6,950 for ustekinumab.

Median point-of-sale prices per fill – meaning pricing with no rebates or discounts – were lowest for apremilast ($3,620.40) and reached $23,492.93 per fill for ustekinumab, the researchers wrote. Other medications with point-of-sale prices above $10,000 were guselkumab ($11,511.52), tildrakizumab ($14,112.13), and risankizumab ($16,248.90).

The study was supported by grants from the Commonwealth Fund and the Leukemia & Lymphoma Society. One author disclosed receiving grants from Arnold Ventures, the Commonwealth Fund, and the Robert Wood Johnson Foundation for unrelated work, as well as honoraria from West Health and the Institute for Clinical and Economic Review.

High out-of-pocket costs for medications remain a barrier for patients with psoriasis or psoriatic arthritis on Medicare, according to findings from a cross-sectional analysis of the Centers for Medicare & Medicaid Services Prescription Drug Plan Formulary Data from the fourth quarter of 2020.

Mathier/Thinkstock

Although biologics have demonstrated safety and effectiveness for psoriasis and psoriatic arthritis, their costs have risen, which has led patients to switch or discontinue biologics and consequently incur greater health care costs, wrote Sarah P. Pourali and colleagues at Vanderbilt University, Nashville, Tenn.

The authors also noted that Medicare patients in particular experience a financial burden if they have no limits on out-of-pocket spending, and while patient assistance programs may offset some out-of-pocket spending for specialty drugs, not all patients are aware of or qualify for them. Ineligibility for low-income subsidies also serves as a barrier and is associated with lower adherence to treatment.

In a study published in JAMA Dermatology, the researchers identified 5,011 formularies using the CMS data. The medications were etanercept, adalimumab, golimumab, ustekinumab, certolizumab pegol, apremilast, secukinumab, abatacept, ixekizumab, brodalumab, tofacitinib, tofacitinib XR, guselkumab, tildrakizumab, and risankizumab.

Overall, coverage for those 15 specialty medications ranged from 10.0% to 99.8% across products and Part D plans. The most commonly covered medications were adalimumab and ustekinumab (99.8% for both) and the least covered were brodalumab and tildrakizumab (10.9% and 10.0%, respectively).

Prior authorization was required by 90.5%-100% of the plans when medications were covered, and plans with limits on the quantity of medications covered ranged from 1.0% of plans (for guselkumab) to 78% of plans (for tofacitinib).

Copays were relatively rare; 2.4%-5.5% of the plans offered copays on any of the 15 medications.

The standard Medicare benefit for 2021 included a $445 deductible, 25% coinsurance for initial drug spending, and 5% coinsurance for drug spending in the catastrophic phase of coverage, the researchers noted. Overall, apremilast had the lowest estimated out-of-pocket costs for initial fills, under the catastrophic coverage phase, and annual cost, and ustekinumab had the highest. The estimated out-of-pocket costs for an initial fill ranged from $1,234 for apremilast to $3,426 for ustekinumab. Out-of-pocket costs for medications under the catastrophic phase ranged from $181 for apremilast to $1,175 for ustekinumab. Estimated out-of-pocket costs for a year of treatment ranged from $4,423 for apremilast to $6,950 for ustekinumab.

Median point-of-sale prices per fill – meaning pricing with no rebates or discounts – were lowest for apremilast ($3,620.40) and reached $23,492.93 per fill for ustekinumab, the researchers wrote. Other medications with point-of-sale prices above $10,000 were guselkumab ($11,511.52), tildrakizumab ($14,112.13), and risankizumab ($16,248.90).

The study was supported by grants from the Commonwealth Fund and the Leukemia & Lymphoma Society. One author disclosed receiving grants from Arnold Ventures, the Commonwealth Fund, and the Robert Wood Johnson Foundation for unrelated work, as well as honoraria from West Health and the Institute for Clinical and Economic Review.

High out-of-pocket costs for medications remain a barrier for patients with psoriasis or psoriatic arthritis on Medicare, according to findings from a cross-sectional analysis of the Centers for Medicare & Medicaid Services Prescription Drug Plan Formulary Data from the fourth quarter of 2020.

Mathier/Thinkstock

Although biologics have demonstrated safety and effectiveness for psoriasis and psoriatic arthritis, their costs have risen, which has led patients to switch or discontinue biologics and consequently incur greater health care costs, wrote Sarah P. Pourali and colleagues at Vanderbilt University, Nashville, Tenn.

The authors also noted that Medicare patients in particular experience a financial burden if they have no limits on out-of-pocket spending, and while patient assistance programs may offset some out-of-pocket spending for specialty drugs, not all patients are aware of or qualify for them. Ineligibility for low-income subsidies also serves as a barrier and is associated with lower adherence to treatment.

In a study published in JAMA Dermatology, the researchers identified 5,011 formularies using the CMS data. The medications were etanercept, adalimumab, golimumab, ustekinumab, certolizumab pegol, apremilast, secukinumab, abatacept, ixekizumab, brodalumab, tofacitinib, tofacitinib XR, guselkumab, tildrakizumab, and risankizumab.

Overall, coverage for those 15 specialty medications ranged from 10.0% to 99.8% across products and Part D plans. The most commonly covered medications were adalimumab and ustekinumab (99.8% for both) and the least covered were brodalumab and tildrakizumab (10.9% and 10.0%, respectively).

Prior authorization was required by 90.5%-100% of the plans when medications were covered, and plans with limits on the quantity of medications covered ranged from 1.0% of plans (for guselkumab) to 78% of plans (for tofacitinib).

Copays were relatively rare; 2.4%-5.5% of the plans offered copays on any of the 15 medications.

The standard Medicare benefit for 2021 included a $445 deductible, 25% coinsurance for initial drug spending, and 5% coinsurance for drug spending in the catastrophic phase of coverage, the researchers noted. Overall, apremilast had the lowest estimated out-of-pocket costs for initial fills, under the catastrophic coverage phase, and annual cost, and ustekinumab had the highest. The estimated out-of-pocket costs for an initial fill ranged from $1,234 for apremilast to $3,426 for ustekinumab. Out-of-pocket costs for medications under the catastrophic phase ranged from $181 for apremilast to $1,175 for ustekinumab. Estimated out-of-pocket costs for a year of treatment ranged from $4,423 for apremilast to $6,950 for ustekinumab.

Median point-of-sale prices per fill – meaning pricing with no rebates or discounts – were lowest for apremilast ($3,620.40) and reached $23,492.93 per fill for ustekinumab, the researchers wrote. Other medications with point-of-sale prices above $10,000 were guselkumab ($11,511.52), tildrakizumab ($14,112.13), and risankizumab ($16,248.90).

The study was supported by grants from the Commonwealth Fund and the Leukemia & Lymphoma Society. One author disclosed receiving grants from Arnold Ventures, the Commonwealth Fund, and the Robert Wood Johnson Foundation for unrelated work, as well as honoraria from West Health and the Institute for Clinical and Economic Review.

Adding two immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy significantly improved both progression-free survival (PFS) and overall survival (OS) in comparison with chemotherapy alone for patients with metastatic non–small cell lung cancer (NSCLC) in the POSEIDON trial.

The study involved over 1,000 patients with stage IV NSCLC. Participants were randomly assigned to receive either two ICIs (tremelimumab and durvalumab [Imfinzi]) plus chemotherapy, or one immunotherapy (durvalumab) plus chemotherapy, or chemotherapy alone.

Adding durvalumab to chemotherapy significantly improved PFS by 26% but did not significantly improve OS, the researchers reported. However, adding both tremelimumab and durvalumab significantly increased both PFS (by 28%) and OS (by 23%). Median OS was 14.0 months versus 11.7 months for chemotherapy.

The results were presented on Sept. 9 at a presidential symposium of the World Conference on Lung Cancer 2021.

The two immunotherapies act at different immune checkpoints – tremelimumab acts at CTLA-4, and durvalumab acts at programmed death–1/PD–ligand 1 (PD-L1). Both drugs are from AstraZeneca, which sponsored the POSEIDON trial.

With no new safety signals identified, the triple therapy combination “represents a potential new frontline treatment option for metastatic non–small cell lung cancer,” said lead researcher Melissa L. Johnson, MD, from the Sarah Cannon Research Institute, Nashville, Tenn.

Reacting to the new results in a discussion of the paper, Julie R. Brahmer, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, said that, with so many first-line treatment choices now available for advanced NSCLC, she feels like “a kid in the candy store.”

POSEIDON may give her “another choice,” but she pointed out that there are some aspects of the study to consider.

The study required patients to undergo four cycles of chemotherapy along with immunotherapy, “which certainly is standard in many of our practices.”

However, only two cycles of chemotherapy were given in the CheckMate 9LA trial, in which nivolumab (Opdivo) and ipilimumab (Yervoy) were added to chemotherapy for the treatment of stage IV NSCLC. This combination of immunotherapies, which block CTLA-4 and PD-1, is similar to the combination that was studied in the current trial, and it is already approved for use in some patients with lung cancer.

“Also key to point out,” said Dr. Brahmer, is that, in the POSEIDON trial, “there was a trend toward more poor prognostic factors in the chemotherapy arm, where these patients had more liver or central nervous system metastases.”

Despite these differences, the survival outcomes were similar in the two trials, and in both trials, the tails of the curves indicate that “we need to see long-term data” to determine whether the benefit is ongoing.
 

Which patients for which combos?

Considering all the data from key trials in advanced NSCLC, Dr. Brahmer said that she believes that, for patients with high PD-L1 expression, treatment with a single immunotherapy directed against PD-1 or PD-L1 “is appropriate” and that she didn’t see that adding a CTLA-4 inhibitor to the PD-L1 inhibitor and chemotherapy would give any advantage.

“But for PD-L1–negative disease, I do think CTLA-4 antibodies seem to provide a benefit, specifically seen in the CheckMate studies,” particularly for patients with squamous disease, although she noted that in POSEIDON, histology and PD-L1 status have not been analyzed.

Dr. Brahmer concluded that, although the triple therapy improved survival outcomes in the current study, several key questions remain.

These include determining what CTLA-4 inhibition adds to PD-L1 blockade and asking whether the “slightly increased toxicity” is “worth the slightly increased long-term duration of response” and improved survival outcomes.

Furthermore, it needs to be determined “which populations truly need” the combined approach; “to get to this, we need to find the biomarker for CTLA-4 benefit,” Dr. Brahmer said.

She also noted “a practical question: Is there room in the clinic for another CTLA-4 antibody in addition to the nivolumab/ipilimumab combinations?”

This last point was appreciated on social media. Jill Feldman, a lung cancer patient and advocate, described it on Twitter as a “great question.”

She said that, for her, “options equal hope,” but that it is “critical” to give the “best treatment first. ... So as a patient, I would ask: How do I know/you know which treatment would be best for me?”

With “so many options in the first-line setting,” subsets of patients who may benefit from quadruplet therapy versus monotherapy need to be defined, commented Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia. He added that “PD-L1 may be one biomarker, but we need more.”
 

More details of the POSEIDON trial

In the POSEIDON trial, investigators had the choice of different chemotherapy regimens: platinum/gemcitabine for patients with squamous disease, platinum/pemetrexed for patients with nonsquamous disease, and nab-paclitaxel/carboplatin for patients with disease of either histology, Dr. Johnson reported.

It is noteworthy that the majority of patients were from Eastern Europe and Asia, “and the proportion of squamous patients enrolled was higher than is typically seen in mixed histology lung cancer studies,” she added.

The patients were stratified by PD-L1 expression at a cutoff of 50%, disease stage, and tumor histology.

Overall, 1,013 patients were enrolled. The three treatment arms were relatively well balanced in terms of baseline characteristics.

Dr. Johnson noted that there were “a few minor imbalances” in the durvalumab plus tremelimumab arm, with “fewer females, fewer Asians, and fewer never-smokers relative to the other two arms.”

The primary endpoint analysis after a median follow-up of 10.3 months demonstrated that PFS was significantly improved with durvalumab plus chemotherapy over chemotherapy alone, at a median of 5.5 months versus 4.8 months (hazard ratio, 0.74; P = .00093).

Although OS improved numerically with the addition of durvalumab to chemotherapy, it did not reach significance (13.3 months vs. 11.7 months with chemotherapy alone; HR, 0.86; P = .07581).

The positive PFS benefit with durvalumab plus chemotherapy triggered a secondary endpoint analysis, which showed that adding tremelimumab to durvalumab plus chemotherapy improved both survival outcomes.

Median PFS with the triple combination therapy was 6.2 months, significantly longer than the 4.8 months seen with chemotherapy alone (HR, 0.72; P = .00031).

At 12 months, 26.6% of patients who underwent treatment with durvalumab plus tremelimumab plus chemotherapy had not experienced disease progression, compared with 13.1% in the chemotherapy-alone arm.

OS was also significantly improved, at 14.0 months among patients in the triple therapy arm versus 11.7 in the chemotherapy-alone arm (HR, 0.77; P = .00304).

The results also showed that at 24 months, 32.9% of triple therapy patients were still alive versus 22.1% in the chemotherapy-alone arm.

Analysis indicated that “most subgroups favored the addition of immunotherapy to chemotherapy.” There was a “trend toward improved survival for all patients treated with durvalumab plus tremelimumab plus chemotherapy,” Dr. Johnson said.

This was seen “in particular for the nonsquamous patients” and for those with tumor PD-L1 expression of less than 1%, he added.

It is notable that for a large proportion of combination-therapy patients, response had continued at 12 months. This was the case for 38.9% of those who underwent treatment with durvalumab plus chemotherapy and for 49.7% of those given triple therapy versus 21.4% in the chemotherapy-alone arm.

As was seen across the whole cohort, among patients with nonsquamous disease, PFS and OS improved with the addition of immunotherapy. Of those patients with nonsquamous disease, 95.5% received pemetrexed plus platinum chemotherapy.

However, among patients with squamous tumors, of whom 88.3% received gemcitabine plus platinum chemotherapy, PFS and OS were “poor ... across all treatment arms,” Dr. Johnson reported, “with little separation of the curves.”

She highlighted the fact that the proportion of patients who experienced grade 3/4 adverse events, whether of any cause or treatment related, was only slightly higher in the two immunotherapy arms, indicating that “most events were driven by the chemotherapy.”

The rates of treatment discontinuation and adverse events leading to death were also similar across the three treatment arms, albeit they were slightly higher with the addition of immunotherapy.

Dr. Johnson also noted that, although there were more immune-mediated adverse events with durvalumab plus tremelimumab plus chemotherapy, compared with durvalumab plus chemotherapy, the “majority were grade 1/2 and were manageable.”

The most common immune-mediated events in the two immunotherapy arms were hypothyroid and hepatic events, pneumonitis, dermatitis, and rash.

The study was sponsored by AstraZeneca. Dr. Johnson reported numerous relationships with pharmaceutical companies. Dr. Brahmer reported relationships with Amgen, AstratZeneca, BMA, Genentech/Roche, Eli Lilly, Eisai, GlaxoSmithKline, Janssen, Merck, RAPT Therapeutics, Regeneron, Revolution Medicine, and Sanofi.

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

Adding two immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy significantly improved both progression-free survival (PFS) and overall survival (OS) in comparison with chemotherapy alone for patients with metastatic non–small cell lung cancer (NSCLC) in the POSEIDON trial.

The study involved over 1,000 patients with stage IV NSCLC. Participants were randomly assigned to receive either two ICIs (tremelimumab and durvalumab [Imfinzi]) plus chemotherapy, or one immunotherapy (durvalumab) plus chemotherapy, or chemotherapy alone.

Adding durvalumab to chemotherapy significantly improved PFS by 26% but did not significantly improve OS, the researchers reported. However, adding both tremelimumab and durvalumab significantly increased both PFS (by 28%) and OS (by 23%). Median OS was 14.0 months versus 11.7 months for chemotherapy.

The results were presented on Sept. 9 at a presidential symposium of the World Conference on Lung Cancer 2021.

The two immunotherapies act at different immune checkpoints – tremelimumab acts at CTLA-4, and durvalumab acts at programmed death–1/PD–ligand 1 (PD-L1). Both drugs are from AstraZeneca, which sponsored the POSEIDON trial.

With no new safety signals identified, the triple therapy combination “represents a potential new frontline treatment option for metastatic non–small cell lung cancer,” said lead researcher Melissa L. Johnson, MD, from the Sarah Cannon Research Institute, Nashville, Tenn.

Reacting to the new results in a discussion of the paper, Julie R. Brahmer, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, said that, with so many first-line treatment choices now available for advanced NSCLC, she feels like “a kid in the candy store.”

POSEIDON may give her “another choice,” but she pointed out that there are some aspects of the study to consider.

The study required patients to undergo four cycles of chemotherapy along with immunotherapy, “which certainly is standard in many of our practices.”

However, only two cycles of chemotherapy were given in the CheckMate 9LA trial, in which nivolumab (Opdivo) and ipilimumab (Yervoy) were added to chemotherapy for the treatment of stage IV NSCLC. This combination of immunotherapies, which block CTLA-4 and PD-1, is similar to the combination that was studied in the current trial, and it is already approved for use in some patients with lung cancer.

“Also key to point out,” said Dr. Brahmer, is that, in the POSEIDON trial, “there was a trend toward more poor prognostic factors in the chemotherapy arm, where these patients had more liver or central nervous system metastases.”

Despite these differences, the survival outcomes were similar in the two trials, and in both trials, the tails of the curves indicate that “we need to see long-term data” to determine whether the benefit is ongoing.
 

Which patients for which combos?

Considering all the data from key trials in advanced NSCLC, Dr. Brahmer said that she believes that, for patients with high PD-L1 expression, treatment with a single immunotherapy directed against PD-1 or PD-L1 “is appropriate” and that she didn’t see that adding a CTLA-4 inhibitor to the PD-L1 inhibitor and chemotherapy would give any advantage.

“But for PD-L1–negative disease, I do think CTLA-4 antibodies seem to provide a benefit, specifically seen in the CheckMate studies,” particularly for patients with squamous disease, although she noted that in POSEIDON, histology and PD-L1 status have not been analyzed.

Dr. Brahmer concluded that, although the triple therapy improved survival outcomes in the current study, several key questions remain.

These include determining what CTLA-4 inhibition adds to PD-L1 blockade and asking whether the “slightly increased toxicity” is “worth the slightly increased long-term duration of response” and improved survival outcomes.

Furthermore, it needs to be determined “which populations truly need” the combined approach; “to get to this, we need to find the biomarker for CTLA-4 benefit,” Dr. Brahmer said.

She also noted “a practical question: Is there room in the clinic for another CTLA-4 antibody in addition to the nivolumab/ipilimumab combinations?”

This last point was appreciated on social media. Jill Feldman, a lung cancer patient and advocate, described it on Twitter as a “great question.”

She said that, for her, “options equal hope,” but that it is “critical” to give the “best treatment first. ... So as a patient, I would ask: How do I know/you know which treatment would be best for me?”

With “so many options in the first-line setting,” subsets of patients who may benefit from quadruplet therapy versus monotherapy need to be defined, commented Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia. He added that “PD-L1 may be one biomarker, but we need more.”
 

More details of the POSEIDON trial

In the POSEIDON trial, investigators had the choice of different chemotherapy regimens: platinum/gemcitabine for patients with squamous disease, platinum/pemetrexed for patients with nonsquamous disease, and nab-paclitaxel/carboplatin for patients with disease of either histology, Dr. Johnson reported.

It is noteworthy that the majority of patients were from Eastern Europe and Asia, “and the proportion of squamous patients enrolled was higher than is typically seen in mixed histology lung cancer studies,” she added.

The patients were stratified by PD-L1 expression at a cutoff of 50%, disease stage, and tumor histology.

Overall, 1,013 patients were enrolled. The three treatment arms were relatively well balanced in terms of baseline characteristics.

Dr. Johnson noted that there were “a few minor imbalances” in the durvalumab plus tremelimumab arm, with “fewer females, fewer Asians, and fewer never-smokers relative to the other two arms.”

The primary endpoint analysis after a median follow-up of 10.3 months demonstrated that PFS was significantly improved with durvalumab plus chemotherapy over chemotherapy alone, at a median of 5.5 months versus 4.8 months (hazard ratio, 0.74; P = .00093).

Although OS improved numerically with the addition of durvalumab to chemotherapy, it did not reach significance (13.3 months vs. 11.7 months with chemotherapy alone; HR, 0.86; P = .07581).

The positive PFS benefit with durvalumab plus chemotherapy triggered a secondary endpoint analysis, which showed that adding tremelimumab to durvalumab plus chemotherapy improved both survival outcomes.

Median PFS with the triple combination therapy was 6.2 months, significantly longer than the 4.8 months seen with chemotherapy alone (HR, 0.72; P = .00031).

At 12 months, 26.6% of patients who underwent treatment with durvalumab plus tremelimumab plus chemotherapy had not experienced disease progression, compared with 13.1% in the chemotherapy-alone arm.

OS was also significantly improved, at 14.0 months among patients in the triple therapy arm versus 11.7 in the chemotherapy-alone arm (HR, 0.77; P = .00304).

The results also showed that at 24 months, 32.9% of triple therapy patients were still alive versus 22.1% in the chemotherapy-alone arm.

Analysis indicated that “most subgroups favored the addition of immunotherapy to chemotherapy.” There was a “trend toward improved survival for all patients treated with durvalumab plus tremelimumab plus chemotherapy,” Dr. Johnson said.

This was seen “in particular for the nonsquamous patients” and for those with tumor PD-L1 expression of less than 1%, he added.

It is notable that for a large proportion of combination-therapy patients, response had continued at 12 months. This was the case for 38.9% of those who underwent treatment with durvalumab plus chemotherapy and for 49.7% of those given triple therapy versus 21.4% in the chemotherapy-alone arm.

As was seen across the whole cohort, among patients with nonsquamous disease, PFS and OS improved with the addition of immunotherapy. Of those patients with nonsquamous disease, 95.5% received pemetrexed plus platinum chemotherapy.

However, among patients with squamous tumors, of whom 88.3% received gemcitabine plus platinum chemotherapy, PFS and OS were “poor ... across all treatment arms,” Dr. Johnson reported, “with little separation of the curves.”

She highlighted the fact that the proportion of patients who experienced grade 3/4 adverse events, whether of any cause or treatment related, was only slightly higher in the two immunotherapy arms, indicating that “most events were driven by the chemotherapy.”

The rates of treatment discontinuation and adverse events leading to death were also similar across the three treatment arms, albeit they were slightly higher with the addition of immunotherapy.

Dr. Johnson also noted that, although there were more immune-mediated adverse events with durvalumab plus tremelimumab plus chemotherapy, compared with durvalumab plus chemotherapy, the “majority were grade 1/2 and were manageable.”

The most common immune-mediated events in the two immunotherapy arms were hypothyroid and hepatic events, pneumonitis, dermatitis, and rash.

The study was sponsored by AstraZeneca. Dr. Johnson reported numerous relationships with pharmaceutical companies. Dr. Brahmer reported relationships with Amgen, AstratZeneca, BMA, Genentech/Roche, Eli Lilly, Eisai, GlaxoSmithKline, Janssen, Merck, RAPT Therapeutics, Regeneron, Revolution Medicine, and Sanofi.

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

Adding two immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy significantly improved both progression-free survival (PFS) and overall survival (OS) in comparison with chemotherapy alone for patients with metastatic non–small cell lung cancer (NSCLC) in the POSEIDON trial.

The study involved over 1,000 patients with stage IV NSCLC. Participants were randomly assigned to receive either two ICIs (tremelimumab and durvalumab [Imfinzi]) plus chemotherapy, or one immunotherapy (durvalumab) plus chemotherapy, or chemotherapy alone.

Adding durvalumab to chemotherapy significantly improved PFS by 26% but did not significantly improve OS, the researchers reported. However, adding both tremelimumab and durvalumab significantly increased both PFS (by 28%) and OS (by 23%). Median OS was 14.0 months versus 11.7 months for chemotherapy.

The results were presented on Sept. 9 at a presidential symposium of the World Conference on Lung Cancer 2021.

The two immunotherapies act at different immune checkpoints – tremelimumab acts at CTLA-4, and durvalumab acts at programmed death–1/PD–ligand 1 (PD-L1). Both drugs are from AstraZeneca, which sponsored the POSEIDON trial.

With no new safety signals identified, the triple therapy combination “represents a potential new frontline treatment option for metastatic non–small cell lung cancer,” said lead researcher Melissa L. Johnson, MD, from the Sarah Cannon Research Institute, Nashville, Tenn.

Reacting to the new results in a discussion of the paper, Julie R. Brahmer, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, said that, with so many first-line treatment choices now available for advanced NSCLC, she feels like “a kid in the candy store.”

POSEIDON may give her “another choice,” but she pointed out that there are some aspects of the study to consider.

The study required patients to undergo four cycles of chemotherapy along with immunotherapy, “which certainly is standard in many of our practices.”

However, only two cycles of chemotherapy were given in the CheckMate 9LA trial, in which nivolumab (Opdivo) and ipilimumab (Yervoy) were added to chemotherapy for the treatment of stage IV NSCLC. This combination of immunotherapies, which block CTLA-4 and PD-1, is similar to the combination that was studied in the current trial, and it is already approved for use in some patients with lung cancer.

“Also key to point out,” said Dr. Brahmer, is that, in the POSEIDON trial, “there was a trend toward more poor prognostic factors in the chemotherapy arm, where these patients had more liver or central nervous system metastases.”

Despite these differences, the survival outcomes were similar in the two trials, and in both trials, the tails of the curves indicate that “we need to see long-term data” to determine whether the benefit is ongoing.
 

Which patients for which combos?

Considering all the data from key trials in advanced NSCLC, Dr. Brahmer said that she believes that, for patients with high PD-L1 expression, treatment with a single immunotherapy directed against PD-1 or PD-L1 “is appropriate” and that she didn’t see that adding a CTLA-4 inhibitor to the PD-L1 inhibitor and chemotherapy would give any advantage.

“But for PD-L1–negative disease, I do think CTLA-4 antibodies seem to provide a benefit, specifically seen in the CheckMate studies,” particularly for patients with squamous disease, although she noted that in POSEIDON, histology and PD-L1 status have not been analyzed.

Dr. Brahmer concluded that, although the triple therapy improved survival outcomes in the current study, several key questions remain.

These include determining what CTLA-4 inhibition adds to PD-L1 blockade and asking whether the “slightly increased toxicity” is “worth the slightly increased long-term duration of response” and improved survival outcomes.

Furthermore, it needs to be determined “which populations truly need” the combined approach; “to get to this, we need to find the biomarker for CTLA-4 benefit,” Dr. Brahmer said.

She also noted “a practical question: Is there room in the clinic for another CTLA-4 antibody in addition to the nivolumab/ipilimumab combinations?”

This last point was appreciated on social media. Jill Feldman, a lung cancer patient and advocate, described it on Twitter as a “great question.”

She said that, for her, “options equal hope,” but that it is “critical” to give the “best treatment first. ... So as a patient, I would ask: How do I know/you know which treatment would be best for me?”

With “so many options in the first-line setting,” subsets of patients who may benefit from quadruplet therapy versus monotherapy need to be defined, commented Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia. He added that “PD-L1 may be one biomarker, but we need more.”
 

More details of the POSEIDON trial

In the POSEIDON trial, investigators had the choice of different chemotherapy regimens: platinum/gemcitabine for patients with squamous disease, platinum/pemetrexed for patients with nonsquamous disease, and nab-paclitaxel/carboplatin for patients with disease of either histology, Dr. Johnson reported.

It is noteworthy that the majority of patients were from Eastern Europe and Asia, “and the proportion of squamous patients enrolled was higher than is typically seen in mixed histology lung cancer studies,” she added.

The patients were stratified by PD-L1 expression at a cutoff of 50%, disease stage, and tumor histology.

Overall, 1,013 patients were enrolled. The three treatment arms were relatively well balanced in terms of baseline characteristics.

Dr. Johnson noted that there were “a few minor imbalances” in the durvalumab plus tremelimumab arm, with “fewer females, fewer Asians, and fewer never-smokers relative to the other two arms.”

The primary endpoint analysis after a median follow-up of 10.3 months demonstrated that PFS was significantly improved with durvalumab plus chemotherapy over chemotherapy alone, at a median of 5.5 months versus 4.8 months (hazard ratio, 0.74; P = .00093).

Although OS improved numerically with the addition of durvalumab to chemotherapy, it did not reach significance (13.3 months vs. 11.7 months with chemotherapy alone; HR, 0.86; P = .07581).

The positive PFS benefit with durvalumab plus chemotherapy triggered a secondary endpoint analysis, which showed that adding tremelimumab to durvalumab plus chemotherapy improved both survival outcomes.

Median PFS with the triple combination therapy was 6.2 months, significantly longer than the 4.8 months seen with chemotherapy alone (HR, 0.72; P = .00031).

At 12 months, 26.6% of patients who underwent treatment with durvalumab plus tremelimumab plus chemotherapy had not experienced disease progression, compared with 13.1% in the chemotherapy-alone arm.

OS was also significantly improved, at 14.0 months among patients in the triple therapy arm versus 11.7 in the chemotherapy-alone arm (HR, 0.77; P = .00304).

The results also showed that at 24 months, 32.9% of triple therapy patients were still alive versus 22.1% in the chemotherapy-alone arm.

Analysis indicated that “most subgroups favored the addition of immunotherapy to chemotherapy.” There was a “trend toward improved survival for all patients treated with durvalumab plus tremelimumab plus chemotherapy,” Dr. Johnson said.

This was seen “in particular for the nonsquamous patients” and for those with tumor PD-L1 expression of less than 1%, he added.

It is notable that for a large proportion of combination-therapy patients, response had continued at 12 months. This was the case for 38.9% of those who underwent treatment with durvalumab plus chemotherapy and for 49.7% of those given triple therapy versus 21.4% in the chemotherapy-alone arm.

As was seen across the whole cohort, among patients with nonsquamous disease, PFS and OS improved with the addition of immunotherapy. Of those patients with nonsquamous disease, 95.5% received pemetrexed plus platinum chemotherapy.

However, among patients with squamous tumors, of whom 88.3% received gemcitabine plus platinum chemotherapy, PFS and OS were “poor ... across all treatment arms,” Dr. Johnson reported, “with little separation of the curves.”

She highlighted the fact that the proportion of patients who experienced grade 3/4 adverse events, whether of any cause or treatment related, was only slightly higher in the two immunotherapy arms, indicating that “most events were driven by the chemotherapy.”

The rates of treatment discontinuation and adverse events leading to death were also similar across the three treatment arms, albeit they were slightly higher with the addition of immunotherapy.

Dr. Johnson also noted that, although there were more immune-mediated adverse events with durvalumab plus tremelimumab plus chemotherapy, compared with durvalumab plus chemotherapy, the “majority were grade 1/2 and were manageable.”

The most common immune-mediated events in the two immunotherapy arms were hypothyroid and hepatic events, pneumonitis, dermatitis, and rash.

The study was sponsored by AstraZeneca. Dr. Johnson reported numerous relationships with pharmaceutical companies. Dr. Brahmer reported relationships with Amgen, AstratZeneca, BMA, Genentech/Roche, Eli Lilly, Eisai, GlaxoSmithKline, Janssen, Merck, RAPT Therapeutics, Regeneron, Revolution Medicine, and Sanofi.

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

Bariatric surgery is associated with a reduction in risk of major adverse cardiac events (MACE), and Roux-en-Y gastric bypass (RYGB) is linked to a greater reduction than sleeve gastrectomy (SG).

Those are the key findings of a retrospective analysis of a large group of patients who received care at the Cleveland Clinic between 1998 and 2017. MACE is defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.

“I think what it tells us is that, in making these choices and in counseling patients about the potential advantages of undergoing bariatric surgery for their obesity and diabetes, that they should know that they’re more likely to be protected by a Roux-en-Y gastric bypass, although certainly sleeve gastrectomy is effective,” said study coauthor Steven E. Nissen, MD, who is the chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic.

Previous studies have shown a benefit to metabolic surgery in patients with type 2 diabetes and obesity, improving diabetes control and altering cardiometabolic risk factors. Others have shown a link between surgery and reduced mortality. Most studies examined the impact of RYGB. SG is a newer procedure, but its relative simplicity and lower complication rate have helped it become the most commonly performed metabolic surgery in the world.

“There was no study to compare gastric bypass and sleeve gastrectomy head to head in terms of reduction in risk of cardiovascular disease. There are studies comparing these two procedures for diabetes control and weight loss, but not specifically in terms of effects on their risk of developing cardiovascular disease. That’s the unique feature of this study,” said lead author Ali Aminian, MD, who is director of the Bariatric and Metabolic Institute at the Cleveland Clinic.

The researchers included 2,287 adults with type 2 diabetes and a body mass index of at least 30 kg/m², with no history of solid organ transplant, severe heart failure, or active cancer. 1,362 underwent RYGB, and 693 SG. Outcomes were compared with 11,435 matched nonsurgical patients.

At 5 years, 13.7% of the RYGB group experienced a MACE (95% confidence interval, 11.4-15.9), compared with 24.7% of the SG group for a relative reduction of 33% (95% CI, 19.0-30.0; adjusted hazard ratio, 0.77; P = .035). The nonsurgical group had a 5-year MACE incidence of 30.4% (95% CI, 29.4-31.5). Compared with usual care, the risk of MACE was lower in both the RYGB group (HR, 0.53; P < .001) and the SG group (HR, 0.69; P < .001). The researchers also analyzed the cumulative incidence of all-cause mortality, myocardial infarction, and ischemic stroke (three-component MACE) at 5 years. The cumulative incidence of three-component MACE at 5 years was 15.5% in the usual care group, 6.4% in the RYGB group (HR, 0.53 versus usual care; P < .001) and 11.8% in the SG group (HR vs. usual care, 0.65; P = .006).

The RYGB group had less nephropathy at 5 years (2.8% vs. 8.3%; HR, 0.47; P = .005), and experienced a greater reduction in weight, glycated hemoglobin, and diabetes and cardiovascular medication use. At 5 years, RYGB was associated with a higher frequency of upper endoscopy (45.8% vs. 35.6%, P < .001) and abdominal surgical procedures (10.8% vs. 5.4%, P = .001), compared with SG.

“Both procedures are extremely safe and extremely effective,” said Dr. Aminian. He pointed out the need to consider multiple factors when choosing between the procedures, including overall health, weight, comorbidities, and the patient’s values and goals.

A few factors may be contraindicated for one procedure or another. The sleeve may worsen severe reflux disease, while the gastric bypass may interfere more with absorption of psychiatric medications. Some patients may have multiple comorbidities that could point to a less risky procedure. “Decision-making should not be solely based on findings of this study. All these conditions need to be considered when patients and surgeons make a final decision about the most appropriate procedure,” said Dr. Aminian.

Dr. Nissen noted that the associations were wide ranging, including classic outcomes like death, stroke, and heart failure, but also extending to heart failure, coronary events, cerebral vascular events, nephropathy, and atrial fibrillation. “I found the nephropathy results to be amongst the most striking, that Roux-en-Y really dramatically reduced the risk of neuropathy,” he added. That’s a particularly important point because end-stage renal disease is a common cause of diabetes mortality.

Dr. Nissen acknowledged the limitations of the retrospective nature of the study, though he feels confident that the relationships are causal. “Bariatric surgery desperately needs a randomized, controlled trial, where both groups get intensive dietary and lifestyle counseling, but one group gets metabolic surgery and the other doesn’t. Given the dramatic effects in diabetic patients of reducing their hemoglobin A1c in a sustained way, reducing their body weight. We think these are very strong data to suggest that we have a major reduction in all the endpoints. If we’re right about this, the randomized controlled trial will show that dramatic effect, and will convince even the skeptics that metabolic surgery is the best way to go.”

Bariatric surgery is associated with a reduction in risk of major adverse cardiac events (MACE), and Roux-en-Y gastric bypass (RYGB) is linked to a greater reduction than sleeve gastrectomy (SG).

Those are the key findings of a retrospective analysis of a large group of patients who received care at the Cleveland Clinic between 1998 and 2017. MACE is defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.

“I think what it tells us is that, in making these choices and in counseling patients about the potential advantages of undergoing bariatric surgery for their obesity and diabetes, that they should know that they’re more likely to be protected by a Roux-en-Y gastric bypass, although certainly sleeve gastrectomy is effective,” said study coauthor Steven E. Nissen, MD, who is the chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic.

Previous studies have shown a benefit to metabolic surgery in patients with type 2 diabetes and obesity, improving diabetes control and altering cardiometabolic risk factors. Others have shown a link between surgery and reduced mortality. Most studies examined the impact of RYGB. SG is a newer procedure, but its relative simplicity and lower complication rate have helped it become the most commonly performed metabolic surgery in the world.

“There was no study to compare gastric bypass and sleeve gastrectomy head to head in terms of reduction in risk of cardiovascular disease. There are studies comparing these two procedures for diabetes control and weight loss, but not specifically in terms of effects on their risk of developing cardiovascular disease. That’s the unique feature of this study,” said lead author Ali Aminian, MD, who is director of the Bariatric and Metabolic Institute at the Cleveland Clinic.

The researchers included 2,287 adults with type 2 diabetes and a body mass index of at least 30 kg/m², with no history of solid organ transplant, severe heart failure, or active cancer. 1,362 underwent RYGB, and 693 SG. Outcomes were compared with 11,435 matched nonsurgical patients.

At 5 years, 13.7% of the RYGB group experienced a MACE (95% confidence interval, 11.4-15.9), compared with 24.7% of the SG group for a relative reduction of 33% (95% CI, 19.0-30.0; adjusted hazard ratio, 0.77; P = .035). The nonsurgical group had a 5-year MACE incidence of 30.4% (95% CI, 29.4-31.5). Compared with usual care, the risk of MACE was lower in both the RYGB group (HR, 0.53; P < .001) and the SG group (HR, 0.69; P < .001). The researchers also analyzed the cumulative incidence of all-cause mortality, myocardial infarction, and ischemic stroke (three-component MACE) at 5 years. The cumulative incidence of three-component MACE at 5 years was 15.5% in the usual care group, 6.4% in the RYGB group (HR, 0.53 versus usual care; P < .001) and 11.8% in the SG group (HR vs. usual care, 0.65; P = .006).

The RYGB group had less nephropathy at 5 years (2.8% vs. 8.3%; HR, 0.47; P = .005), and experienced a greater reduction in weight, glycated hemoglobin, and diabetes and cardiovascular medication use. At 5 years, RYGB was associated with a higher frequency of upper endoscopy (45.8% vs. 35.6%, P < .001) and abdominal surgical procedures (10.8% vs. 5.4%, P = .001), compared with SG.

“Both procedures are extremely safe and extremely effective,” said Dr. Aminian. He pointed out the need to consider multiple factors when choosing between the procedures, including overall health, weight, comorbidities, and the patient’s values and goals.

A few factors may be contraindicated for one procedure or another. The sleeve may worsen severe reflux disease, while the gastric bypass may interfere more with absorption of psychiatric medications. Some patients may have multiple comorbidities that could point to a less risky procedure. “Decision-making should not be solely based on findings of this study. All these conditions need to be considered when patients and surgeons make a final decision about the most appropriate procedure,” said Dr. Aminian.

Dr. Nissen noted that the associations were wide ranging, including classic outcomes like death, stroke, and heart failure, but also extending to heart failure, coronary events, cerebral vascular events, nephropathy, and atrial fibrillation. “I found the nephropathy results to be amongst the most striking, that Roux-en-Y really dramatically reduced the risk of neuropathy,” he added. That’s a particularly important point because end-stage renal disease is a common cause of diabetes mortality.

Dr. Nissen acknowledged the limitations of the retrospective nature of the study, though he feels confident that the relationships are causal. “Bariatric surgery desperately needs a randomized, controlled trial, where both groups get intensive dietary and lifestyle counseling, but one group gets metabolic surgery and the other doesn’t. Given the dramatic effects in diabetic patients of reducing their hemoglobin A1c in a sustained way, reducing their body weight. We think these are very strong data to suggest that we have a major reduction in all the endpoints. If we’re right about this, the randomized controlled trial will show that dramatic effect, and will convince even the skeptics that metabolic surgery is the best way to go.”

Bariatric surgery is associated with a reduction in risk of major adverse cardiac events (MACE), and Roux-en-Y gastric bypass (RYGB) is linked to a greater reduction than sleeve gastrectomy (SG).

Those are the key findings of a retrospective analysis of a large group of patients who received care at the Cleveland Clinic between 1998 and 2017. MACE is defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.

“I think what it tells us is that, in making these choices and in counseling patients about the potential advantages of undergoing bariatric surgery for their obesity and diabetes, that they should know that they’re more likely to be protected by a Roux-en-Y gastric bypass, although certainly sleeve gastrectomy is effective,” said study coauthor Steven E. Nissen, MD, who is the chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic.

Previous studies have shown a benefit to metabolic surgery in patients with type 2 diabetes and obesity, improving diabetes control and altering cardiometabolic risk factors. Others have shown a link between surgery and reduced mortality. Most studies examined the impact of RYGB. SG is a newer procedure, but its relative simplicity and lower complication rate have helped it become the most commonly performed metabolic surgery in the world.

“There was no study to compare gastric bypass and sleeve gastrectomy head to head in terms of reduction in risk of cardiovascular disease. There are studies comparing these two procedures for diabetes control and weight loss, but not specifically in terms of effects on their risk of developing cardiovascular disease. That’s the unique feature of this study,” said lead author Ali Aminian, MD, who is director of the Bariatric and Metabolic Institute at the Cleveland Clinic.

The researchers included 2,287 adults with type 2 diabetes and a body mass index of at least 30 kg/m², with no history of solid organ transplant, severe heart failure, or active cancer. 1,362 underwent RYGB, and 693 SG. Outcomes were compared with 11,435 matched nonsurgical patients.

At 5 years, 13.7% of the RYGB group experienced a MACE (95% confidence interval, 11.4-15.9), compared with 24.7% of the SG group for a relative reduction of 33% (95% CI, 19.0-30.0; adjusted hazard ratio, 0.77; P = .035). The nonsurgical group had a 5-year MACE incidence of 30.4% (95% CI, 29.4-31.5). Compared with usual care, the risk of MACE was lower in both the RYGB group (HR, 0.53; P < .001) and the SG group (HR, 0.69; P < .001). The researchers also analyzed the cumulative incidence of all-cause mortality, myocardial infarction, and ischemic stroke (three-component MACE) at 5 years. The cumulative incidence of three-component MACE at 5 years was 15.5% in the usual care group, 6.4% in the RYGB group (HR, 0.53 versus usual care; P < .001) and 11.8% in the SG group (HR vs. usual care, 0.65; P = .006).

The RYGB group had less nephropathy at 5 years (2.8% vs. 8.3%; HR, 0.47; P = .005), and experienced a greater reduction in weight, glycated hemoglobin, and diabetes and cardiovascular medication use. At 5 years, RYGB was associated with a higher frequency of upper endoscopy (45.8% vs. 35.6%, P < .001) and abdominal surgical procedures (10.8% vs. 5.4%, P = .001), compared with SG.

“Both procedures are extremely safe and extremely effective,” said Dr. Aminian. He pointed out the need to consider multiple factors when choosing between the procedures, including overall health, weight, comorbidities, and the patient’s values and goals.

A few factors may be contraindicated for one procedure or another. The sleeve may worsen severe reflux disease, while the gastric bypass may interfere more with absorption of psychiatric medications. Some patients may have multiple comorbidities that could point to a less risky procedure. “Decision-making should not be solely based on findings of this study. All these conditions need to be considered when patients and surgeons make a final decision about the most appropriate procedure,” said Dr. Aminian.

Dr. Nissen noted that the associations were wide ranging, including classic outcomes like death, stroke, and heart failure, but also extending to heart failure, coronary events, cerebral vascular events, nephropathy, and atrial fibrillation. “I found the nephropathy results to be amongst the most striking, that Roux-en-Y really dramatically reduced the risk of neuropathy,” he added. That’s a particularly important point because end-stage renal disease is a common cause of diabetes mortality.

Dr. Nissen acknowledged the limitations of the retrospective nature of the study, though he feels confident that the relationships are causal. “Bariatric surgery desperately needs a randomized, controlled trial, where both groups get intensive dietary and lifestyle counseling, but one group gets metabolic surgery and the other doesn’t. Given the dramatic effects in diabetic patients of reducing their hemoglobin A1c in a sustained way, reducing their body weight. We think these are very strong data to suggest that we have a major reduction in all the endpoints. If we’re right about this, the randomized controlled trial will show that dramatic effect, and will convince even the skeptics that metabolic surgery is the best way to go.”

Use of cannabidiol (CBD) as an add-on pain management technique in patients with either hand osteoarthritis (OA) or psoriatic arthritis (PsA) did not significantly decrease pain intensity when compared with a placebo in a randomized, double-blind trial described as the first of its kind to investigate the effect of pure CBD as an add-on analgesic therapy in patients with joint disease.

Anatoliy Sizov/Getty Images

Although data on the use of medical cannabis as a modulator of joint pain are limited, some studies suggest an effect from CBD without the addition of delta-9-tetrahydrocannabinol (THC), wrote Jonathan Vela, MD, of Aalborg (Denmark) University Hospital, and colleagues.

CBD is being used for pain conditions despite a lack of data on safety and effectiveness, the researchers emphasized. Notably, in a 2018 online survey, 62% of respondents reported using CBD for medical conditions, primarily for chronic pain and arthritis or joint pain, they wrote.

In a study published in the journal Pain, the researchers randomized 59 adults with PsA and 77 adults with hand OA to 20-30 mg of synthetic CBD or a placebo daily for 12 weeks in addition to conventional pain management. Patients initially received either oral CBD 10 mg or a placebo tablet once daily, increasing to 10 mg twice daily after 2 weeks, and once again up to 10 mg three times daily at 4 weeks if the patient did not experience more than 20-mm improvement on the visual analog scale (VAS).

The primary outcome in the trial was patient-reported pain intensity during the last 24 hours as assessed on a paper-based 100-mm VAS with the text, “How much pain have you experienced in the most symptomatic joint during the last 24 hours?” with 0 representing no pain and 100 representing the worst pain imaginable.

Overall, both CBD and placebo groups achieved significant reductions in pain intensity of 11-12 mm at 12 weeks. The mean between-group difference on the VAS was 0.23 mm (P = .96). Twenty-two percent of patients who received CBD and 21% who received placebo demonstrated a pain intensity reduction greater than 30 mm on the VAS. Pain reduction greater than 50% was reported by 17 patients (25%) in the CBD group and 16 (27%) in the placebo group. CBD had a similar effect in patients with either PsA or hand OA.

Four serious adverse events occurred during the 12-week study period, but none of these were deemed adverse drug reactions. Serious adverse events in the CBD patients included one case of ductal carcinoma and one case of lipotymia; serious adverse events in the placebo group included one case of acute shoulder fracture and one case of malignant hypertension. Fifty-nine patients reported adverse events during the study. The CBD group reported more ear-nose-throat adverse events, compared with the placebo group (8 vs. 0).

The researchers assessed the impact of CBD vs. placebo on sleep quality, depression, anxiety, or pain catastrophizing scores using the Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, and Health Assessment Questionnaire but found no differences in patients taking CBD vs. placebo.

The study findings were limited by several factors, including the potentially insufficient dose level to evoke a pain relief response, and a lack of data on additional daily use of analgesics or of the study drug beyond the prescribed dosage, the researchers noted.

The results were strengthened by the randomized, double-blind trial design and its relatively large sample size, they wrote. However, the researchers also cautioned that their study focused on CBD as a single ingredient, and the results might not generalize to other CBD formulations. They also noted that more research is needed to examine both higher doses of CBD and different types of pain disorders.

The study was supported by the Danish Psoriasis Foundation Grant and the Danish Rheumatism Foundation. The researchers had no financial conflicts to disclose.

Use of cannabidiol (CBD) as an add-on pain management technique in patients with either hand osteoarthritis (OA) or psoriatic arthritis (PsA) did not significantly decrease pain intensity when compared with a placebo in a randomized, double-blind trial described as the first of its kind to investigate the effect of pure CBD as an add-on analgesic therapy in patients with joint disease.

Anatoliy Sizov/Getty Images

Although data on the use of medical cannabis as a modulator of joint pain are limited, some studies suggest an effect from CBD without the addition of delta-9-tetrahydrocannabinol (THC), wrote Jonathan Vela, MD, of Aalborg (Denmark) University Hospital, and colleagues.

CBD is being used for pain conditions despite a lack of data on safety and effectiveness, the researchers emphasized. Notably, in a 2018 online survey, 62% of respondents reported using CBD for medical conditions, primarily for chronic pain and arthritis or joint pain, they wrote.

In a study published in the journal Pain, the researchers randomized 59 adults with PsA and 77 adults with hand OA to 20-30 mg of synthetic CBD or a placebo daily for 12 weeks in addition to conventional pain management. Patients initially received either oral CBD 10 mg or a placebo tablet once daily, increasing to 10 mg twice daily after 2 weeks, and once again up to 10 mg three times daily at 4 weeks if the patient did not experience more than 20-mm improvement on the visual analog scale (VAS).

The primary outcome in the trial was patient-reported pain intensity during the last 24 hours as assessed on a paper-based 100-mm VAS with the text, “How much pain have you experienced in the most symptomatic joint during the last 24 hours?” with 0 representing no pain and 100 representing the worst pain imaginable.

Overall, both CBD and placebo groups achieved significant reductions in pain intensity of 11-12 mm at 12 weeks. The mean between-group difference on the VAS was 0.23 mm (P = .96). Twenty-two percent of patients who received CBD and 21% who received placebo demonstrated a pain intensity reduction greater than 30 mm on the VAS. Pain reduction greater than 50% was reported by 17 patients (25%) in the CBD group and 16 (27%) in the placebo group. CBD had a similar effect in patients with either PsA or hand OA.

Four serious adverse events occurred during the 12-week study period, but none of these were deemed adverse drug reactions. Serious adverse events in the CBD patients included one case of ductal carcinoma and one case of lipotymia; serious adverse events in the placebo group included one case of acute shoulder fracture and one case of malignant hypertension. Fifty-nine patients reported adverse events during the study. The CBD group reported more ear-nose-throat adverse events, compared with the placebo group (8 vs. 0).

The researchers assessed the impact of CBD vs. placebo on sleep quality, depression, anxiety, or pain catastrophizing scores using the Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, and Health Assessment Questionnaire but found no differences in patients taking CBD vs. placebo.

The study findings were limited by several factors, including the potentially insufficient dose level to evoke a pain relief response, and a lack of data on additional daily use of analgesics or of the study drug beyond the prescribed dosage, the researchers noted.

The results were strengthened by the randomized, double-blind trial design and its relatively large sample size, they wrote. However, the researchers also cautioned that their study focused on CBD as a single ingredient, and the results might not generalize to other CBD formulations. They also noted that more research is needed to examine both higher doses of CBD and different types of pain disorders.

The study was supported by the Danish Psoriasis Foundation Grant and the Danish Rheumatism Foundation. The researchers had no financial conflicts to disclose.

Use of cannabidiol (CBD) as an add-on pain management technique in patients with either hand osteoarthritis (OA) or psoriatic arthritis (PsA) did not significantly decrease pain intensity when compared with a placebo in a randomized, double-blind trial described as the first of its kind to investigate the effect of pure CBD as an add-on analgesic therapy in patients with joint disease.

Anatoliy Sizov/Getty Images

Although data on the use of medical cannabis as a modulator of joint pain are limited, some studies suggest an effect from CBD without the addition of delta-9-tetrahydrocannabinol (THC), wrote Jonathan Vela, MD, of Aalborg (Denmark) University Hospital, and colleagues.

CBD is being used for pain conditions despite a lack of data on safety and effectiveness, the researchers emphasized. Notably, in a 2018 online survey, 62% of respondents reported using CBD for medical conditions, primarily for chronic pain and arthritis or joint pain, they wrote.

In a study published in the journal Pain, the researchers randomized 59 adults with PsA and 77 adults with hand OA to 20-30 mg of synthetic CBD or a placebo daily for 12 weeks in addition to conventional pain management. Patients initially received either oral CBD 10 mg or a placebo tablet once daily, increasing to 10 mg twice daily after 2 weeks, and once again up to 10 mg three times daily at 4 weeks if the patient did not experience more than 20-mm improvement on the visual analog scale (VAS).

The primary outcome in the trial was patient-reported pain intensity during the last 24 hours as assessed on a paper-based 100-mm VAS with the text, “How much pain have you experienced in the most symptomatic joint during the last 24 hours?” with 0 representing no pain and 100 representing the worst pain imaginable.

Overall, both CBD and placebo groups achieved significant reductions in pain intensity of 11-12 mm at 12 weeks. The mean between-group difference on the VAS was 0.23 mm (P = .96). Twenty-two percent of patients who received CBD and 21% who received placebo demonstrated a pain intensity reduction greater than 30 mm on the VAS. Pain reduction greater than 50% was reported by 17 patients (25%) in the CBD group and 16 (27%) in the placebo group. CBD had a similar effect in patients with either PsA or hand OA.

Four serious adverse events occurred during the 12-week study period, but none of these were deemed adverse drug reactions. Serious adverse events in the CBD patients included one case of ductal carcinoma and one case of lipotymia; serious adverse events in the placebo group included one case of acute shoulder fracture and one case of malignant hypertension. Fifty-nine patients reported adverse events during the study. The CBD group reported more ear-nose-throat adverse events, compared with the placebo group (8 vs. 0).

The researchers assessed the impact of CBD vs. placebo on sleep quality, depression, anxiety, or pain catastrophizing scores using the Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, and Health Assessment Questionnaire but found no differences in patients taking CBD vs. placebo.

The study findings were limited by several factors, including the potentially insufficient dose level to evoke a pain relief response, and a lack of data on additional daily use of analgesics or of the study drug beyond the prescribed dosage, the researchers noted.

The results were strengthened by the randomized, double-blind trial design and its relatively large sample size, they wrote. However, the researchers also cautioned that their study focused on CBD as a single ingredient, and the results might not generalize to other CBD formulations. They also noted that more research is needed to examine both higher doses of CBD and different types of pain disorders.

The study was supported by the Danish Psoriasis Foundation Grant and the Danish Rheumatism Foundation. The researchers had no financial conflicts to disclose.

THE CASE

A 75-year-old man with a history of osteoarthritis presented to our clinic with worsening weakness over the previous month. His signs and symptoms included profound fatigue, subjective fevers, a 10-pound weight loss, ankle swelling, myalgias in his legs and back, shortness of breath, and a persistent cough. The patient was otherwise previously healthy.

The patient’s heart and lung exams were normal. Initial outpatient labs showed significantly elevated inflammatory markers, with an erythrocyte sedimentation rate (ESR) of 102 mm/h (normal range for men ≥ 50 years, 0-20 mm/h) and a C-reactive protein (CRP) level of 11.1 mg/L (normal range, < 3 mg/L). The patient also had an elevated white blood cell count of 12,000/mcL (normal range, 4500-11,000/mcL). His hemoglobin was low (11 g/dL; normal range, 13.5-17.5 g/dL) and so was his albumin level (2.9 g/dL; normal range, 3.4-5.4 g/dL). The results of his prostate-specific antigen and brain natriuretic peptide tests were both normal. The results of a computed tomography scan of his thorax, abdomen, and pelvis were negative for malignancy.

The patient returned to our clinic 3 days later with severe weakness, which inhibited him from walking. He complained of a severe spasmodic pain between his shoulder blades. He denied joint stiffness, headaches, vision changes, or jaw claudication. The patient’s son had noted an overall increase in his father’s baseline heart rate, with readings increasing from the 50 beats/min range to the 70 beats/min range; this raised concern for a ­catecholamine-secreting tumor. There was also concern for occult infection and malignancy, or an autoimmune process, such as polymyalgia rheumatica. Due to his extreme weakness, the patient was directly admitted to the hospital for further work-up.

THE DIAGNOSIS

Concern for a smoldering infection prompted an order for a ­transthoracic echocardiogram. Images revealed a large mass on the mitral valve (FIGURE 1). Blood cultures quickly grew Streptococcus sanguinis. Additional work-up with a transesophageal echocardiogram (TEE) showed a “windsock” deformity (thinning and ballooning of the mitral valve), a known sequela of infective endocarditis (FIGURE 2).¹ Further history obtained after the TEE revealed the patient had had a routine dental cleaning the month before his symptoms began. A murmur was then also detected.

DISCUSSION

Infective endocarditis (IE) is uncommon and difficult to diagnose; it has a high early-­mortality rate of 30%.² TEE is the recommended imaging study for IE, because it is more sensitive than a transthoracic echocardiogram for identifying vegetations on the valves and it is more cost effective.³

The modified Duke Criteria provide guidance for diagnosis of endocarditis. Major criteria focus on positive blood cultures and evidence of endocardial involvement. Minor criteria include predisposing heart conditions, intravenous drug use (IVDU), fever, and vascular and immunologic phenomena. As many as 90% of patients have a fever and often experience weight loss.⁴ Murmurs are auscultated in up to 85% of patients, and embolic features are present in up to 25% of patients at the time of diagnosis.⁴ In the developed world, Janeway lesions, Osler nodes, and splinter hemorrhages are increasingly rare, as patients usually present earlier in the disease course.⁴ While ESR and CRP are generally elevated in cases of IE, they are not part of the Duke Criteria.⁴

A closer look at risk factors

In 2007, guidelines for the prevention, treatment, and management of endocarditis were given significant categorical revision by the American Heart Association for the first time in 50 years.⁵ Recommendations for antibiotic prophylaxis prior to dental procedures became more restrictive, to include only 4 groups of high-risk patients: those with prosthetic cardiac valves, those with a history of IE, those with congenital heart disease, and cardiac transplant recipients.⁴ The rationale for these restrictions included the small risk for anaphylaxis and potential increase in risk for bacterial resistance associated with antibiotic prophylaxis.⁴ A review published in 2021 noted no increase in the frequency of, nor the morbidity and mortality from, viridans group streptococcal IE since the guideline updates.⁵

Continue to: There is an emerging consensus...

There is an emerging consensus that poor oral hygiene and gingival bleeding after tooth brushing promote a chronic low-grade bacteremia that may be more strongly associated with IE than an isolated dental extraction.⁶ Poor dental hygiene, defined as dental plaque and calculus, is especially common in the elderly, who are known to let their dental hygiene lapse.⁶ In our patient’s case, his generally poor oral hygiene was more likely the cause of his IE than his routine dental cleaning.

Other risk factors include IV drug use. At our tertiary care hospital in western North Carolina, 48% of patients with endocarditis had an additional diagnosis of opiate or narcotic dependence (Ryan Tilton, PharmD, email communication, June 7, 2018). Interestingly, though, only 16% of patients in North America with endocarditis were found to be currently using IV drugs.⁷

Our patient was treated with IV antibiotics for 4 weeks and underwent rehabilitation at a skilled nursing facility. Four weeks after diagnosis, he underwent an endoscopic porcine mitral valve replacement. Two months after that, he returned to his previously active lifestyle and began riding his stationary bike. The patient also began taking a daily aspirin. Consistent with current guidelines, he now gets antibiotic prophylaxis prior to dental procedures.

THE TAKEAWAY

This patient, without any history of IVDU or cardiac valvular abnormalities, presented with symptoms classic for a developing malignancy or possible rheumatologic condition. Subacute IE may manifest similarly, with vague symptoms such as myalgias, fatigue, chills, and/or anemia. In non-drug users, suspicion for endocarditis should be highest in men older than age 60. Also, it’s important to auscultate for a new heart murmur. In our patient’s case, no murmur was auscultated until after his TEE. JFP

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

THE CASE

A 75-year-old man with a history of osteoarthritis presented to our clinic with worsening weakness over the previous month. His signs and symptoms included profound fatigue, subjective fevers, a 10-pound weight loss, ankle swelling, myalgias in his legs and back, shortness of breath, and a persistent cough. The patient was otherwise previously healthy.

The patient’s heart and lung exams were normal. Initial outpatient labs showed significantly elevated inflammatory markers, with an erythrocyte sedimentation rate (ESR) of 102 mm/h (normal range for men ≥ 50 years, 0-20 mm/h) and a C-reactive protein (CRP) level of 11.1 mg/L (normal range, < 3 mg/L). The patient also had an elevated white blood cell count of 12,000/mcL (normal range, 4500-11,000/mcL). His hemoglobin was low (11 g/dL; normal range, 13.5-17.5 g/dL) and so was his albumin level (2.9 g/dL; normal range, 3.4-5.4 g/dL). The results of his prostate-specific antigen and brain natriuretic peptide tests were both normal. The results of a computed tomography scan of his thorax, abdomen, and pelvis were negative for malignancy.

The patient returned to our clinic 3 days later with severe weakness, which inhibited him from walking. He complained of a severe spasmodic pain between his shoulder blades. He denied joint stiffness, headaches, vision changes, or jaw claudication. The patient’s son had noted an overall increase in his father’s baseline heart rate, with readings increasing from the 50 beats/min range to the 70 beats/min range; this raised concern for a ­catecholamine-secreting tumor. There was also concern for occult infection and malignancy, or an autoimmune process, such as polymyalgia rheumatica. Due to his extreme weakness, the patient was directly admitted to the hospital for further work-up.

THE DIAGNOSIS

Concern for a smoldering infection prompted an order for a ­transthoracic echocardiogram. Images revealed a large mass on the mitral valve (FIGURE 1). Blood cultures quickly grew Streptococcus sanguinis. Additional work-up with a transesophageal echocardiogram (TEE) showed a “windsock” deformity (thinning and ballooning of the mitral valve), a known sequela of infective endocarditis (FIGURE 2).¹ Further history obtained after the TEE revealed the patient had had a routine dental cleaning the month before his symptoms began. A murmur was then also detected.

DISCUSSION

Infective endocarditis (IE) is uncommon and difficult to diagnose; it has a high early-­mortality rate of 30%.² TEE is the recommended imaging study for IE, because it is more sensitive than a transthoracic echocardiogram for identifying vegetations on the valves and it is more cost effective.³

The modified Duke Criteria provide guidance for diagnosis of endocarditis. Major criteria focus on positive blood cultures and evidence of endocardial involvement. Minor criteria include predisposing heart conditions, intravenous drug use (IVDU), fever, and vascular and immunologic phenomena. As many as 90% of patients have a fever and often experience weight loss.⁴ Murmurs are auscultated in up to 85% of patients, and embolic features are present in up to 25% of patients at the time of diagnosis.⁴ In the developed world, Janeway lesions, Osler nodes, and splinter hemorrhages are increasingly rare, as patients usually present earlier in the disease course.⁴ While ESR and CRP are generally elevated in cases of IE, they are not part of the Duke Criteria.⁴

A closer look at risk factors

In 2007, guidelines for the prevention, treatment, and management of endocarditis were given significant categorical revision by the American Heart Association for the first time in 50 years.⁵ Recommendations for antibiotic prophylaxis prior to dental procedures became more restrictive, to include only 4 groups of high-risk patients: those with prosthetic cardiac valves, those with a history of IE, those with congenital heart disease, and cardiac transplant recipients.⁴ The rationale for these restrictions included the small risk for anaphylaxis and potential increase in risk for bacterial resistance associated with antibiotic prophylaxis.⁴ A review published in 2021 noted no increase in the frequency of, nor the morbidity and mortality from, viridans group streptococcal IE since the guideline updates.⁵

Continue to: There is an emerging consensus...

There is an emerging consensus that poor oral hygiene and gingival bleeding after tooth brushing promote a chronic low-grade bacteremia that may be more strongly associated with IE than an isolated dental extraction.⁶ Poor dental hygiene, defined as dental plaque and calculus, is especially common in the elderly, who are known to let their dental hygiene lapse.⁶ In our patient’s case, his generally poor oral hygiene was more likely the cause of his IE than his routine dental cleaning.

Other risk factors include IV drug use. At our tertiary care hospital in western North Carolina, 48% of patients with endocarditis had an additional diagnosis of opiate or narcotic dependence (Ryan Tilton, PharmD, email communication, June 7, 2018). Interestingly, though, only 16% of patients in North America with endocarditis were found to be currently using IV drugs.⁷

Our patient was treated with IV antibiotics for 4 weeks and underwent rehabilitation at a skilled nursing facility. Four weeks after diagnosis, he underwent an endoscopic porcine mitral valve replacement. Two months after that, he returned to his previously active lifestyle and began riding his stationary bike. The patient also began taking a daily aspirin. Consistent with current guidelines, he now gets antibiotic prophylaxis prior to dental procedures.

THE TAKEAWAY

This patient, without any history of IVDU or cardiac valvular abnormalities, presented with symptoms classic for a developing malignancy or possible rheumatologic condition. Subacute IE may manifest similarly, with vague symptoms such as myalgias, fatigue, chills, and/or anemia. In non-drug users, suspicion for endocarditis should be highest in men older than age 60. Also, it’s important to auscultate for a new heart murmur. In our patient’s case, no murmur was auscultated until after his TEE. JFP

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

THE CASE

A 75-year-old man with a history of osteoarthritis presented to our clinic with worsening weakness over the previous month. His signs and symptoms included profound fatigue, subjective fevers, a 10-pound weight loss, ankle swelling, myalgias in his legs and back, shortness of breath, and a persistent cough. The patient was otherwise previously healthy.

The patient’s heart and lung exams were normal. Initial outpatient labs showed significantly elevated inflammatory markers, with an erythrocyte sedimentation rate (ESR) of 102 mm/h (normal range for men ≥ 50 years, 0-20 mm/h) and a C-reactive protein (CRP) level of 11.1 mg/L (normal range, < 3 mg/L). The patient also had an elevated white blood cell count of 12,000/mcL (normal range, 4500-11,000/mcL). His hemoglobin was low (11 g/dL; normal range, 13.5-17.5 g/dL) and so was his albumin level (2.9 g/dL; normal range, 3.4-5.4 g/dL). The results of his prostate-specific antigen and brain natriuretic peptide tests were both normal. The results of a computed tomography scan of his thorax, abdomen, and pelvis were negative for malignancy.

The patient returned to our clinic 3 days later with severe weakness, which inhibited him from walking. He complained of a severe spasmodic pain between his shoulder blades. He denied joint stiffness, headaches, vision changes, or jaw claudication. The patient’s son had noted an overall increase in his father’s baseline heart rate, with readings increasing from the 50 beats/min range to the 70 beats/min range; this raised concern for a ­catecholamine-secreting tumor. There was also concern for occult infection and malignancy, or an autoimmune process, such as polymyalgia rheumatica. Due to his extreme weakness, the patient was directly admitted to the hospital for further work-up.

THE DIAGNOSIS

Concern for a smoldering infection prompted an order for a ­transthoracic echocardiogram. Images revealed a large mass on the mitral valve (FIGURE 1). Blood cultures quickly grew Streptococcus sanguinis. Additional work-up with a transesophageal echocardiogram (TEE) showed a “windsock” deformity (thinning and ballooning of the mitral valve), a known sequela of infective endocarditis (FIGURE 2).¹ Further history obtained after the TEE revealed the patient had had a routine dental cleaning the month before his symptoms began. A murmur was then also detected.

DISCUSSION

Infective endocarditis (IE) is uncommon and difficult to diagnose; it has a high early-­mortality rate of 30%.² TEE is the recommended imaging study for IE, because it is more sensitive than a transthoracic echocardiogram for identifying vegetations on the valves and it is more cost effective.³

The modified Duke Criteria provide guidance for diagnosis of endocarditis. Major criteria focus on positive blood cultures and evidence of endocardial involvement. Minor criteria include predisposing heart conditions, intravenous drug use (IVDU), fever, and vascular and immunologic phenomena. As many as 90% of patients have a fever and often experience weight loss.⁴ Murmurs are auscultated in up to 85% of patients, and embolic features are present in up to 25% of patients at the time of diagnosis.⁴ In the developed world, Janeway lesions, Osler nodes, and splinter hemorrhages are increasingly rare, as patients usually present earlier in the disease course.⁴ While ESR and CRP are generally elevated in cases of IE, they are not part of the Duke Criteria.⁴

A closer look at risk factors

In 2007, guidelines for the prevention, treatment, and management of endocarditis were given significant categorical revision by the American Heart Association for the first time in 50 years.⁵ Recommendations for antibiotic prophylaxis prior to dental procedures became more restrictive, to include only 4 groups of high-risk patients: those with prosthetic cardiac valves, those with a history of IE, those with congenital heart disease, and cardiac transplant recipients.⁴ The rationale for these restrictions included the small risk for anaphylaxis and potential increase in risk for bacterial resistance associated with antibiotic prophylaxis.⁴ A review published in 2021 noted no increase in the frequency of, nor the morbidity and mortality from, viridans group streptococcal IE since the guideline updates.⁵

Continue to: There is an emerging consensus...

There is an emerging consensus that poor oral hygiene and gingival bleeding after tooth brushing promote a chronic low-grade bacteremia that may be more strongly associated with IE than an isolated dental extraction.⁶ Poor dental hygiene, defined as dental plaque and calculus, is especially common in the elderly, who are known to let their dental hygiene lapse.⁶ In our patient’s case, his generally poor oral hygiene was more likely the cause of his IE than his routine dental cleaning.

Other risk factors include IV drug use. At our tertiary care hospital in western North Carolina, 48% of patients with endocarditis had an additional diagnosis of opiate or narcotic dependence (Ryan Tilton, PharmD, email communication, June 7, 2018). Interestingly, though, only 16% of patients in North America with endocarditis were found to be currently using IV drugs.⁷

Our patient was treated with IV antibiotics for 4 weeks and underwent rehabilitation at a skilled nursing facility. Four weeks after diagnosis, he underwent an endoscopic porcine mitral valve replacement. Two months after that, he returned to his previously active lifestyle and began riding his stationary bike. The patient also began taking a daily aspirin. Consistent with current guidelines, he now gets antibiotic prophylaxis prior to dental procedures.

THE TAKEAWAY

This patient, without any history of IVDU or cardiac valvular abnormalities, presented with symptoms classic for a developing malignancy or possible rheumatologic condition. Subacute IE may manifest similarly, with vague symptoms such as myalgias, fatigue, chills, and/or anemia. In non-drug users, suspicion for endocarditis should be highest in men older than age 60. Also, it’s important to auscultate for a new heart murmur. In our patient’s case, no murmur was auscultated until after his TEE. JFP

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

Patients with rheumatoid arthritis in remission had a rate of flare following vaccination with the Pfizer/BioNtech COVID-19 vaccine that appears to be on par with rates seen with other vaccines in patients with RA, according to results from a small Italian cohort study.

“Our data show a very low flare rate [7.8% (6 of 77)] after the BNT162b2 COVID-19 vaccine in patients with RA in remission and are consistent with previous findings about varicella-zoster virus (6.7%) and hepatitis B virus (2.2%) vaccinations,” Riccardo Bixio, MD, and colleagues from University of Verona (Italy) Hospital Trust wrote in ACR Open Rheumatology. “Because remission is not commonly obtained in the real world, we are aware that our findings may not be generalizable to all patients with RA receiving COVID-19 vaccination.”

Other studies of flare rate after COVID-19 vaccination in patients with a variety of rheumatic and musculoskeletal diseases have reported rates ranging from 5% to 17%, they said.

The 77 consecutive patients from the University of Verona center that conducted the study were all in clinical remission in the 3 months before vaccination based on a 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) of less than 2.6, and all had discontinued antirheumatic therapies according to American College of Rheumatology COVID-19 recommendations. The researchers defined flares as agreement between patient and rheumatologist assessments and a DAS28-CRP increase of more than 1.2.

Five of the six people with a flare had it occur after the second dose at a mean of 2.6 days later, and all flares were resolved within 2 weeks using glucocorticoids with or without anti-inflammatory drugs. One flare was called severe. The overall disease activity of the cohort after 3 months was not significantly changed after vaccination.

In noting that five out of the six patients with flares had withdrawn or delayed antirheumatic therapies around the time of vaccination according to ACR recommendations, the authors wrote that “Even if there is no direct evidence that holding therapies could occur in a higher proportion of disease flares, we suggest that clinicians consider this possibility when counseling patients about COVID-19 vaccination.”

The authors had no outside funding for the study and had no potential conflicts of interest to disclose.

[email protected]

Patients with rheumatoid arthritis in remission had a rate of flare following vaccination with the Pfizer/BioNtech COVID-19 vaccine that appears to be on par with rates seen with other vaccines in patients with RA, according to results from a small Italian cohort study.

“Our data show a very low flare rate [7.8% (6 of 77)] after the BNT162b2 COVID-19 vaccine in patients with RA in remission and are consistent with previous findings about varicella-zoster virus (6.7%) and hepatitis B virus (2.2%) vaccinations,” Riccardo Bixio, MD, and colleagues from University of Verona (Italy) Hospital Trust wrote in ACR Open Rheumatology. “Because remission is not commonly obtained in the real world, we are aware that our findings may not be generalizable to all patients with RA receiving COVID-19 vaccination.”

Other studies of flare rate after COVID-19 vaccination in patients with a variety of rheumatic and musculoskeletal diseases have reported rates ranging from 5% to 17%, they said.

The 77 consecutive patients from the University of Verona center that conducted the study were all in clinical remission in the 3 months before vaccination based on a 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) of less than 2.6, and all had discontinued antirheumatic therapies according to American College of Rheumatology COVID-19 recommendations. The researchers defined flares as agreement between patient and rheumatologist assessments and a DAS28-CRP increase of more than 1.2.

Five of the six people with a flare had it occur after the second dose at a mean of 2.6 days later, and all flares were resolved within 2 weeks using glucocorticoids with or without anti-inflammatory drugs. One flare was called severe. The overall disease activity of the cohort after 3 months was not significantly changed after vaccination.

In noting that five out of the six patients with flares had withdrawn or delayed antirheumatic therapies around the time of vaccination according to ACR recommendations, the authors wrote that “Even if there is no direct evidence that holding therapies could occur in a higher proportion of disease flares, we suggest that clinicians consider this possibility when counseling patients about COVID-19 vaccination.”

The authors had no outside funding for the study and had no potential conflicts of interest to disclose.

[email protected]

Patients with rheumatoid arthritis in remission had a rate of flare following vaccination with the Pfizer/BioNtech COVID-19 vaccine that appears to be on par with rates seen with other vaccines in patients with RA, according to results from a small Italian cohort study.

“Our data show a very low flare rate [7.8% (6 of 77)] after the BNT162b2 COVID-19 vaccine in patients with RA in remission and are consistent with previous findings about varicella-zoster virus (6.7%) and hepatitis B virus (2.2%) vaccinations,” Riccardo Bixio, MD, and colleagues from University of Verona (Italy) Hospital Trust wrote in ACR Open Rheumatology. “Because remission is not commonly obtained in the real world, we are aware that our findings may not be generalizable to all patients with RA receiving COVID-19 vaccination.”

Other studies of flare rate after COVID-19 vaccination in patients with a variety of rheumatic and musculoskeletal diseases have reported rates ranging from 5% to 17%, they said.

The 77 consecutive patients from the University of Verona center that conducted the study were all in clinical remission in the 3 months before vaccination based on a 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) of less than 2.6, and all had discontinued antirheumatic therapies according to American College of Rheumatology COVID-19 recommendations. The researchers defined flares as agreement between patient and rheumatologist assessments and a DAS28-CRP increase of more than 1.2.

Five of the six people with a flare had it occur after the second dose at a mean of 2.6 days later, and all flares were resolved within 2 weeks using glucocorticoids with or without anti-inflammatory drugs. One flare was called severe. The overall disease activity of the cohort after 3 months was not significantly changed after vaccination.

In noting that five out of the six patients with flares had withdrawn or delayed antirheumatic therapies around the time of vaccination according to ACR recommendations, the authors wrote that “Even if there is no direct evidence that holding therapies could occur in a higher proportion of disease flares, we suggest that clinicians consider this possibility when counseling patients about COVID-19 vaccination.”

The authors had no outside funding for the study and had no potential conflicts of interest to disclose.

[email protected]

A single-arm, phase 2 clinical trial of atezolizumab with chemotherapy for patients with nonsquamous non-small cell lung cancer (NSCLC) and brain metastases shows promise for improving progression-free survival, according to a study presented at the 2021 World Congress on Lung Cancer.

The trial is noteworthy because to date, few patients with nonsquamous NSCLC and untreated asymptomatic brain metastases (or those treated with corticosteroids), were ever included in clinical trials that examine the efficacy and safety of chemotherapy and immunotherapy together as first-line treatment, said Ernest Nadal, MD, PhD, of the University of Barcelona Catalan Institute of Oncology at L’Hospitalet de Llobregat. He and his colleagues presented their findings at the meeting, which was organized by the International Association for the Study of Lung Cancer (IASLC).

With only 40 patients, the clinical trial was small, but the safety profile of atezolizumab combined with carboplatin and pemetrexed was favorable in patients with untreated brain metastases and those receiving corticosteroids (dexamethasone of 4 mg once a day or less).

At a median follow-up of 17.3 months, median intracranial and systemic progression-free survival – the co-primary study endpoints, along with safety – were 6.9 months and 8.9 months in 40 patients treated with the immune checkpoint inhibitor and chemotherapy combination, and the 18-month progression-free survival rates were 10.4% and 24.9%, respectively, Dr. Nadal said.

Secondary study endpoints included response rate and overall survival rate. The overall response rate was 40% at 12 weeks; 19 patients (47.5%) had stable disease in the central nervous system, and 19 (47.5%) had a systemic response. The median overall survival was 13.6 months, and 2-year overall survival was 32%.

“The 12-week progression-free survival rate was 60%, [which was] above the expected rate of 50%, and the grade 2-4 toxicity rate was 27.5%, [which was] below the threshold of 35%,” Dr. Nadal said.

Four patients achieved complete response in the brain, and four patients had discordance between systemic and central nervous system response: two with progressive disease in the body and stable disease in the brain, and two with progressive disease in the brain and stable disease in the body.

Study subjects were chemotherapy-naive patients with stage IV non-squamous NSCLC without estimated glomerular filtration rate (EGFR) or anaplastic lymphoma kinase (ALK) genetic alterations and with untreated brain metastases. They were enrolled from 11 clinical sites and treated with carboplatin (5 AUCs) and pemetrexed (500 mg/m²) plus atezolizumab (1,200 mg) every 3 weeks for four to six cycles, followed by maintenance with pemetrexed plus atezolizumab for 2 years or until disease progression or unacceptable toxicity.

Grade 3 treatment-related adverse events occurring in at least 5% of patients were anemia (eight patients), back pain (four patients), thrombocytopenia (two patients) and dyspnea, pneumonitis, and elevated alanine transaminase (one patient each). Grade 4 treatment-related adverse events occurred in three patients and included thrombocytopenia, neutropenia, and hallucinations.

“Brain metastases are the most frequent cancer-related neurological complication and have a major impact on the neurocognitive function, quality of life, and the patient’s prognosis,” Dr. Nadal said, adding that local therapy could add toxicity and delay systemic treatment.

The progression-free survival findings in this study are similar to those reported in the KEYNOTE-189 clinical trial in patients with brain metastases, which showed improved outcomes with pembrolizumab plus chemotherapy in patients with previously untreated metastatic nonsquamous NSCLC, Dr. Nadal said.

The safety profile was also favorable – even in the 17 patients receiving corticosteroids at baseline.

“This combination can result in clinical benefit in terms of overall survival in this population “Correlative studies with brain imaging and blood samples are currently ongoing,” he said.

Charu Aggarwal, MD, MPH, an oncologist with Penn Medicine who specializes in lung cancer, said the findings help address how patients with untreated, asymptomatic brain metastases should be treated.

Taken together with findings from other prospective and retrospective trials in this population, the outcomes demonstrate that “in patients with asymptomatic brain metastases, upfront immunochemotherapy is associated with intracranial response rates,” she said. Patients with asymptomatic brain metastases can be safely treated with chemoimmunotherapy, but “proper patient selection is going to be key.”

Unanswered questions from this study include the size of brain metastases at trial enrollment, whether programmed death-ligand 1 status matters, and whether there is an optimal dose of steroids that should be mandated for inclusion into trials, Dr. Aggarwal added, noting that several trials enrolling patients with lung cancer are seeking to answer these questions.

Dr. Nadal reported receiving research support, speaker bureau fees, and/or honoraria from multiple pharmaceutical companies. Dr. Aggarwal reported serving on an advisory board for multiple pharmaceutical companies. She also reported clinical trial funding to her institution from multiple companies.

[email protected]

A single-arm, phase 2 clinical trial of atezolizumab with chemotherapy for patients with nonsquamous non-small cell lung cancer (NSCLC) and brain metastases shows promise for improving progression-free survival, according to a study presented at the 2021 World Congress on Lung Cancer.

The trial is noteworthy because to date, few patients with nonsquamous NSCLC and untreated asymptomatic brain metastases (or those treated with corticosteroids), were ever included in clinical trials that examine the efficacy and safety of chemotherapy and immunotherapy together as first-line treatment, said Ernest Nadal, MD, PhD, of the University of Barcelona Catalan Institute of Oncology at L’Hospitalet de Llobregat. He and his colleagues presented their findings at the meeting, which was organized by the International Association for the Study of Lung Cancer (IASLC).

With only 40 patients, the clinical trial was small, but the safety profile of atezolizumab combined with carboplatin and pemetrexed was favorable in patients with untreated brain metastases and those receiving corticosteroids (dexamethasone of 4 mg once a day or less).

At a median follow-up of 17.3 months, median intracranial and systemic progression-free survival – the co-primary study endpoints, along with safety – were 6.9 months and 8.9 months in 40 patients treated with the immune checkpoint inhibitor and chemotherapy combination, and the 18-month progression-free survival rates were 10.4% and 24.9%, respectively, Dr. Nadal said.

Secondary study endpoints included response rate and overall survival rate. The overall response rate was 40% at 12 weeks; 19 patients (47.5%) had stable disease in the central nervous system, and 19 (47.5%) had a systemic response. The median overall survival was 13.6 months, and 2-year overall survival was 32%.

“The 12-week progression-free survival rate was 60%, [which was] above the expected rate of 50%, and the grade 2-4 toxicity rate was 27.5%, [which was] below the threshold of 35%,” Dr. Nadal said.

Four patients achieved complete response in the brain, and four patients had discordance between systemic and central nervous system response: two with progressive disease in the body and stable disease in the brain, and two with progressive disease in the brain and stable disease in the body.

Study subjects were chemotherapy-naive patients with stage IV non-squamous NSCLC without estimated glomerular filtration rate (EGFR) or anaplastic lymphoma kinase (ALK) genetic alterations and with untreated brain metastases. They were enrolled from 11 clinical sites and treated with carboplatin (5 AUCs) and pemetrexed (500 mg/m²) plus atezolizumab (1,200 mg) every 3 weeks for four to six cycles, followed by maintenance with pemetrexed plus atezolizumab for 2 years or until disease progression or unacceptable toxicity.

Grade 3 treatment-related adverse events occurring in at least 5% of patients were anemia (eight patients), back pain (four patients), thrombocytopenia (two patients) and dyspnea, pneumonitis, and elevated alanine transaminase (one patient each). Grade 4 treatment-related adverse events occurred in three patients and included thrombocytopenia, neutropenia, and hallucinations.

“Brain metastases are the most frequent cancer-related neurological complication and have a major impact on the neurocognitive function, quality of life, and the patient’s prognosis,” Dr. Nadal said, adding that local therapy could add toxicity and delay systemic treatment.

The progression-free survival findings in this study are similar to those reported in the KEYNOTE-189 clinical trial in patients with brain metastases, which showed improved outcomes with pembrolizumab plus chemotherapy in patients with previously untreated metastatic nonsquamous NSCLC, Dr. Nadal said.

The safety profile was also favorable – even in the 17 patients receiving corticosteroids at baseline.

“This combination can result in clinical benefit in terms of overall survival in this population “Correlative studies with brain imaging and blood samples are currently ongoing,” he said.

Charu Aggarwal, MD, MPH, an oncologist with Penn Medicine who specializes in lung cancer, said the findings help address how patients with untreated, asymptomatic brain metastases should be treated.

Taken together with findings from other prospective and retrospective trials in this population, the outcomes demonstrate that “in patients with asymptomatic brain metastases, upfront immunochemotherapy is associated with intracranial response rates,” she said. Patients with asymptomatic brain metastases can be safely treated with chemoimmunotherapy, but “proper patient selection is going to be key.”

Unanswered questions from this study include the size of brain metastases at trial enrollment, whether programmed death-ligand 1 status matters, and whether there is an optimal dose of steroids that should be mandated for inclusion into trials, Dr. Aggarwal added, noting that several trials enrolling patients with lung cancer are seeking to answer these questions.

Dr. Nadal reported receiving research support, speaker bureau fees, and/or honoraria from multiple pharmaceutical companies. Dr. Aggarwal reported serving on an advisory board for multiple pharmaceutical companies. She also reported clinical trial funding to her institution from multiple companies.

[email protected]

A single-arm, phase 2 clinical trial of atezolizumab with chemotherapy for patients with nonsquamous non-small cell lung cancer (NSCLC) and brain metastases shows promise for improving progression-free survival, according to a study presented at the 2021 World Congress on Lung Cancer.

The trial is noteworthy because to date, few patients with nonsquamous NSCLC and untreated asymptomatic brain metastases (or those treated with corticosteroids), were ever included in clinical trials that examine the efficacy and safety of chemotherapy and immunotherapy together as first-line treatment, said Ernest Nadal, MD, PhD, of the University of Barcelona Catalan Institute of Oncology at L’Hospitalet de Llobregat. He and his colleagues presented their findings at the meeting, which was organized by the International Association for the Study of Lung Cancer (IASLC).

With only 40 patients, the clinical trial was small, but the safety profile of atezolizumab combined with carboplatin and pemetrexed was favorable in patients with untreated brain metastases and those receiving corticosteroids (dexamethasone of 4 mg once a day or less).

At a median follow-up of 17.3 months, median intracranial and systemic progression-free survival – the co-primary study endpoints, along with safety – were 6.9 months and 8.9 months in 40 patients treated with the immune checkpoint inhibitor and chemotherapy combination, and the 18-month progression-free survival rates were 10.4% and 24.9%, respectively, Dr. Nadal said.

Secondary study endpoints included response rate and overall survival rate. The overall response rate was 40% at 12 weeks; 19 patients (47.5%) had stable disease in the central nervous system, and 19 (47.5%) had a systemic response. The median overall survival was 13.6 months, and 2-year overall survival was 32%.

“The 12-week progression-free survival rate was 60%, [which was] above the expected rate of 50%, and the grade 2-4 toxicity rate was 27.5%, [which was] below the threshold of 35%,” Dr. Nadal said.

Four patients achieved complete response in the brain, and four patients had discordance between systemic and central nervous system response: two with progressive disease in the body and stable disease in the brain, and two with progressive disease in the brain and stable disease in the body.

Study subjects were chemotherapy-naive patients with stage IV non-squamous NSCLC without estimated glomerular filtration rate (EGFR) or anaplastic lymphoma kinase (ALK) genetic alterations and with untreated brain metastases. They were enrolled from 11 clinical sites and treated with carboplatin (5 AUCs) and pemetrexed (500 mg/m²) plus atezolizumab (1,200 mg) every 3 weeks for four to six cycles, followed by maintenance with pemetrexed plus atezolizumab for 2 years or until disease progression or unacceptable toxicity.

Grade 3 treatment-related adverse events occurring in at least 5% of patients were anemia (eight patients), back pain (four patients), thrombocytopenia (two patients) and dyspnea, pneumonitis, and elevated alanine transaminase (one patient each). Grade 4 treatment-related adverse events occurred in three patients and included thrombocytopenia, neutropenia, and hallucinations.

“Brain metastases are the most frequent cancer-related neurological complication and have a major impact on the neurocognitive function, quality of life, and the patient’s prognosis,” Dr. Nadal said, adding that local therapy could add toxicity and delay systemic treatment.

The progression-free survival findings in this study are similar to those reported in the KEYNOTE-189 clinical trial in patients with brain metastases, which showed improved outcomes with pembrolizumab plus chemotherapy in patients with previously untreated metastatic nonsquamous NSCLC, Dr. Nadal said.

The safety profile was also favorable – even in the 17 patients receiving corticosteroids at baseline.

“This combination can result in clinical benefit in terms of overall survival in this population “Correlative studies with brain imaging and blood samples are currently ongoing,” he said.

Charu Aggarwal, MD, MPH, an oncologist with Penn Medicine who specializes in lung cancer, said the findings help address how patients with untreated, asymptomatic brain metastases should be treated.

Taken together with findings from other prospective and retrospective trials in this population, the outcomes demonstrate that “in patients with asymptomatic brain metastases, upfront immunochemotherapy is associated with intracranial response rates,” she said. Patients with asymptomatic brain metastases can be safely treated with chemoimmunotherapy, but “proper patient selection is going to be key.”

Unanswered questions from this study include the size of brain metastases at trial enrollment, whether programmed death-ligand 1 status matters, and whether there is an optimal dose of steroids that should be mandated for inclusion into trials, Dr. Aggarwal added, noting that several trials enrolling patients with lung cancer are seeking to answer these questions.

Dr. Nadal reported receiving research support, speaker bureau fees, and/or honoraria from multiple pharmaceutical companies. Dr. Aggarwal reported serving on an advisory board for multiple pharmaceutical companies. She also reported clinical trial funding to her institution from multiple companies.

[email protected]

Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.

To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.

Success for some

Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.

In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
 

Looking forward

“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.

The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.

To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.

Success for some

Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.

In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
 

Looking forward

“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.

The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.

To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.

Success for some

Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.

In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
 

Looking forward

“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.

The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

Clinicians should pay particular attention to malignant pleural mesothelioma patients with COVID-19. Among people with thoracic malignancies, they have an especially high risk of bad outcomes, according to Susana Cedres, MD, PhD, a thoracic medical oncologist at Vall d’Hebron University Hospital, Barcelona.

At the annual World Conference on Lung Cancer, she reported on her institution’s experience during the first year of the pandemic before widespread vaccine rollouts.

Among 38 malignant pleural mesothelioma (MPM) patients, seven (18%) patients were diagnosed with COVID-19 and of these, three patients were asymptomatic, four (57%) died of complications including bilateral pneumonia within a median of less than half a month after diagnosis, and a fifth patient died from MPM progression.

The findings confirm the particular risk of COVID in MPM. According to researchers reporting in Scientific Reports, mesothelioma was the only cancer linked to significantly worse outcomes. Other risks included tuberculosis, drug use, hepatitis, HIV/AIDS, cardiomyopathy, and diabetes.

However, the Barcelona report only has seven patients, and it’s one of only a few to address the specifics of COVID in MPM.

“There really is a need for more inclusion of MPM patients in international [COVID] registries” to better characterize the course of infection and improve outcomes, said study discussant Francoise Galateau-Salle, MD, PhD, a mesothelioma expert at the Cancer Center Leon Berard in Lyon, France.

Among the seven positive cases in Barcelona, almost all had comorbidities, with the most common being cardiovascular disease in four patients (57%). Only two patients (29%) were on oncologic treatment at the time they were diagnosed, and the median age at diagnosis was 62 years. Four cases were in men, three in women. MPM stage was not reported.

WCLC 2021 was organized by the International Association for the Study of Lung Cancer.

No funding source was reported. Dr. Cedres is an adviser and/or reported travel expenses from a number of companies, including Merck, Pfizer, and Bristol-Myers Squibb. Dr. Galateau-Salle had no disclosures.

[email protected]

Clinicians should pay particular attention to malignant pleural mesothelioma patients with COVID-19. Among people with thoracic malignancies, they have an especially high risk of bad outcomes, according to Susana Cedres, MD, PhD, a thoracic medical oncologist at Vall d’Hebron University Hospital, Barcelona.

At the annual World Conference on Lung Cancer, she reported on her institution’s experience during the first year of the pandemic before widespread vaccine rollouts.

Among 38 malignant pleural mesothelioma (MPM) patients, seven (18%) patients were diagnosed with COVID-19 and of these, three patients were asymptomatic, four (57%) died of complications including bilateral pneumonia within a median of less than half a month after diagnosis, and a fifth patient died from MPM progression.

The findings confirm the particular risk of COVID in MPM. According to researchers reporting in Scientific Reports, mesothelioma was the only cancer linked to significantly worse outcomes. Other risks included tuberculosis, drug use, hepatitis, HIV/AIDS, cardiomyopathy, and diabetes.

However, the Barcelona report only has seven patients, and it’s one of only a few to address the specifics of COVID in MPM.

“There really is a need for more inclusion of MPM patients in international [COVID] registries” to better characterize the course of infection and improve outcomes, said study discussant Francoise Galateau-Salle, MD, PhD, a mesothelioma expert at the Cancer Center Leon Berard in Lyon, France.

Among the seven positive cases in Barcelona, almost all had comorbidities, with the most common being cardiovascular disease in four patients (57%). Only two patients (29%) were on oncologic treatment at the time they were diagnosed, and the median age at diagnosis was 62 years. Four cases were in men, three in women. MPM stage was not reported.

WCLC 2021 was organized by the International Association for the Study of Lung Cancer.

No funding source was reported. Dr. Cedres is an adviser and/or reported travel expenses from a number of companies, including Merck, Pfizer, and Bristol-Myers Squibb. Dr. Galateau-Salle had no disclosures.

[email protected]

Clinicians should pay particular attention to malignant pleural mesothelioma patients with COVID-19. Among people with thoracic malignancies, they have an especially high risk of bad outcomes, according to Susana Cedres, MD, PhD, a thoracic medical oncologist at Vall d’Hebron University Hospital, Barcelona.

At the annual World Conference on Lung Cancer, she reported on her institution’s experience during the first year of the pandemic before widespread vaccine rollouts.

Among 38 malignant pleural mesothelioma (MPM) patients, seven (18%) patients were diagnosed with COVID-19 and of these, three patients were asymptomatic, four (57%) died of complications including bilateral pneumonia within a median of less than half a month after diagnosis, and a fifth patient died from MPM progression.

The findings confirm the particular risk of COVID in MPM. According to researchers reporting in Scientific Reports, mesothelioma was the only cancer linked to significantly worse outcomes. Other risks included tuberculosis, drug use, hepatitis, HIV/AIDS, cardiomyopathy, and diabetes.

However, the Barcelona report only has seven patients, and it’s one of only a few to address the specifics of COVID in MPM.

“There really is a need for more inclusion of MPM patients in international [COVID] registries” to better characterize the course of infection and improve outcomes, said study discussant Francoise Galateau-Salle, MD, PhD, a mesothelioma expert at the Cancer Center Leon Berard in Lyon, France.

Among the seven positive cases in Barcelona, almost all had comorbidities, with the most common being cardiovascular disease in four patients (57%). Only two patients (29%) were on oncologic treatment at the time they were diagnosed, and the median age at diagnosis was 62 years. Four cases were in men, three in women. MPM stage was not reported.

WCLC 2021 was organized by the International Association for the Study of Lung Cancer.

No funding source was reported. Dr. Cedres is an adviser and/or reported travel expenses from a number of companies, including Merck, Pfizer, and Bristol-Myers Squibb. Dr. Galateau-Salle had no disclosures.

[email protected]

High-value care (HVC) is a philosophy and approach to medicine that focuses on achieving the best patient outcomes through evidence-based practice while minimizing harm to patients, wasted healthcare resources, and costs. Incorporating HVC principles in pediatric clinical decision-making is particularly important owing to the harms of hospitalization, overutilization, and overdiagnosis, as well as rising costs of pediatric care.^1-4 How can we maintain these principles in the face of a global pandemic and new emerging syndrome, multisystem inflammatory syndrome in children (MIS-C), which has dramatically impacted healthcare systems for children?

In this article, we discuss the barriers and opportunities around practicing HVC in our evolving approach to novel COVID-19 management in hospitalized children. We also draw lessons from our experiences on how we can respond to future events that rapidly shift our approach to care.

As children’s hospitals and pediatric providers responded to the COVID-19 pandemic, practice recommendations were implemented rapidly and changed rapidly. A major challenge with an event like this is how we respond to the unknown and uncertainty, something most healthcare workers are not comfortable doing at baseline,^5,6 particularly trainees and early-career physicians.⁷ With the benefit of hindsight, many early clinical approaches to care may now be seen as low-value care (LVC). For example, COVID-19 test availability was initially limited, and many hospitals utilized respiratory viral panels (RVPs) to potentially eliminate COVID-19 as an etiology of symptoms. RVP use increased during this time⁸; however, studies have shown that the co-infection rate of SARS-CoV2 with other respiratory viruses varies widely, so a positive RVP was of uncertain benefit.⁹ In addition, routine RVP use is often low value and may lead to overdiagnosis, additional overtesting cascades, and, at times, false reassurance and premature closure of the diagnostic workup.¹⁰

As our understanding of COVID-19 has expanded, rapid changes in treatment have also occurred. Early data were often preliminary and based on small trials of adults, and treatments ranged from inexpensive and available (dexamethasone) to quite expensive (remdesivir, monoclonal antibodies). Pragmatic randomized controlled trials (RCTs) are an important tool that may have been underutilized in pediatrics. Similar to our adult hospitalist colleagues’ experience,¹¹ the rapid rise in cases provided an opportunity to collaborate across institutions to assess which treatments were most effective. In particular, the predictable rise in rates of MIS-C after a surge in COVID-19 cases could have provided an avenue to evaluate the relative effectiveness of the various treatments used.¹² However, there were limited pediatric RCTs and thus a missed opportunity to establish an evidence-based pediatric standard of care for COVID-19 and MIS-C. This resulted in the development and dissemination of care practices before they were fully tested in children.

Similarly, the medical community has become increasingly aware of laboratory findings that may be predictive of clinical course.¹³ The outcomes of COVID and MIS-C are potentially severe, so looking for “early warning signs” with diagnostic testing is appealing. Clinicians responding to early data, and with a fear of missing something, may order a full panel of bloodwork for admitted patients to assist with decision-making and may underestimate the perceived minor harms and cost of unnecessary testing/admissions.³ However, most of the evidence regarding lab values came from the adult population. There is little understanding of how lab values impact pediatric-specific outcomes.¹⁴ Even for MIS-C, a pediatric-specific condition, early protocols emphasize broad testing approaches.¹⁵ A focus on grave (but rare) outcomes from a novel virus may also distract from more common causes of symptoms and lead to missed common diagnoses that are less severe.¹⁶ For both testing and treatment, having this early information before clear evidence on how it guided care may have caused more harm than benefit. Again, RCTs may have helped guide MIS-C therapies and protocol development.

Changing workflows may also create new barriers to HVC. One of the recommendations from Choosing Wisely^® during the COVID-19 pandemic was to batch lab draws¹⁷ to reduce the risk of exposure to healthcare workers performing phlebotomy, as well as staff who transport, handle, and process bloodwork in the lab. This may inadvertently encourage the approach of getting a lab test “in case” we need it with a single daily blood draw. In trying to avoid multiple encounters (and conserve personal protective equipment [PPE]), we may be taking a less stepwise approach than in prepandemic times.

Finally, children’s hospitals witnessed significant financial challenges and reductions in patient volume related to the pandemic.¹⁸ Reductions in patient volume could present a potential opportunity for practicing HVC (eg, more time to discuss downstream effects) or alternatively could inadvertently incentivize low-value, low-priority care via messaging around preserving financial viability.

For clinicians and healthcare systems, these examples highlight why we may be predisposed to practicing LVC during a pandemic or similar emerging threat.

In light of these challenging clinical scenarios and nonclinical factors that predispose us to LVC, how can we reinforce a high-value approach to care during a pandemic or similar emerging threat? The following five specific concepts may help providers and organizations optimize HVC during this pandemic and in future situations:

1. Utilize pediatric RCTs to provide evidence-based recommendations. In the face of a novel virus with unclear manifestations, treatment options were rapidly implemented without time for careful evaluation. In the future, collaboratively utilizing shared resources in the research community could help rapidly and rigorously evaluate outcomes in the pursuit of evidence-based practice.
2. Use standardization as a tool to mitigate uncertainty. Knowing that uncertainty can be a driver of overuse and that during emerging threats, evidence is scarce and rapidly changing, a structured method for standardizing practice across your institution or multiple institutions can be helpful in many ways. Electronic health record–based orders and guidelines provide a standard of care to relieve uncertainty and have been shown to reduce overtesting.¹⁹ These resources can also be adapted rapidly as evidence emerges, reducing the burden on providers to know the latest evolving best practice. Experts who have reviewed the literature should have a method to quickly disseminate these findings through standardized practice, providing a venue for rapid learning and implementation.²⁰
3. Plan for active deimplementation from the outset. It is inevitable that some practices implemented early in pandemic response may need to be deimplemented later as the evidence and situation evolve. However, there is ample evidence that deimplementation can be difficult.²¹ Building in deimplementation mechanisms, such as standing educational sessions or hospital committees dedicated to value that review practices, from the beginning may ease these changes.
4. Take advantage of novel opportunities to improve value. Early stop-gap interventions may be wasteful, but the upheaval from major events may also create novel opportunities to improve value in other ways. Some of these efforts, like PPE conservation and as-needed follow-up visits, may become useful methods to improve value even after the pandemic ends.^22,23 The decreased pursuit of healthcare during the pandemic may also have given us an opportunity to better define when delayed diagnosis or even nondiagnosis for certain conditions is acceptable and when it may cause harm.
5. Highlight harms of overuse. While avoiding unnecessary costs is an important aspect of reducing overuse, often the other human-centered harms of overuse are better motivators for HVC. Especially during the response to an emerging threat, the impacts of overuse may be compounded. Laboratory resources that are strained to meet COVID-19 testing demand will be further stretched by overuse of other laboratory testing. Overuse of ineffective treatments adds stress to nurses, pharmacists, and other front-line staff taking care of ill patients. Side effects of unnecessary interventions, including those that could prolong hospitalization, would also increase strain on the system. Reducing overuse is also a way to reduce workload for hospital staff during a time of crisis. Improved efficiency of practice and less time spent on practices that do not add value to patient care can insulate staff against burnout.²⁴ Hospitalization and healthcare costs can add to the stress and financial burden of patients and families.²⁵ Clinicians can highlight harms of overuse through openly talking about it on rounds with the patients, families, and entire care team and incorporating it into health system–wide messaging.

As vaccine distribution continues, like many clinicians, we are hopeful that the worst days of the pandemic are behind us. The crucible of the COVID-19 pandemic has undoubtedly changed us as clinicians and impacted our future practice patterns. We believe there is a need to challenge ourselves to continue to think from a value mindset even in times of crisis. Furthermore, there are important opportunities to learn from our response to the COVID-19 pandemic and find strategies for minimizing LVC outside the pandemic. We believe the lessons learned around improving value during this pandemic can strengthen our response to the next novel, widespread threat and reduce waste in our care systems, with a potential to increase the resilience of systems in the future.

High-value care (HVC) is a philosophy and approach to medicine that focuses on achieving the best patient outcomes through evidence-based practice while minimizing harm to patients, wasted healthcare resources, and costs. Incorporating HVC principles in pediatric clinical decision-making is particularly important owing to the harms of hospitalization, overutilization, and overdiagnosis, as well as rising costs of pediatric care.^1-4 How can we maintain these principles in the face of a global pandemic and new emerging syndrome, multisystem inflammatory syndrome in children (MIS-C), which has dramatically impacted healthcare systems for children?

In this article, we discuss the barriers and opportunities around practicing HVC in our evolving approach to novel COVID-19 management in hospitalized children. We also draw lessons from our experiences on how we can respond to future events that rapidly shift our approach to care.

As children’s hospitals and pediatric providers responded to the COVID-19 pandemic, practice recommendations were implemented rapidly and changed rapidly. A major challenge with an event like this is how we respond to the unknown and uncertainty, something most healthcare workers are not comfortable doing at baseline,^5,6 particularly trainees and early-career physicians.⁷ With the benefit of hindsight, many early clinical approaches to care may now be seen as low-value care (LVC). For example, COVID-19 test availability was initially limited, and many hospitals utilized respiratory viral panels (RVPs) to potentially eliminate COVID-19 as an etiology of symptoms. RVP use increased during this time⁸; however, studies have shown that the co-infection rate of SARS-CoV2 with other respiratory viruses varies widely, so a positive RVP was of uncertain benefit.⁹ In addition, routine RVP use is often low value and may lead to overdiagnosis, additional overtesting cascades, and, at times, false reassurance and premature closure of the diagnostic workup.¹⁰

As our understanding of COVID-19 has expanded, rapid changes in treatment have also occurred. Early data were often preliminary and based on small trials of adults, and treatments ranged from inexpensive and available (dexamethasone) to quite expensive (remdesivir, monoclonal antibodies). Pragmatic randomized controlled trials (RCTs) are an important tool that may have been underutilized in pediatrics. Similar to our adult hospitalist colleagues’ experience,¹¹ the rapid rise in cases provided an opportunity to collaborate across institutions to assess which treatments were most effective. In particular, the predictable rise in rates of MIS-C after a surge in COVID-19 cases could have provided an avenue to evaluate the relative effectiveness of the various treatments used.¹² However, there were limited pediatric RCTs and thus a missed opportunity to establish an evidence-based pediatric standard of care for COVID-19 and MIS-C. This resulted in the development and dissemination of care practices before they were fully tested in children.

Similarly, the medical community has become increasingly aware of laboratory findings that may be predictive of clinical course.¹³ The outcomes of COVID and MIS-C are potentially severe, so looking for “early warning signs” with diagnostic testing is appealing. Clinicians responding to early data, and with a fear of missing something, may order a full panel of bloodwork for admitted patients to assist with decision-making and may underestimate the perceived minor harms and cost of unnecessary testing/admissions.³ However, most of the evidence regarding lab values came from the adult population. There is little understanding of how lab values impact pediatric-specific outcomes.¹⁴ Even for MIS-C, a pediatric-specific condition, early protocols emphasize broad testing approaches.¹⁵ A focus on grave (but rare) outcomes from a novel virus may also distract from more common causes of symptoms and lead to missed common diagnoses that are less severe.¹⁶ For both testing and treatment, having this early information before clear evidence on how it guided care may have caused more harm than benefit. Again, RCTs may have helped guide MIS-C therapies and protocol development.

Changing workflows may also create new barriers to HVC. One of the recommendations from Choosing Wisely^® during the COVID-19 pandemic was to batch lab draws¹⁷ to reduce the risk of exposure to healthcare workers performing phlebotomy, as well as staff who transport, handle, and process bloodwork in the lab. This may inadvertently encourage the approach of getting a lab test “in case” we need it with a single daily blood draw. In trying to avoid multiple encounters (and conserve personal protective equipment [PPE]), we may be taking a less stepwise approach than in prepandemic times.

Finally, children’s hospitals witnessed significant financial challenges and reductions in patient volume related to the pandemic.¹⁸ Reductions in patient volume could present a potential opportunity for practicing HVC (eg, more time to discuss downstream effects) or alternatively could inadvertently incentivize low-value, low-priority care via messaging around preserving financial viability.

For clinicians and healthcare systems, these examples highlight why we may be predisposed to practicing LVC during a pandemic or similar emerging threat.

In light of these challenging clinical scenarios and nonclinical factors that predispose us to LVC, how can we reinforce a high-value approach to care during a pandemic or similar emerging threat? The following five specific concepts may help providers and organizations optimize HVC during this pandemic and in future situations:

1. Utilize pediatric RCTs to provide evidence-based recommendations. In the face of a novel virus with unclear manifestations, treatment options were rapidly implemented without time for careful evaluation. In the future, collaboratively utilizing shared resources in the research community could help rapidly and rigorously evaluate outcomes in the pursuit of evidence-based practice.
2. Use standardization as a tool to mitigate uncertainty. Knowing that uncertainty can be a driver of overuse and that during emerging threats, evidence is scarce and rapidly changing, a structured method for standardizing practice across your institution or multiple institutions can be helpful in many ways. Electronic health record–based orders and guidelines provide a standard of care to relieve uncertainty and have been shown to reduce overtesting.¹⁹ These resources can also be adapted rapidly as evidence emerges, reducing the burden on providers to know the latest evolving best practice. Experts who have reviewed the literature should have a method to quickly disseminate these findings through standardized practice, providing a venue for rapid learning and implementation.²⁰
3. Plan for active deimplementation from the outset. It is inevitable that some practices implemented early in pandemic response may need to be deimplemented later as the evidence and situation evolve. However, there is ample evidence that deimplementation can be difficult.²¹ Building in deimplementation mechanisms, such as standing educational sessions or hospital committees dedicated to value that review practices, from the beginning may ease these changes.
4. Take advantage of novel opportunities to improve value. Early stop-gap interventions may be wasteful, but the upheaval from major events may also create novel opportunities to improve value in other ways. Some of these efforts, like PPE conservation and as-needed follow-up visits, may become useful methods to improve value even after the pandemic ends.^22,23 The decreased pursuit of healthcare during the pandemic may also have given us an opportunity to better define when delayed diagnosis or even nondiagnosis for certain conditions is acceptable and when it may cause harm.
5. Highlight harms of overuse. While avoiding unnecessary costs is an important aspect of reducing overuse, often the other human-centered harms of overuse are better motivators for HVC. Especially during the response to an emerging threat, the impacts of overuse may be compounded. Laboratory resources that are strained to meet COVID-19 testing demand will be further stretched by overuse of other laboratory testing. Overuse of ineffective treatments adds stress to nurses, pharmacists, and other front-line staff taking care of ill patients. Side effects of unnecessary interventions, including those that could prolong hospitalization, would also increase strain on the system. Reducing overuse is also a way to reduce workload for hospital staff during a time of crisis. Improved efficiency of practice and less time spent on practices that do not add value to patient care can insulate staff against burnout.²⁴ Hospitalization and healthcare costs can add to the stress and financial burden of patients and families.²⁵ Clinicians can highlight harms of overuse through openly talking about it on rounds with the patients, families, and entire care team and incorporating it into health system–wide messaging.

As vaccine distribution continues, like many clinicians, we are hopeful that the worst days of the pandemic are behind us. The crucible of the COVID-19 pandemic has undoubtedly changed us as clinicians and impacted our future practice patterns. We believe there is a need to challenge ourselves to continue to think from a value mindset even in times of crisis. Furthermore, there are important opportunities to learn from our response to the COVID-19 pandemic and find strategies for minimizing LVC outside the pandemic. We believe the lessons learned around improving value during this pandemic can strengthen our response to the next novel, widespread threat and reduce waste in our care systems, with a potential to increase the resilience of systems in the future.

High-value care (HVC) is a philosophy and approach to medicine that focuses on achieving the best patient outcomes through evidence-based practice while minimizing harm to patients, wasted healthcare resources, and costs. Incorporating HVC principles in pediatric clinical decision-making is particularly important owing to the harms of hospitalization, overutilization, and overdiagnosis, as well as rising costs of pediatric care.^1-4 How can we maintain these principles in the face of a global pandemic and new emerging syndrome, multisystem inflammatory syndrome in children (MIS-C), which has dramatically impacted healthcare systems for children?

In this article, we discuss the barriers and opportunities around practicing HVC in our evolving approach to novel COVID-19 management in hospitalized children. We also draw lessons from our experiences on how we can respond to future events that rapidly shift our approach to care.

As children’s hospitals and pediatric providers responded to the COVID-19 pandemic, practice recommendations were implemented rapidly and changed rapidly. A major challenge with an event like this is how we respond to the unknown and uncertainty, something most healthcare workers are not comfortable doing at baseline,^5,6 particularly trainees and early-career physicians.⁷ With the benefit of hindsight, many early clinical approaches to care may now be seen as low-value care (LVC). For example, COVID-19 test availability was initially limited, and many hospitals utilized respiratory viral panels (RVPs) to potentially eliminate COVID-19 as an etiology of symptoms. RVP use increased during this time⁸; however, studies have shown that the co-infection rate of SARS-CoV2 with other respiratory viruses varies widely, so a positive RVP was of uncertain benefit.⁹ In addition, routine RVP use is often low value and may lead to overdiagnosis, additional overtesting cascades, and, at times, false reassurance and premature closure of the diagnostic workup.¹⁰

As our understanding of COVID-19 has expanded, rapid changes in treatment have also occurred. Early data were often preliminary and based on small trials of adults, and treatments ranged from inexpensive and available (dexamethasone) to quite expensive (remdesivir, monoclonal antibodies). Pragmatic randomized controlled trials (RCTs) are an important tool that may have been underutilized in pediatrics. Similar to our adult hospitalist colleagues’ experience,¹¹ the rapid rise in cases provided an opportunity to collaborate across institutions to assess which treatments were most effective. In particular, the predictable rise in rates of MIS-C after a surge in COVID-19 cases could have provided an avenue to evaluate the relative effectiveness of the various treatments used.¹² However, there were limited pediatric RCTs and thus a missed opportunity to establish an evidence-based pediatric standard of care for COVID-19 and MIS-C. This resulted in the development and dissemination of care practices before they were fully tested in children.

Similarly, the medical community has become increasingly aware of laboratory findings that may be predictive of clinical course.¹³ The outcomes of COVID and MIS-C are potentially severe, so looking for “early warning signs” with diagnostic testing is appealing. Clinicians responding to early data, and with a fear of missing something, may order a full panel of bloodwork for admitted patients to assist with decision-making and may underestimate the perceived minor harms and cost of unnecessary testing/admissions.³ However, most of the evidence regarding lab values came from the adult population. There is little understanding of how lab values impact pediatric-specific outcomes.¹⁴ Even for MIS-C, a pediatric-specific condition, early protocols emphasize broad testing approaches.¹⁵ A focus on grave (but rare) outcomes from a novel virus may also distract from more common causes of symptoms and lead to missed common diagnoses that are less severe.¹⁶ For both testing and treatment, having this early information before clear evidence on how it guided care may have caused more harm than benefit. Again, RCTs may have helped guide MIS-C therapies and protocol development.

Changing workflows may also create new barriers to HVC. One of the recommendations from Choosing Wisely^® during the COVID-19 pandemic was to batch lab draws¹⁷ to reduce the risk of exposure to healthcare workers performing phlebotomy, as well as staff who transport, handle, and process bloodwork in the lab. This may inadvertently encourage the approach of getting a lab test “in case” we need it with a single daily blood draw. In trying to avoid multiple encounters (and conserve personal protective equipment [PPE]), we may be taking a less stepwise approach than in prepandemic times.

Finally, children’s hospitals witnessed significant financial challenges and reductions in patient volume related to the pandemic.¹⁸ Reductions in patient volume could present a potential opportunity for practicing HVC (eg, more time to discuss downstream effects) or alternatively could inadvertently incentivize low-value, low-priority care via messaging around preserving financial viability.

For clinicians and healthcare systems, these examples highlight why we may be predisposed to practicing LVC during a pandemic or similar emerging threat.

In light of these challenging clinical scenarios and nonclinical factors that predispose us to LVC, how can we reinforce a high-value approach to care during a pandemic or similar emerging threat? The following five specific concepts may help providers and organizations optimize HVC during this pandemic and in future situations:

1. Utilize pediatric RCTs to provide evidence-based recommendations. In the face of a novel virus with unclear manifestations, treatment options were rapidly implemented without time for careful evaluation. In the future, collaboratively utilizing shared resources in the research community could help rapidly and rigorously evaluate outcomes in the pursuit of evidence-based practice.
2. Use standardization as a tool to mitigate uncertainty. Knowing that uncertainty can be a driver of overuse and that during emerging threats, evidence is scarce and rapidly changing, a structured method for standardizing practice across your institution or multiple institutions can be helpful in many ways. Electronic health record–based orders and guidelines provide a standard of care to relieve uncertainty and have been shown to reduce overtesting.¹⁹ These resources can also be adapted rapidly as evidence emerges, reducing the burden on providers to know the latest evolving best practice. Experts who have reviewed the literature should have a method to quickly disseminate these findings through standardized practice, providing a venue for rapid learning and implementation.²⁰
3. Plan for active deimplementation from the outset. It is inevitable that some practices implemented early in pandemic response may need to be deimplemented later as the evidence and situation evolve. However, there is ample evidence that deimplementation can be difficult.²¹ Building in deimplementation mechanisms, such as standing educational sessions or hospital committees dedicated to value that review practices, from the beginning may ease these changes.
4. Take advantage of novel opportunities to improve value. Early stop-gap interventions may be wasteful, but the upheaval from major events may also create novel opportunities to improve value in other ways. Some of these efforts, like PPE conservation and as-needed follow-up visits, may become useful methods to improve value even after the pandemic ends.^22,23 The decreased pursuit of healthcare during the pandemic may also have given us an opportunity to better define when delayed diagnosis or even nondiagnosis for certain conditions is acceptable and when it may cause harm.
5. Highlight harms of overuse. While avoiding unnecessary costs is an important aspect of reducing overuse, often the other human-centered harms of overuse are better motivators for HVC. Especially during the response to an emerging threat, the impacts of overuse may be compounded. Laboratory resources that are strained to meet COVID-19 testing demand will be further stretched by overuse of other laboratory testing. Overuse of ineffective treatments adds stress to nurses, pharmacists, and other front-line staff taking care of ill patients. Side effects of unnecessary interventions, including those that could prolong hospitalization, would also increase strain on the system. Reducing overuse is also a way to reduce workload for hospital staff during a time of crisis. Improved efficiency of practice and less time spent on practices that do not add value to patient care can insulate staff against burnout.²⁴ Hospitalization and healthcare costs can add to the stress and financial burden of patients and families.²⁵ Clinicians can highlight harms of overuse through openly talking about it on rounds with the patients, families, and entire care team and incorporating it into health system–wide messaging.

As vaccine distribution continues, like many clinicians, we are hopeful that the worst days of the pandemic are behind us. The crucible of the COVID-19 pandemic has undoubtedly changed us as clinicians and impacted our future practice patterns. We believe there is a need to challenge ourselves to continue to think from a value mindset even in times of crisis. Furthermore, there are important opportunities to learn from our response to the COVID-19 pandemic and find strategies for minimizing LVC outside the pandemic. We believe the lessons learned around improving value during this pandemic can strengthen our response to the next novel, widespread threat and reduce waste in our care systems, with a potential to increase the resilience of systems in the future.