For biologic-naive adults with moderate to severe Crohn’s disease, treatment with adalimumab or ustekinumab leads to similar outcomes, according to results of the head-to-head SEAVUE trial.

When lead author Bruce E. Sands, MD, of Icahn School of Medicine at Mount Sinai, New York, compared treatment arms, patients had similar rates of clinical remission at one year. All major secondary endpoints, such as endoscopic remission, were comparable, as were safety profiles, Dr. Sands reported at the annual Digestive Disease Week^® (DDW).

“From my perspective, this is an important study,” Dr. Sands wrote in a virtual chat following his presentation. “We need more head-to-head studies!”

Results from the SEAVUE trial come almost 2 years after Dr. Sands reported findings of another head-to-head IBD trial: VARSITY, which demonstrated the superiority of vedolizumab over adalimumab among patients with moderate to severe ulcerative colitis.

The multicenter, double-blinded SEAVUE trial involved 386 patients with biologic-naive Crohn’s disease who had failed corticosteroids or immunomodulators. All patients had Crohn’s Disease Activity Index (CDAI) scores ranging from 220 to 450 and had at least one ulcer detected at baseline ileocolonoscopy.

Participants were randomized in a 1:1 ratio to receive monotherapy with either subcutaneous adalimumab (citrate-free; 160 mg at baseline, 70 mg at week 2, then 40 mg every 2 weeks) or ustekinumab, which was given first intravenously at a dose of 6 mg/kg then subcutaneously at 90 mg every 8 weeks.

The primary endpoint was clinical remission at week 52, defined by a CDAI score less than 150. Major secondary endpoints included clinical response, corticosteroid-free remission, endoscopic remission, remission in patient-reported CDAI components, and clinical remission at week 16.

Results were statistically similar across all endpoints, with clinical remission at 1 year occurring in 64.9% and 61.0% of patients receiving ustekinumab and adalimumab, respectively (P = .417).

“Both treatments demonstrated rapid onset of action and robust endoscopy results,” Dr. Sands noted during his presentation; he reported comparable rates of endoscopic remission, at 28.5% and 30.7% for ustekinumab and adalimumab, respectively (P = .631).

Among secondary endpoints, ustekinumab demonstrated some superiority, with greater maintenance of clinical response at week 52 among patients with response at week 16 (88.6% vs. 78.0%; P = .016), greater reduction in liquid/soft stools in prior 7 days from baseline to week 52 (–19.9 vs. –16.2; P = .004), and greater reduction in sum number of liquid/soft stools and abdominal pain scores in prior 7 days from baseline to week 52 (–29.6 vs. –25.1; P = .013).

Safety metrics were similar between groups, and consistent with previous experience. Although the adalimumab group had a higher rate of discontinuation due to adverse events, this trend was not statistically significant (11.3% vs. 6.3%; P value not provided).
 

Don’t ignore discontinuation rates

Jordan E. Axelrad, MD, assistant professor of medicine at NYU and a clinician at the Inflammatory Bowel Disease Center at NYU Langone Health, New York, commended the SEAVUE trial for its head-to-head design, which is a first for biologics in Crohn’s disease.

“With newer drugs, there’s a critical need for head-to-head studies for us to understand where to position a lot of these agents,” he said in an interview. “[T]his was a good undifferentiated group to understand what’s the first biologic you should use in a patient with moderate-to-severe Crohn’s disease. The primary, major take-home is that [ustekinumab and adalimumab] are similarly effective.”

When asked about the slight superiority in minor secondary endpoints associated with ustekinumab, Dr. Axelrad suggested that rates of discontinuation deserve more attention.

“For me, maybe the major focus would be on the number of patients who stopped treatment,” Dr. Axelrad said, noting a higher rate of discontinuation in the adalimumab group. “Although that was just numerical, that to me is actually more important than [the minor secondary endpoints].” He also highlighted the lower injection burden associated with ustekinumab, which is given every 8 weeks, compared with every 2 weeks for adalimumab.

Ultimately, however, it’s unlikely that treatment sequencing will depend on these finer points, Dr. Axelrad suggested, and will instead come down to finances, especially with adalimumab biosimilars on the horizon, which may be the most cost-effective.

“A lot of the decision-making of where to position [ustekinumab in Crohn’s disease] is going to come down to the payer,” Dr. Axelrad said. “If there was a clear signal, providers such as myself would have a better leg to stand on, like we saw with VARSITY, where vedolizumab was clearly superior to adalimumab on multiple endpoints. We didn’t see that sort of robust signal here.”

The SEAVUE trial was supported by Janssen Scientific Affairs. Dr. Sands disclosed relationships with Janssen, AbbVie, Takeda, and others. Dr. Axelrad disclosed previous consulting fees from Janssen and research support from BioFire.

For biologic-naive adults with moderate to severe Crohn’s disease, treatment with adalimumab or ustekinumab leads to similar outcomes, according to results of the head-to-head SEAVUE trial.

When lead author Bruce E. Sands, MD, of Icahn School of Medicine at Mount Sinai, New York, compared treatment arms, patients had similar rates of clinical remission at one year. All major secondary endpoints, such as endoscopic remission, were comparable, as were safety profiles, Dr. Sands reported at the annual Digestive Disease Week^® (DDW).

“From my perspective, this is an important study,” Dr. Sands wrote in a virtual chat following his presentation. “We need more head-to-head studies!”

Results from the SEAVUE trial come almost 2 years after Dr. Sands reported findings of another head-to-head IBD trial: VARSITY, which demonstrated the superiority of vedolizumab over adalimumab among patients with moderate to severe ulcerative colitis.

The multicenter, double-blinded SEAVUE trial involved 386 patients with biologic-naive Crohn’s disease who had failed corticosteroids or immunomodulators. All patients had Crohn’s Disease Activity Index (CDAI) scores ranging from 220 to 450 and had at least one ulcer detected at baseline ileocolonoscopy.

Participants were randomized in a 1:1 ratio to receive monotherapy with either subcutaneous adalimumab (citrate-free; 160 mg at baseline, 70 mg at week 2, then 40 mg every 2 weeks) or ustekinumab, which was given first intravenously at a dose of 6 mg/kg then subcutaneously at 90 mg every 8 weeks.

The primary endpoint was clinical remission at week 52, defined by a CDAI score less than 150. Major secondary endpoints included clinical response, corticosteroid-free remission, endoscopic remission, remission in patient-reported CDAI components, and clinical remission at week 16.

Results were statistically similar across all endpoints, with clinical remission at 1 year occurring in 64.9% and 61.0% of patients receiving ustekinumab and adalimumab, respectively (P = .417).

“Both treatments demonstrated rapid onset of action and robust endoscopy results,” Dr. Sands noted during his presentation; he reported comparable rates of endoscopic remission, at 28.5% and 30.7% for ustekinumab and adalimumab, respectively (P = .631).

Among secondary endpoints, ustekinumab demonstrated some superiority, with greater maintenance of clinical response at week 52 among patients with response at week 16 (88.6% vs. 78.0%; P = .016), greater reduction in liquid/soft stools in prior 7 days from baseline to week 52 (–19.9 vs. –16.2; P = .004), and greater reduction in sum number of liquid/soft stools and abdominal pain scores in prior 7 days from baseline to week 52 (–29.6 vs. –25.1; P = .013).

Safety metrics were similar between groups, and consistent with previous experience. Although the adalimumab group had a higher rate of discontinuation due to adverse events, this trend was not statistically significant (11.3% vs. 6.3%; P value not provided).
 

Don’t ignore discontinuation rates

Jordan E. Axelrad, MD, assistant professor of medicine at NYU and a clinician at the Inflammatory Bowel Disease Center at NYU Langone Health, New York, commended the SEAVUE trial for its head-to-head design, which is a first for biologics in Crohn’s disease.

“With newer drugs, there’s a critical need for head-to-head studies for us to understand where to position a lot of these agents,” he said in an interview. “[T]his was a good undifferentiated group to understand what’s the first biologic you should use in a patient with moderate-to-severe Crohn’s disease. The primary, major take-home is that [ustekinumab and adalimumab] are similarly effective.”

When asked about the slight superiority in minor secondary endpoints associated with ustekinumab, Dr. Axelrad suggested that rates of discontinuation deserve more attention.

“For me, maybe the major focus would be on the number of patients who stopped treatment,” Dr. Axelrad said, noting a higher rate of discontinuation in the adalimumab group. “Although that was just numerical, that to me is actually more important than [the minor secondary endpoints].” He also highlighted the lower injection burden associated with ustekinumab, which is given every 8 weeks, compared with every 2 weeks for adalimumab.

Ultimately, however, it’s unlikely that treatment sequencing will depend on these finer points, Dr. Axelrad suggested, and will instead come down to finances, especially with adalimumab biosimilars on the horizon, which may be the most cost-effective.

“A lot of the decision-making of where to position [ustekinumab in Crohn’s disease] is going to come down to the payer,” Dr. Axelrad said. “If there was a clear signal, providers such as myself would have a better leg to stand on, like we saw with VARSITY, where vedolizumab was clearly superior to adalimumab on multiple endpoints. We didn’t see that sort of robust signal here.”

The SEAVUE trial was supported by Janssen Scientific Affairs. Dr. Sands disclosed relationships with Janssen, AbbVie, Takeda, and others. Dr. Axelrad disclosed previous consulting fees from Janssen and research support from BioFire.

For biologic-naive adults with moderate to severe Crohn’s disease, treatment with adalimumab or ustekinumab leads to similar outcomes, according to results of the head-to-head SEAVUE trial.

When lead author Bruce E. Sands, MD, of Icahn School of Medicine at Mount Sinai, New York, compared treatment arms, patients had similar rates of clinical remission at one year. All major secondary endpoints, such as endoscopic remission, were comparable, as were safety profiles, Dr. Sands reported at the annual Digestive Disease Week^® (DDW).

“From my perspective, this is an important study,” Dr. Sands wrote in a virtual chat following his presentation. “We need more head-to-head studies!”

Results from the SEAVUE trial come almost 2 years after Dr. Sands reported findings of another head-to-head IBD trial: VARSITY, which demonstrated the superiority of vedolizumab over adalimumab among patients with moderate to severe ulcerative colitis.

The multicenter, double-blinded SEAVUE trial involved 386 patients with biologic-naive Crohn’s disease who had failed corticosteroids or immunomodulators. All patients had Crohn’s Disease Activity Index (CDAI) scores ranging from 220 to 450 and had at least one ulcer detected at baseline ileocolonoscopy.

Participants were randomized in a 1:1 ratio to receive monotherapy with either subcutaneous adalimumab (citrate-free; 160 mg at baseline, 70 mg at week 2, then 40 mg every 2 weeks) or ustekinumab, which was given first intravenously at a dose of 6 mg/kg then subcutaneously at 90 mg every 8 weeks.

The primary endpoint was clinical remission at week 52, defined by a CDAI score less than 150. Major secondary endpoints included clinical response, corticosteroid-free remission, endoscopic remission, remission in patient-reported CDAI components, and clinical remission at week 16.

Results were statistically similar across all endpoints, with clinical remission at 1 year occurring in 64.9% and 61.0% of patients receiving ustekinumab and adalimumab, respectively (P = .417).

“Both treatments demonstrated rapid onset of action and robust endoscopy results,” Dr. Sands noted during his presentation; he reported comparable rates of endoscopic remission, at 28.5% and 30.7% for ustekinumab and adalimumab, respectively (P = .631).

Among secondary endpoints, ustekinumab demonstrated some superiority, with greater maintenance of clinical response at week 52 among patients with response at week 16 (88.6% vs. 78.0%; P = .016), greater reduction in liquid/soft stools in prior 7 days from baseline to week 52 (–19.9 vs. –16.2; P = .004), and greater reduction in sum number of liquid/soft stools and abdominal pain scores in prior 7 days from baseline to week 52 (–29.6 vs. –25.1; P = .013).

Safety metrics were similar between groups, and consistent with previous experience. Although the adalimumab group had a higher rate of discontinuation due to adverse events, this trend was not statistically significant (11.3% vs. 6.3%; P value not provided).
 

Don’t ignore discontinuation rates

Jordan E. Axelrad, MD, assistant professor of medicine at NYU and a clinician at the Inflammatory Bowel Disease Center at NYU Langone Health, New York, commended the SEAVUE trial for its head-to-head design, which is a first for biologics in Crohn’s disease.

“With newer drugs, there’s a critical need for head-to-head studies for us to understand where to position a lot of these agents,” he said in an interview. “[T]his was a good undifferentiated group to understand what’s the first biologic you should use in a patient with moderate-to-severe Crohn’s disease. The primary, major take-home is that [ustekinumab and adalimumab] are similarly effective.”

When asked about the slight superiority in minor secondary endpoints associated with ustekinumab, Dr. Axelrad suggested that rates of discontinuation deserve more attention.

“For me, maybe the major focus would be on the number of patients who stopped treatment,” Dr. Axelrad said, noting a higher rate of discontinuation in the adalimumab group. “Although that was just numerical, that to me is actually more important than [the minor secondary endpoints].” He also highlighted the lower injection burden associated with ustekinumab, which is given every 8 weeks, compared with every 2 weeks for adalimumab.

Ultimately, however, it’s unlikely that treatment sequencing will depend on these finer points, Dr. Axelrad suggested, and will instead come down to finances, especially with adalimumab biosimilars on the horizon, which may be the most cost-effective.

“A lot of the decision-making of where to position [ustekinumab in Crohn’s disease] is going to come down to the payer,” Dr. Axelrad said. “If there was a clear signal, providers such as myself would have a better leg to stand on, like we saw with VARSITY, where vedolizumab was clearly superior to adalimumab on multiple endpoints. We didn’t see that sort of robust signal here.”

The SEAVUE trial was supported by Janssen Scientific Affairs. Dr. Sands disclosed relationships with Janssen, AbbVie, Takeda, and others. Dr. Axelrad disclosed previous consulting fees from Janssen and research support from BioFire.

SER-109, an oral microbiome therapeutic, safely protects against Clostridioides difficile recurrence for up to 24 weeks, according to a recent phase 3 trial. Three days of treatment with purified Firmicutes spores reduced risk of recurrence by 54%, suggesting a sustained, clinically meaningful response, according to a multicenter study presented at this year’s Digestive Disease Week^® (DDW).

“Antibiotics targeted against C. difficile bacteria are necessary but insufficient to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome,” the investigators reported at the meeting.

“The manufacturing processes for SER-109 are designed to inactivate potential pathogens, while enriching for beneficial Firmicutes spores, which play a central role in inhibiting the cycle of C. difficile,” said Louis Y. Korman, MD, a gastroenterologist in Washington, who was lead author.
 

Extended data from ECOSPOR-III

The ECOSPOR-III trial involved 182 patients with at least three episodes of C. difficile infection in the previous 12 months. Patients underwent 10-21 days of antibiotic therapy with fidaxomicin or vancomycin to resolve symptoms before they were then randomized in a 1:1 ratio to receive either SER-109 (four capsules daily for 3 days) or placebo, with stratification by specific antibiotic and patient age (threshold of 65 years).

The primary objectives were safety and efficacy at 8 weeks. These results, which were previously reported at ACG 2020, showed a 68% relative risk reduction in the SER-109 group, and favorable safety data. The findings presented at DDW added to those earlier ones by providing safety and efficacy data extending to week 24. At this time point, patients treated with SER-109 had a 54% relative risk reduction in C. difficile recurrence. Recurrence rates were 21.3% and 47.3% for the treatment and placebo groups, respectively (P less than .001).

Patients 65 years and older benefited the most from SER-109 therapy, based on a relative risk reduction of 56% (P less than .001), versus a 49% relative risk reduction (lacking statistical significance) for patients younger than 65 years (P = .093). The specific antibiotic therapy patients received also appeared to impact outcomes. Patients treated with fidaxomicin had a 73% relative risk reduction (P = .009), compared with 48% for vancomycin (P = .006). Safety profiles were similar between study arms.

“By enriching for Firmicutes spores, SER-109 achieves high efficacy, while mitigating risk of transmitting infectious agents and represents a major paradigm shift in the clinical management of patients with recurrent C. difficile infection,” the investigators concluded, noting that “an open-label study for patients with recurrent C. difficile infection is currently enrolling.”
 

Microbiome restoration therapies

According to Sahil Khanna, MBBS, professor of medicine at Mayo Clinic, Rochester, Minn., these findings “advance the field” because they show a sustained response. “We know that microbiome restoration therapies help restore colonization resistance,” Dr. Khanna said in an interview, noting that they offer benefits comparable to fecal microbiota transplantation (FMT) without the downsides.

SER-109, an oral microbiome therapeutic, safely protects against Clostridioides difficile recurrence for up to 24 weeks, according to a recent phase 3 trial. Three days of treatment with purified Firmicutes spores reduced risk of recurrence by 54%, suggesting a sustained, clinically meaningful response, according to a multicenter study presented at this year’s Digestive Disease Week^® (DDW).

“Antibiotics targeted against C. difficile bacteria are necessary but insufficient to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome,” the investigators reported at the meeting.

“The manufacturing processes for SER-109 are designed to inactivate potential pathogens, while enriching for beneficial Firmicutes spores, which play a central role in inhibiting the cycle of C. difficile,” said Louis Y. Korman, MD, a gastroenterologist in Washington, who was lead author.
 

Extended data from ECOSPOR-III

The ECOSPOR-III trial involved 182 patients with at least three episodes of C. difficile infection in the previous 12 months. Patients underwent 10-21 days of antibiotic therapy with fidaxomicin or vancomycin to resolve symptoms before they were then randomized in a 1:1 ratio to receive either SER-109 (four capsules daily for 3 days) or placebo, with stratification by specific antibiotic and patient age (threshold of 65 years).

The primary objectives were safety and efficacy at 8 weeks. These results, which were previously reported at ACG 2020, showed a 68% relative risk reduction in the SER-109 group, and favorable safety data. The findings presented at DDW added to those earlier ones by providing safety and efficacy data extending to week 24. At this time point, patients treated with SER-109 had a 54% relative risk reduction in C. difficile recurrence. Recurrence rates were 21.3% and 47.3% for the treatment and placebo groups, respectively (P less than .001).

Patients 65 years and older benefited the most from SER-109 therapy, based on a relative risk reduction of 56% (P less than .001), versus a 49% relative risk reduction (lacking statistical significance) for patients younger than 65 years (P = .093). The specific antibiotic therapy patients received also appeared to impact outcomes. Patients treated with fidaxomicin had a 73% relative risk reduction (P = .009), compared with 48% for vancomycin (P = .006). Safety profiles were similar between study arms.

“By enriching for Firmicutes spores, SER-109 achieves high efficacy, while mitigating risk of transmitting infectious agents and represents a major paradigm shift in the clinical management of patients with recurrent C. difficile infection,” the investigators concluded, noting that “an open-label study for patients with recurrent C. difficile infection is currently enrolling.”
 

Microbiome restoration therapies

According to Sahil Khanna, MBBS, professor of medicine at Mayo Clinic, Rochester, Minn., these findings “advance the field” because they show a sustained response. “We know that microbiome restoration therapies help restore colonization resistance,” Dr. Khanna said in an interview, noting that they offer benefits comparable to fecal microbiota transplantation (FMT) without the downsides.

SER-109, an oral microbiome therapeutic, safely protects against Clostridioides difficile recurrence for up to 24 weeks, according to a recent phase 3 trial. Three days of treatment with purified Firmicutes spores reduced risk of recurrence by 54%, suggesting a sustained, clinically meaningful response, according to a multicenter study presented at this year’s Digestive Disease Week^® (DDW).

“Antibiotics targeted against C. difficile bacteria are necessary but insufficient to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome,” the investigators reported at the meeting.

“The manufacturing processes for SER-109 are designed to inactivate potential pathogens, while enriching for beneficial Firmicutes spores, which play a central role in inhibiting the cycle of C. difficile,” said Louis Y. Korman, MD, a gastroenterologist in Washington, who was lead author.
 

Extended data from ECOSPOR-III

The ECOSPOR-III trial involved 182 patients with at least three episodes of C. difficile infection in the previous 12 months. Patients underwent 10-21 days of antibiotic therapy with fidaxomicin or vancomycin to resolve symptoms before they were then randomized in a 1:1 ratio to receive either SER-109 (four capsules daily for 3 days) or placebo, with stratification by specific antibiotic and patient age (threshold of 65 years).

The primary objectives were safety and efficacy at 8 weeks. These results, which were previously reported at ACG 2020, showed a 68% relative risk reduction in the SER-109 group, and favorable safety data. The findings presented at DDW added to those earlier ones by providing safety and efficacy data extending to week 24. At this time point, patients treated with SER-109 had a 54% relative risk reduction in C. difficile recurrence. Recurrence rates were 21.3% and 47.3% for the treatment and placebo groups, respectively (P less than .001).

Patients 65 years and older benefited the most from SER-109 therapy, based on a relative risk reduction of 56% (P less than .001), versus a 49% relative risk reduction (lacking statistical significance) for patients younger than 65 years (P = .093). The specific antibiotic therapy patients received also appeared to impact outcomes. Patients treated with fidaxomicin had a 73% relative risk reduction (P = .009), compared with 48% for vancomycin (P = .006). Safety profiles were similar between study arms.

“By enriching for Firmicutes spores, SER-109 achieves high efficacy, while mitigating risk of transmitting infectious agents and represents a major paradigm shift in the clinical management of patients with recurrent C. difficile infection,” the investigators concluded, noting that “an open-label study for patients with recurrent C. difficile infection is currently enrolling.”
 

Microbiome restoration therapies

According to Sahil Khanna, MBBS, professor of medicine at Mayo Clinic, Rochester, Minn., these findings “advance the field” because they show a sustained response. “We know that microbiome restoration therapies help restore colonization resistance,” Dr. Khanna said in an interview, noting that they offer benefits comparable to fecal microbiota transplantation (FMT) without the downsides.

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

Real-world use of the immune checkpoint inhibitors for first-line treatment of advanced non–small cell lung cancer (NSCLC) provides nowhere near the same survival advantage as seen in clinical trials, according to a retrospective cohort study of nearly 20,000 Medicare patients.

For example, the median overall survival (OS) in the “real world” was 11.4 months for patients treated with pembrolizumab (Keytruda, Merck) monotherapy – approximately 15 months shorter than the median OS among pembrolizumab-treated participants in the KEYNOTE-024 trial.  

Indeed, OS was shorter for Medicare patients treated with an immune checkpoint inhibitor alone than it was for patients treated with a chemoimmunotherapy regimen of platinum plus pemetrexed plus pembrolizumab, at a median of 12.9 months – which in itself was approximately 10 months shorter than survival outcomes with this triplet therapy in the KEYNOTE-189 trial.

“These results, based on the nationwide experience for patients on Medicare, may inform discussions between physicians and patients with respect to expectations for outcomes among older patients with NSCLC,” lead author Kenneth Kehl, MD, assistant professor of medicine, Harvard Medical School, Boston, said in a statement.

Deborah Schrag, MD, chief, division of population sciences, Dana-Farber Cancer Institute, Boston, and Harvard Medical School, agreed, adding in the same statement that “this information empowers patients and clinicians with realistic expectations and equips them to make informed decisions.”

The study was published online May 21 in JAMA Network Open and was done in conjunction with the Health Data Analytics Institute, an analytics firm that applies artificial intelligence for measuring health risks.
 

Systemic therapy

For the study, the team analyzed Medicare data for 19,529 patients (median age, 73.8 years) who had all initiated first palliative-intent systemic therapy for lung cancer between January 2016 and December 2018. Some 3,079 patients received pembrolizumab monotherapy, 5,159 patients received a platinum-based regimen plus pemetrexed, 9,866 received a platinum plus a taxane, and 1,425 received platinum, pemetrexed, and pembrolizumab.

The authors noted that uptake of pembrolizumab-containing regimens in the Medicare population was rapid.

In the second quarter of 2016, pembrolizumab was used in only 0.7% of first-line treatments for advanced NSCLC, but increased to 42.4% of first-line treatments 2 years later, in the third quarter of 2018.

“The primary outcome was OS, which was measured using the restricted mean survival time (RMST),” Dr. Kehl and colleagues noted.

After propensity-score stratification, patients who received pembrolizumab had an adjusted RMST of 11 months compared with an adjusted RMST of 11.1 months for those who received the combination of platinum plus pemetrexed.

Survival was statistically worse for patients who received pembrolizumab than it was for those treated with a platinum/taxane combination, although the magnitude of difference between the two groups was small, at 0.7 months (P < .001). Patients who received the platinum/pemetrexed/pembrolizumab triplet had an adjusted RMST of 11.7 months, which was significantly better than the adjusted RMST of 11.2 months for patients who received the platinum/pemetrexed doublet, but the magnitude of the difference between these two groups was small, at 0.5 months (P = .02), the investigators added.
 

Different patient groups

Patients who received immunotherapy alone may have been more ill than those who received chemotherapy, the authors suggested. Patients who were 70 years of age or older, who were female, and who had a higher baseline mortality risk were more likely to receive single-agent pembrolizumab than chemotherapy, they noted. “Indeed, immunotherapy may be construed as a potential first-line treatment for patients who would otherwise have been deemed too frail for treatment at all, including patients older than 80 years,” they observed.

It is also possible that the Medicare patients included in the current analysis may differ substantively from advanced NSCLC participants enrolled in clinical trials, they wrote. For example, the median age of the Medicare cohort was approximately 10 years older than the median age of participants in both KEYNOTE-024 and KEYNOTE-189, the authors pointed out.

“If clinicians recommend immunotherapy disproportionately to Medicare patients with poor performance status or greater comorbidity – perhaps even if PD-L1 (programmed cell death-ligand-1) expression levels are below thresholds associated with the most substantial immunotherapy benefit – it may not be surprising that large survival improvements associated with immunotherapy were not observed in this analysis,” Dr. Kehl and colleagues suggested.

It is possible that durable benefit from immunotherapy, at least among some subgroups of patients included in the Medicare analysis, might have become more evident with additional follow-up beyond 18 months, they noted. However, they added, in “both KEYNOTE-024 and KEYNOTE-189, pembrolizumab was associated with substantial improvements in overall survival by that point.

“These results may inform prognostic considerations in practice and reinforce the importance of understanding patient selection dynamics in assessing the value and clinical utility of transformative treatment strategies,” they cautioned.

Dr. Kehl has reported receiving personal fees from Aetion, Roche, and IBM. Dr. Schrag has reported receiving personal fees from JAMA for editorial services and travel reimbursement/speaker fees from Pfizer.
 

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

Real-world use of the immune checkpoint inhibitors for first-line treatment of advanced non–small cell lung cancer (NSCLC) provides nowhere near the same survival advantage as seen in clinical trials, according to a retrospective cohort study of nearly 20,000 Medicare patients.

For example, the median overall survival (OS) in the “real world” was 11.4 months for patients treated with pembrolizumab (Keytruda, Merck) monotherapy – approximately 15 months shorter than the median OS among pembrolizumab-treated participants in the KEYNOTE-024 trial.  

Indeed, OS was shorter for Medicare patients treated with an immune checkpoint inhibitor alone than it was for patients treated with a chemoimmunotherapy regimen of platinum plus pemetrexed plus pembrolizumab, at a median of 12.9 months – which in itself was approximately 10 months shorter than survival outcomes with this triplet therapy in the KEYNOTE-189 trial.

“These results, based on the nationwide experience for patients on Medicare, may inform discussions between physicians and patients with respect to expectations for outcomes among older patients with NSCLC,” lead author Kenneth Kehl, MD, assistant professor of medicine, Harvard Medical School, Boston, said in a statement.

Deborah Schrag, MD, chief, division of population sciences, Dana-Farber Cancer Institute, Boston, and Harvard Medical School, agreed, adding in the same statement that “this information empowers patients and clinicians with realistic expectations and equips them to make informed decisions.”

The study was published online May 21 in JAMA Network Open and was done in conjunction with the Health Data Analytics Institute, an analytics firm that applies artificial intelligence for measuring health risks.
 

Systemic therapy

For the study, the team analyzed Medicare data for 19,529 patients (median age, 73.8 years) who had all initiated first palliative-intent systemic therapy for lung cancer between January 2016 and December 2018. Some 3,079 patients received pembrolizumab monotherapy, 5,159 patients received a platinum-based regimen plus pemetrexed, 9,866 received a platinum plus a taxane, and 1,425 received platinum, pemetrexed, and pembrolizumab.

The authors noted that uptake of pembrolizumab-containing regimens in the Medicare population was rapid.

In the second quarter of 2016, pembrolizumab was used in only 0.7% of first-line treatments for advanced NSCLC, but increased to 42.4% of first-line treatments 2 years later, in the third quarter of 2018.

“The primary outcome was OS, which was measured using the restricted mean survival time (RMST),” Dr. Kehl and colleagues noted.

After propensity-score stratification, patients who received pembrolizumab had an adjusted RMST of 11 months compared with an adjusted RMST of 11.1 months for those who received the combination of platinum plus pemetrexed.

Survival was statistically worse for patients who received pembrolizumab than it was for those treated with a platinum/taxane combination, although the magnitude of difference between the two groups was small, at 0.7 months (P < .001). Patients who received the platinum/pemetrexed/pembrolizumab triplet had an adjusted RMST of 11.7 months, which was significantly better than the adjusted RMST of 11.2 months for patients who received the platinum/pemetrexed doublet, but the magnitude of the difference between these two groups was small, at 0.5 months (P = .02), the investigators added.
 

Different patient groups

Patients who received immunotherapy alone may have been more ill than those who received chemotherapy, the authors suggested. Patients who were 70 years of age or older, who were female, and who had a higher baseline mortality risk were more likely to receive single-agent pembrolizumab than chemotherapy, they noted. “Indeed, immunotherapy may be construed as a potential first-line treatment for patients who would otherwise have been deemed too frail for treatment at all, including patients older than 80 years,” they observed.

It is also possible that the Medicare patients included in the current analysis may differ substantively from advanced NSCLC participants enrolled in clinical trials, they wrote. For example, the median age of the Medicare cohort was approximately 10 years older than the median age of participants in both KEYNOTE-024 and KEYNOTE-189, the authors pointed out.

“If clinicians recommend immunotherapy disproportionately to Medicare patients with poor performance status or greater comorbidity – perhaps even if PD-L1 (programmed cell death-ligand-1) expression levels are below thresholds associated with the most substantial immunotherapy benefit – it may not be surprising that large survival improvements associated with immunotherapy were not observed in this analysis,” Dr. Kehl and colleagues suggested.

It is possible that durable benefit from immunotherapy, at least among some subgroups of patients included in the Medicare analysis, might have become more evident with additional follow-up beyond 18 months, they noted. However, they added, in “both KEYNOTE-024 and KEYNOTE-189, pembrolizumab was associated with substantial improvements in overall survival by that point.

“These results may inform prognostic considerations in practice and reinforce the importance of understanding patient selection dynamics in assessing the value and clinical utility of transformative treatment strategies,” they cautioned.

Dr. Kehl has reported receiving personal fees from Aetion, Roche, and IBM. Dr. Schrag has reported receiving personal fees from JAMA for editorial services and travel reimbursement/speaker fees from Pfizer.
 

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

Real-world use of the immune checkpoint inhibitors for first-line treatment of advanced non–small cell lung cancer (NSCLC) provides nowhere near the same survival advantage as seen in clinical trials, according to a retrospective cohort study of nearly 20,000 Medicare patients.

For example, the median overall survival (OS) in the “real world” was 11.4 months for patients treated with pembrolizumab (Keytruda, Merck) monotherapy – approximately 15 months shorter than the median OS among pembrolizumab-treated participants in the KEYNOTE-024 trial.  

Indeed, OS was shorter for Medicare patients treated with an immune checkpoint inhibitor alone than it was for patients treated with a chemoimmunotherapy regimen of platinum plus pemetrexed plus pembrolizumab, at a median of 12.9 months – which in itself was approximately 10 months shorter than survival outcomes with this triplet therapy in the KEYNOTE-189 trial.

“These results, based on the nationwide experience for patients on Medicare, may inform discussions between physicians and patients with respect to expectations for outcomes among older patients with NSCLC,” lead author Kenneth Kehl, MD, assistant professor of medicine, Harvard Medical School, Boston, said in a statement.

Deborah Schrag, MD, chief, division of population sciences, Dana-Farber Cancer Institute, Boston, and Harvard Medical School, agreed, adding in the same statement that “this information empowers patients and clinicians with realistic expectations and equips them to make informed decisions.”

The study was published online May 21 in JAMA Network Open and was done in conjunction with the Health Data Analytics Institute, an analytics firm that applies artificial intelligence for measuring health risks.
 

Systemic therapy

For the study, the team analyzed Medicare data for 19,529 patients (median age, 73.8 years) who had all initiated first palliative-intent systemic therapy for lung cancer between January 2016 and December 2018. Some 3,079 patients received pembrolizumab monotherapy, 5,159 patients received a platinum-based regimen plus pemetrexed, 9,866 received a platinum plus a taxane, and 1,425 received platinum, pemetrexed, and pembrolizumab.

The authors noted that uptake of pembrolizumab-containing regimens in the Medicare population was rapid.

In the second quarter of 2016, pembrolizumab was used in only 0.7% of first-line treatments for advanced NSCLC, but increased to 42.4% of first-line treatments 2 years later, in the third quarter of 2018.

“The primary outcome was OS, which was measured using the restricted mean survival time (RMST),” Dr. Kehl and colleagues noted.

After propensity-score stratification, patients who received pembrolizumab had an adjusted RMST of 11 months compared with an adjusted RMST of 11.1 months for those who received the combination of platinum plus pemetrexed.

Survival was statistically worse for patients who received pembrolizumab than it was for those treated with a platinum/taxane combination, although the magnitude of difference between the two groups was small, at 0.7 months (P < .001). Patients who received the platinum/pemetrexed/pembrolizumab triplet had an adjusted RMST of 11.7 months, which was significantly better than the adjusted RMST of 11.2 months for patients who received the platinum/pemetrexed doublet, but the magnitude of the difference between these two groups was small, at 0.5 months (P = .02), the investigators added.
 

Different patient groups

Patients who received immunotherapy alone may have been more ill than those who received chemotherapy, the authors suggested. Patients who were 70 years of age or older, who were female, and who had a higher baseline mortality risk were more likely to receive single-agent pembrolizumab than chemotherapy, they noted. “Indeed, immunotherapy may be construed as a potential first-line treatment for patients who would otherwise have been deemed too frail for treatment at all, including patients older than 80 years,” they observed.

It is also possible that the Medicare patients included in the current analysis may differ substantively from advanced NSCLC participants enrolled in clinical trials, they wrote. For example, the median age of the Medicare cohort was approximately 10 years older than the median age of participants in both KEYNOTE-024 and KEYNOTE-189, the authors pointed out.

“If clinicians recommend immunotherapy disproportionately to Medicare patients with poor performance status or greater comorbidity – perhaps even if PD-L1 (programmed cell death-ligand-1) expression levels are below thresholds associated with the most substantial immunotherapy benefit – it may not be surprising that large survival improvements associated with immunotherapy were not observed in this analysis,” Dr. Kehl and colleagues suggested.

It is possible that durable benefit from immunotherapy, at least among some subgroups of patients included in the Medicare analysis, might have become more evident with additional follow-up beyond 18 months, they noted. However, they added, in “both KEYNOTE-024 and KEYNOTE-189, pembrolizumab was associated with substantial improvements in overall survival by that point.

“These results may inform prognostic considerations in practice and reinforce the importance of understanding patient selection dynamics in assessing the value and clinical utility of transformative treatment strategies,” they cautioned.

Dr. Kehl has reported receiving personal fees from Aetion, Roche, and IBM. Dr. Schrag has reported receiving personal fees from JAMA for editorial services and travel reimbursement/speaker fees from Pfizer.
 

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

Despite a small drop in income, slightly more dermatologists said that they felt fairly compensated in 2020 than in 2019, according to survey results from Medscape.

The numbers look like this: Average income was $394,000 in 2020, compared with $411,000 in 2019 – a drop of 4.1% – but 67% of dermatologists said they felt fairly compensated in 2020, compared with 65% in 2019, Medscape said in its 2021 Dermatologist Compensation Report. Only 3 of the 29 participating specialties had a more favorable reaction: oncology (79%), psychiatry (69%), and plastic surgery (68%).

“Most dermatologists who saw a drop in income cited COVID-19–related issues, such as job loss, fewer hours, and fewer patients,” Keith L. Martin wrote in the annual report, while also noting that 45% of dermatologist respondents “said that the pandemic did not cause them financial or practice-related harm.”

For the dermatologists who did see such negative effects, just over half (54%) said that they expect income to return to pre–COVID-19 levels in the next year, while 31% believe it will take 2-3 years and 12% said that their income would never return to normal. For all specialists included in the survey, the corresponding numbers were 42%, 41%, and 12%, with primary care physicians coming in at 39%, 43%, and 10%, the report said.

Among all participating specialties, plastic surgeons reported the highest average earnings at $526,000, with orthopedists ($511,000) and cardiologists ($459,000) next. Pediatricians had not just the lowest average income ($221,000) for 2020, but also the largest decline in patients seen per week (18%), according to the results of the survey, which was conducted from Oct. 6, 2020, to Feb. 11, 2021, and involved 17,903 physicians.

Dermatologists also experienced a larger-than-average decline (16%) in patient traffic – only the pediatricians had a larger drop – as their weekly patient count fell from 141 before the pandemic to the current 119. Despite that drop, though, average hours worked per week remained at 45, as time is now being spent on office safety protocols and other issues involving COVID-19, Medscape pointed out.

Dermatologists also spent more time on paperwork and administration in 2020 than in 2019: 14.6 hours per week versus 13.2 hours. Their 2020 average, however, was still lower than that of all physicians, 16.3 hours, and much lower than that of the infectious disease physicians, who topped the survey with an average of 24.2 hours per week, the Medscape data show.

One area where dermatologists did lead the survey was in their commitment to their specialty: 96% said they would choose dermatology again if given the chance, which was equaled by orthopedics and oncology, Medscape said.

[email protected]

Despite a small drop in income, slightly more dermatologists said that they felt fairly compensated in 2020 than in 2019, according to survey results from Medscape.

The numbers look like this: Average income was $394,000 in 2020, compared with $411,000 in 2019 – a drop of 4.1% – but 67% of dermatologists said they felt fairly compensated in 2020, compared with 65% in 2019, Medscape said in its 2021 Dermatologist Compensation Report. Only 3 of the 29 participating specialties had a more favorable reaction: oncology (79%), psychiatry (69%), and plastic surgery (68%).

“Most dermatologists who saw a drop in income cited COVID-19–related issues, such as job loss, fewer hours, and fewer patients,” Keith L. Martin wrote in the annual report, while also noting that 45% of dermatologist respondents “said that the pandemic did not cause them financial or practice-related harm.”

For the dermatologists who did see such negative effects, just over half (54%) said that they expect income to return to pre–COVID-19 levels in the next year, while 31% believe it will take 2-3 years and 12% said that their income would never return to normal. For all specialists included in the survey, the corresponding numbers were 42%, 41%, and 12%, with primary care physicians coming in at 39%, 43%, and 10%, the report said.

Among all participating specialties, plastic surgeons reported the highest average earnings at $526,000, with orthopedists ($511,000) and cardiologists ($459,000) next. Pediatricians had not just the lowest average income ($221,000) for 2020, but also the largest decline in patients seen per week (18%), according to the results of the survey, which was conducted from Oct. 6, 2020, to Feb. 11, 2021, and involved 17,903 physicians.

Dermatologists also experienced a larger-than-average decline (16%) in patient traffic – only the pediatricians had a larger drop – as their weekly patient count fell from 141 before the pandemic to the current 119. Despite that drop, though, average hours worked per week remained at 45, as time is now being spent on office safety protocols and other issues involving COVID-19, Medscape pointed out.

Dermatologists also spent more time on paperwork and administration in 2020 than in 2019: 14.6 hours per week versus 13.2 hours. Their 2020 average, however, was still lower than that of all physicians, 16.3 hours, and much lower than that of the infectious disease physicians, who topped the survey with an average of 24.2 hours per week, the Medscape data show.

One area where dermatologists did lead the survey was in their commitment to their specialty: 96% said they would choose dermatology again if given the chance, which was equaled by orthopedics and oncology, Medscape said.

[email protected]

Despite a small drop in income, slightly more dermatologists said that they felt fairly compensated in 2020 than in 2019, according to survey results from Medscape.

The numbers look like this: Average income was $394,000 in 2020, compared with $411,000 in 2019 – a drop of 4.1% – but 67% of dermatologists said they felt fairly compensated in 2020, compared with 65% in 2019, Medscape said in its 2021 Dermatologist Compensation Report. Only 3 of the 29 participating specialties had a more favorable reaction: oncology (79%), psychiatry (69%), and plastic surgery (68%).

“Most dermatologists who saw a drop in income cited COVID-19–related issues, such as job loss, fewer hours, and fewer patients,” Keith L. Martin wrote in the annual report, while also noting that 45% of dermatologist respondents “said that the pandemic did not cause them financial or practice-related harm.”

For the dermatologists who did see such negative effects, just over half (54%) said that they expect income to return to pre–COVID-19 levels in the next year, while 31% believe it will take 2-3 years and 12% said that their income would never return to normal. For all specialists included in the survey, the corresponding numbers were 42%, 41%, and 12%, with primary care physicians coming in at 39%, 43%, and 10%, the report said.

Among all participating specialties, plastic surgeons reported the highest average earnings at $526,000, with orthopedists ($511,000) and cardiologists ($459,000) next. Pediatricians had not just the lowest average income ($221,000) for 2020, but also the largest decline in patients seen per week (18%), according to the results of the survey, which was conducted from Oct. 6, 2020, to Feb. 11, 2021, and involved 17,903 physicians.

Dermatologists also experienced a larger-than-average decline (16%) in patient traffic – only the pediatricians had a larger drop – as their weekly patient count fell from 141 before the pandemic to the current 119. Despite that drop, though, average hours worked per week remained at 45, as time is now being spent on office safety protocols and other issues involving COVID-19, Medscape pointed out.

Dermatologists also spent more time on paperwork and administration in 2020 than in 2019: 14.6 hours per week versus 13.2 hours. Their 2020 average, however, was still lower than that of all physicians, 16.3 hours, and much lower than that of the infectious disease physicians, who topped the survey with an average of 24.2 hours per week, the Medscape data show.

One area where dermatologists did lead the survey was in their commitment to their specialty: 96% said they would choose dermatology again if given the chance, which was equaled by orthopedics and oncology, Medscape said.

[email protected]

With another long winter officially in the rearview mirror and spring sunshine displaying new signs of life outdoors, I am excited to share some of the changes happening inside the offices of the Journal of Clinical Outcomes Management (JCOM). It is my pleasure to introduce Ebrahim Barkoudah, MD, MPH, as the journal’s new physician Editor in Chief. Dr. Barkoudah’s extensive experience in education and his work to improve patient outcomes will be assets to JCOM.

Specializing in both internal medicine and hospital medicine, Dr. Barkoudah is the Associate Director of the Hospital Medicine Unit and a Medical Director in the Department of Medicine at Brigham and Women’s Hospital in Boston. He is also Assistant Professor of Medicine at Harvard Medical School, where he led the school’s international education efforts.

Dr. Barkoudah serves patients with a range of complex clinical disorders, managing their care and seeking innovative treatment options. His research interest is in health care outcomes as well as clinical trials of therapeutic interventions. Dr. Barkoudah also serves on numerous clinical innovation committees at Brigham Health and national task forces.

Dr. Barkoudah is an active member of several professional societies including the American College of Physicians, Society of Hospital Medicine, American Heart Association, Massachusetts Medical Society, among others. He was the Institutional Administration Fellow of the Safety and Quality Fellowship Program at the Institution for Healthcare Improvement.

On behalf of the JCOM Editorial Review Board, I want to extend a special thank you to outgoing editor Lori Tishler, MD, MPH. Dr. Tishler’s impact on the journal cannot be overstated, and we are indebted to the time and expertise she shared with the journal during her tenure.

—Eric Seger

With another long winter officially in the rearview mirror and spring sunshine displaying new signs of life outdoors, I am excited to share some of the changes happening inside the offices of the Journal of Clinical Outcomes Management (JCOM). It is my pleasure to introduce Ebrahim Barkoudah, MD, MPH, as the journal’s new physician Editor in Chief. Dr. Barkoudah’s extensive experience in education and his work to improve patient outcomes will be assets to JCOM.

Specializing in both internal medicine and hospital medicine, Dr. Barkoudah is the Associate Director of the Hospital Medicine Unit and a Medical Director in the Department of Medicine at Brigham and Women’s Hospital in Boston. He is also Assistant Professor of Medicine at Harvard Medical School, where he led the school’s international education efforts.

Dr. Barkoudah serves patients with a range of complex clinical disorders, managing their care and seeking innovative treatment options. His research interest is in health care outcomes as well as clinical trials of therapeutic interventions. Dr. Barkoudah also serves on numerous clinical innovation committees at Brigham Health and national task forces.

Dr. Barkoudah is an active member of several professional societies including the American College of Physicians, Society of Hospital Medicine, American Heart Association, Massachusetts Medical Society, among others. He was the Institutional Administration Fellow of the Safety and Quality Fellowship Program at the Institution for Healthcare Improvement.

On behalf of the JCOM Editorial Review Board, I want to extend a special thank you to outgoing editor Lori Tishler, MD, MPH. Dr. Tishler’s impact on the journal cannot be overstated, and we are indebted to the time and expertise she shared with the journal during her tenure.

—Eric Seger

With another long winter officially in the rearview mirror and spring sunshine displaying new signs of life outdoors, I am excited to share some of the changes happening inside the offices of the Journal of Clinical Outcomes Management (JCOM). It is my pleasure to introduce Ebrahim Barkoudah, MD, MPH, as the journal’s new physician Editor in Chief. Dr. Barkoudah’s extensive experience in education and his work to improve patient outcomes will be assets to JCOM.

Specializing in both internal medicine and hospital medicine, Dr. Barkoudah is the Associate Director of the Hospital Medicine Unit and a Medical Director in the Department of Medicine at Brigham and Women’s Hospital in Boston. He is also Assistant Professor of Medicine at Harvard Medical School, where he led the school’s international education efforts.

Dr. Barkoudah serves patients with a range of complex clinical disorders, managing their care and seeking innovative treatment options. His research interest is in health care outcomes as well as clinical trials of therapeutic interventions. Dr. Barkoudah also serves on numerous clinical innovation committees at Brigham Health and national task forces.

Dr. Barkoudah is an active member of several professional societies including the American College of Physicians, Society of Hospital Medicine, American Heart Association, Massachusetts Medical Society, among others. He was the Institutional Administration Fellow of the Safety and Quality Fellowship Program at the Institution for Healthcare Improvement.

On behalf of the JCOM Editorial Review Board, I want to extend a special thank you to outgoing editor Lori Tishler, MD, MPH. Dr. Tishler’s impact on the journal cannot be overstated, and we are indebted to the time and expertise she shared with the journal during her tenure.

—Eric Seger

Study Overview

Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.

Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.

Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).

Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.

Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).

Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.

Commentary

Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.¹ Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.² This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes³; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.

A particular challenge in determining when to initiate palliative care lies in predicting outcomes,⁴ particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.⁵ These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.

Applications for Clinical Practice

Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.

Study Overview

Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.

Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.

Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).

Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.

Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).

Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.

Commentary

Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.¹ Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.² This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes³; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.

A particular challenge in determining when to initiate palliative care lies in predicting outcomes,⁴ particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.⁵ These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.

Applications for Clinical Practice

Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.

Study Overview

Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.

Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.

Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).

Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.

Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).

Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.

Commentary

Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.¹ Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.² This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes³; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.

A particular challenge in determining when to initiate palliative care lies in predicting outcomes,⁴ particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.⁵ These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.

Applications for Clinical Practice

Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.

Study Overview

Objective. To determine the effectiveness of a person-centered intervention (comprising personalized and cocreated treatment plans to promote physical activity) for individuals with chronic widespread pain when delivered with digital eHealth support compared with standard telephone follow-up.

Design. Single-blinded multicenter randomized controlled trial.

Settings and participants. Participants with chronic widespread pain (CWP) who had participated in a pain management program from 2010–16 at 5 primary health care rehabilitation centers in 5 cities or towns in the western part of Sweden were invited to join the study between March 2018 and April 2019 via letter providing information about the intervention. The letter was followed by a phone call 1-2 weeks later to screen for inclusion and exclusion criteria and interest in participating. Additional participants were invited to participate via a newspaper advertisement in 1 of the 5 cities.

Inclusion criteria were Swedish-speaking persons aged 20–65 years with CWP (defined as having pain in both sides of the body, pain above and below the waist, and axial pain for at least 3 months). Exclusion criteria included having other severe somatic or psychiatric disorders, dominating causes of pain other than CWP, or other severe disease interfering with the ability to be physically active, pregnancy, not having access to a smartphone or a computer, inability to speak or understand Swedish, ongoing physiotherapy treatment, and already exercising regularly. Of 716 people initially assessed for eligibility, 425 completed telephone screening, and 139 were randomized (using block randomization) to either the intervention arm (n = 69) or the active control arm (n = 70). Due to the nature of the intervention, it was not possible to blind the participants or the physiotherapist to group allocation. All participants provided written informed consent.

The 2 groups underwent the same first individual meeting with a physiotherapist to cocreate a health plan with physical activities, and, if needed, stress management, based on each participant’s individual preferences, obstacles, goals, and resources. The difference between the groups was the type of follow-up support. Participants in the intervention group had 1 follow-up meeting with the physiotherapist a week after the initial meeting (to review and adjust the health plan as needed) and thereafter were supported through a digital e-health platform (accessed via the participant’s smartphone or computer) during the 6-month follow-up period. Participants were encouraged to access the platform once a week to answer questions regarding their health, and the extent to which they had been able to manage their health plan during the previous week. In addition, the participant and physiotherapist could communicate via the platform as needed. Participants in the active control group had 1 follow-up phone call with the physiotherapist 1 month after the initial meeting (similarly to review and adjust the health plan as needed), and no further contact or support from the physiotherapist during the 6-month follow-up period.

Measures and analysis. The primary outcome measure was pain intensity during the previous week assessed with a 0–100 subscale from the Fibromyalgia Impact Questionnaire (FIQ-pain). Secondary outcome measures included overall health status (via FIQ-total with 10 subscales), global fatigue (via FIQ-fatigue subscale), multidimensional fatigue (via Multidimensional Fatigue Inventory, a 20-item questionnaire rated on a 1-5 Likert scale), clinical manifestations of stress (via Stress and Crisis Inventory, a 35-item questionnaire rated on a 0-4 Likert scale), self-efficacy (via General Self-Efficacy Scale, a 10-item questionnaire rated on a 1-4 Likert scale), health-related quality of life (via Short Form 36, specifically the Physical Component Summary composite score), leisure-time physical activity (via Leisure Time Physical Activity Instrument), and physical function (via 1-min chair-stand test). Additional demographic data on age, pain localization, pharmacological treatment, tobacco use, country of birth, level of education, family status, economic status, work status, sick-leave, and disability pension were collected via a questionnaire.

Between-group differences for changes in outcomes from baseline to 6-month follow-up were calculated using the Mann–Whitney U test for continuous data, and Pearson’s χ² or Fisher’s exact test for categorical data. Significance level was set at 5% with no adjustment for multiple comparisons. All analyses were made according to intention-to-treat by originally assigned group; missing cases were not included in the analysis.

Main results. Participants consisted of primarily middle-age, middle income, educated (> 12 years of education) females, with > 60% of participants working at least part-time (between-group differences in baseline data and demographic data not detailed in the article). A total of 29 participants were lost to follow-up. In the intervention group, lost-to-follow up participants were older, performed fewer hours of physical activity, and had lower mental fatigue at baseline, compared with those who were lost to follow-up in the active control group.

In between-group analyses, there were no significant differences in the primary outcome (pain intensity) from baseline to 6-month follow-up. The only significant difference in secondary outcomes was seen in global fatigue – the active control group improved significantly compared with the intervention group (P = .004).

In the intervention group, 87% of participants used the digital platform. Among these users, 35% contacted the physiotherapist (75% of these communications were health- or study-related issues, 25% were issues with the digital platform), 33% were contacted by the physiotherapist (96% of these communications were about the health plan and physical activity), and 32% never had any contact with the physiotherapist. There was a significant difference in the primary outcome (pain intensity) from baseline to 6-month follow-up between platform users and non-users (P = .03, mean change [SD] 3.8 [19.66] mm vs –20.5 [6.36] mm, respectively).

Conclusion. No significant differences were found between the groups after 6 months (except for a significant decrease in global fatigue in the active control group compared with the intervention group). Further development of interventions to support persons with CWP to maintain regular physical activity is needed.

Commentary

Chronic widespread pain is a disorder characterized by diffuse body pain persisting for at least 3 months.^1-2 It has been associated with lost work productivity, mental ill health, and reduced quality of life. The development of clinically effective and cost-effective pain management strategies for CWP is challenging given the syndrome complexity and heterogenous symptomology. Thus, multimodal, multidisciplinary management is widely advocated, often a combination of education and self-management, with integration of physical, non-pharmacological and pharmacological treatments.^1-3 Of note, physical exercise and cognitive behavioral therapy are 2 non-pharmacological treatments that hold some promise based on available evidence.

The pervasiveness of technology in nearly all aspects of daily life has corresponded with the development of implementation of a wide range of technology-based interventions for health purposes.⁴ Examples of electronic health or eHealth modalities include internet-based, telephone supported, interactive voice-response, videoconferencing, mobile apps, and virtual reality. While the use of technology in chronic pain management interventions has increased in recent years, the literature is still limited, heterogenous, and provides limited evidence on the efficacy of eHealth/digital interventions, let alone which specific modalities are most effective.^4-9

This study adds to the literature as a randomized controlled trial evaluating the effectiveness of a person-centered intervention for individuals with CWP delivered with digital eHealth support compared with standard telephone follow-up. Results showed no significant difference in the primary outcome of pain intensity and nearly all secondary outcomes between the intervention group (supported by the digital platform) and the active control group (supported by a follow-up phone call). Further, intervention participants who did not use the platform improved significantly more in pain intensity than those who used the platform.

While these results imply that digital support does not contribute to improvements in the outcomes measured, it is important these findings are interpreted with caution given the limitations of the study design as well as limitations with the intervention itself. Importantly, while this study was designed as a randomized controlled trial, the authors indicated that it was not possible to blind the participants or the physiotherapist to group allocation, which may have impacted their behaviors while in the study. In addition, as the authors note, an intervention aimed at increasing physical activity should ideally include an objective measure of activity and this was lacking in this study. The use of an actigraphy device for example would have provided objective, continuous data on movement and could have helped assess an important outcome measure – whether participants reached their physical activity goals or had increased their overall physical activity. In the analysis, there was no adjustment for multiple comparisons or use of imputation methods to handle missing values. Further, it was unclear whether differences in baseline data were evaluated and taken into consideration in between-group analyses. Lastly, results are only attributable to the eHealth mode used in this study (digital web-based with limited mechanisms of behavior change and engagement built-in) and thus should not be generalized to all digital/eHealth interventions persons with CWP.

Applications for Clinical Practice

While the results of this study failed to demonstrate significant differences between a physical activity-promoting intervention for persons with CWP with digital follow-up vs telephone follow-up, it remains important to consider person-centered principles when offering CWP management support. In this spirit, clinicians should consider a management approach that takes into account the individual’s knowledge, resources, and barriers, and also actively involves the patient in treatment planning to enhance the patient’s self-efficacy to manage their health. In addition, individual preference for a specific (or combination of) eHealth/digital modality should be considered and used to guide a comprehensive management plan, as well as used as a complementary modality to face-to-face care/support.

Study Overview

Objective. To determine the effectiveness of a person-centered intervention (comprising personalized and cocreated treatment plans to promote physical activity) for individuals with chronic widespread pain when delivered with digital eHealth support compared with standard telephone follow-up.

Design. Single-blinded multicenter randomized controlled trial.

Settings and participants. Participants with chronic widespread pain (CWP) who had participated in a pain management program from 2010–16 at 5 primary health care rehabilitation centers in 5 cities or towns in the western part of Sweden were invited to join the study between March 2018 and April 2019 via letter providing information about the intervention. The letter was followed by a phone call 1-2 weeks later to screen for inclusion and exclusion criteria and interest in participating. Additional participants were invited to participate via a newspaper advertisement in 1 of the 5 cities.

Inclusion criteria were Swedish-speaking persons aged 20–65 years with CWP (defined as having pain in both sides of the body, pain above and below the waist, and axial pain for at least 3 months). Exclusion criteria included having other severe somatic or psychiatric disorders, dominating causes of pain other than CWP, or other severe disease interfering with the ability to be physically active, pregnancy, not having access to a smartphone or a computer, inability to speak or understand Swedish, ongoing physiotherapy treatment, and already exercising regularly. Of 716 people initially assessed for eligibility, 425 completed telephone screening, and 139 were randomized (using block randomization) to either the intervention arm (n = 69) or the active control arm (n = 70). Due to the nature of the intervention, it was not possible to blind the participants or the physiotherapist to group allocation. All participants provided written informed consent.

The 2 groups underwent the same first individual meeting with a physiotherapist to cocreate a health plan with physical activities, and, if needed, stress management, based on each participant’s individual preferences, obstacles, goals, and resources. The difference between the groups was the type of follow-up support. Participants in the intervention group had 1 follow-up meeting with the physiotherapist a week after the initial meeting (to review and adjust the health plan as needed) and thereafter were supported through a digital e-health platform (accessed via the participant’s smartphone or computer) during the 6-month follow-up period. Participants were encouraged to access the platform once a week to answer questions regarding their health, and the extent to which they had been able to manage their health plan during the previous week. In addition, the participant and physiotherapist could communicate via the platform as needed. Participants in the active control group had 1 follow-up phone call with the physiotherapist 1 month after the initial meeting (similarly to review and adjust the health plan as needed), and no further contact or support from the physiotherapist during the 6-month follow-up period.

Measures and analysis. The primary outcome measure was pain intensity during the previous week assessed with a 0–100 subscale from the Fibromyalgia Impact Questionnaire (FIQ-pain). Secondary outcome measures included overall health status (via FIQ-total with 10 subscales), global fatigue (via FIQ-fatigue subscale), multidimensional fatigue (via Multidimensional Fatigue Inventory, a 20-item questionnaire rated on a 1-5 Likert scale), clinical manifestations of stress (via Stress and Crisis Inventory, a 35-item questionnaire rated on a 0-4 Likert scale), self-efficacy (via General Self-Efficacy Scale, a 10-item questionnaire rated on a 1-4 Likert scale), health-related quality of life (via Short Form 36, specifically the Physical Component Summary composite score), leisure-time physical activity (via Leisure Time Physical Activity Instrument), and physical function (via 1-min chair-stand test). Additional demographic data on age, pain localization, pharmacological treatment, tobacco use, country of birth, level of education, family status, economic status, work status, sick-leave, and disability pension were collected via a questionnaire.

Between-group differences for changes in outcomes from baseline to 6-month follow-up were calculated using the Mann–Whitney U test for continuous data, and Pearson’s χ² or Fisher’s exact test for categorical data. Significance level was set at 5% with no adjustment for multiple comparisons. All analyses were made according to intention-to-treat by originally assigned group; missing cases were not included in the analysis.

Main results. Participants consisted of primarily middle-age, middle income, educated (> 12 years of education) females, with > 60% of participants working at least part-time (between-group differences in baseline data and demographic data not detailed in the article). A total of 29 participants were lost to follow-up. In the intervention group, lost-to-follow up participants were older, performed fewer hours of physical activity, and had lower mental fatigue at baseline, compared with those who were lost to follow-up in the active control group.

In between-group analyses, there were no significant differences in the primary outcome (pain intensity) from baseline to 6-month follow-up. The only significant difference in secondary outcomes was seen in global fatigue – the active control group improved significantly compared with the intervention group (P = .004).

In the intervention group, 87% of participants used the digital platform. Among these users, 35% contacted the physiotherapist (75% of these communications were health- or study-related issues, 25% were issues with the digital platform), 33% were contacted by the physiotherapist (96% of these communications were about the health plan and physical activity), and 32% never had any contact with the physiotherapist. There was a significant difference in the primary outcome (pain intensity) from baseline to 6-month follow-up between platform users and non-users (P = .03, mean change [SD] 3.8 [19.66] mm vs –20.5 [6.36] mm, respectively).

Conclusion. No significant differences were found between the groups after 6 months (except for a significant decrease in global fatigue in the active control group compared with the intervention group). Further development of interventions to support persons with CWP to maintain regular physical activity is needed.

Commentary

Chronic widespread pain is a disorder characterized by diffuse body pain persisting for at least 3 months.^1-2 It has been associated with lost work productivity, mental ill health, and reduced quality of life. The development of clinically effective and cost-effective pain management strategies for CWP is challenging given the syndrome complexity and heterogenous symptomology. Thus, multimodal, multidisciplinary management is widely advocated, often a combination of education and self-management, with integration of physical, non-pharmacological and pharmacological treatments.^1-3 Of note, physical exercise and cognitive behavioral therapy are 2 non-pharmacological treatments that hold some promise based on available evidence.

The pervasiveness of technology in nearly all aspects of daily life has corresponded with the development of implementation of a wide range of technology-based interventions for health purposes.⁴ Examples of electronic health or eHealth modalities include internet-based, telephone supported, interactive voice-response, videoconferencing, mobile apps, and virtual reality. While the use of technology in chronic pain management interventions has increased in recent years, the literature is still limited, heterogenous, and provides limited evidence on the efficacy of eHealth/digital interventions, let alone which specific modalities are most effective.^4-9

This study adds to the literature as a randomized controlled trial evaluating the effectiveness of a person-centered intervention for individuals with CWP delivered with digital eHealth support compared with standard telephone follow-up. Results showed no significant difference in the primary outcome of pain intensity and nearly all secondary outcomes between the intervention group (supported by the digital platform) and the active control group (supported by a follow-up phone call). Further, intervention participants who did not use the platform improved significantly more in pain intensity than those who used the platform.

While these results imply that digital support does not contribute to improvements in the outcomes measured, it is important these findings are interpreted with caution given the limitations of the study design as well as limitations with the intervention itself. Importantly, while this study was designed as a randomized controlled trial, the authors indicated that it was not possible to blind the participants or the physiotherapist to group allocation, which may have impacted their behaviors while in the study. In addition, as the authors note, an intervention aimed at increasing physical activity should ideally include an objective measure of activity and this was lacking in this study. The use of an actigraphy device for example would have provided objective, continuous data on movement and could have helped assess an important outcome measure – whether participants reached their physical activity goals or had increased their overall physical activity. In the analysis, there was no adjustment for multiple comparisons or use of imputation methods to handle missing values. Further, it was unclear whether differences in baseline data were evaluated and taken into consideration in between-group analyses. Lastly, results are only attributable to the eHealth mode used in this study (digital web-based with limited mechanisms of behavior change and engagement built-in) and thus should not be generalized to all digital/eHealth interventions persons with CWP.

Applications for Clinical Practice

While the results of this study failed to demonstrate significant differences between a physical activity-promoting intervention for persons with CWP with digital follow-up vs telephone follow-up, it remains important to consider person-centered principles when offering CWP management support. In this spirit, clinicians should consider a management approach that takes into account the individual’s knowledge, resources, and barriers, and also actively involves the patient in treatment planning to enhance the patient’s self-efficacy to manage their health. In addition, individual preference for a specific (or combination of) eHealth/digital modality should be considered and used to guide a comprehensive management plan, as well as used as a complementary modality to face-to-face care/support.

Study Overview

Objective. To determine the effectiveness of a person-centered intervention (comprising personalized and cocreated treatment plans to promote physical activity) for individuals with chronic widespread pain when delivered with digital eHealth support compared with standard telephone follow-up.

Design. Single-blinded multicenter randomized controlled trial.

Settings and participants. Participants with chronic widespread pain (CWP) who had participated in a pain management program from 2010–16 at 5 primary health care rehabilitation centers in 5 cities or towns in the western part of Sweden were invited to join the study between March 2018 and April 2019 via letter providing information about the intervention. The letter was followed by a phone call 1-2 weeks later to screen for inclusion and exclusion criteria and interest in participating. Additional participants were invited to participate via a newspaper advertisement in 1 of the 5 cities.

Inclusion criteria were Swedish-speaking persons aged 20–65 years with CWP (defined as having pain in both sides of the body, pain above and below the waist, and axial pain for at least 3 months). Exclusion criteria included having other severe somatic or psychiatric disorders, dominating causes of pain other than CWP, or other severe disease interfering with the ability to be physically active, pregnancy, not having access to a smartphone or a computer, inability to speak or understand Swedish, ongoing physiotherapy treatment, and already exercising regularly. Of 716 people initially assessed for eligibility, 425 completed telephone screening, and 139 were randomized (using block randomization) to either the intervention arm (n = 69) or the active control arm (n = 70). Due to the nature of the intervention, it was not possible to blind the participants or the physiotherapist to group allocation. All participants provided written informed consent.

The 2 groups underwent the same first individual meeting with a physiotherapist to cocreate a health plan with physical activities, and, if needed, stress management, based on each participant’s individual preferences, obstacles, goals, and resources. The difference between the groups was the type of follow-up support. Participants in the intervention group had 1 follow-up meeting with the physiotherapist a week after the initial meeting (to review and adjust the health plan as needed) and thereafter were supported through a digital e-health platform (accessed via the participant’s smartphone or computer) during the 6-month follow-up period. Participants were encouraged to access the platform once a week to answer questions regarding their health, and the extent to which they had been able to manage their health plan during the previous week. In addition, the participant and physiotherapist could communicate via the platform as needed. Participants in the active control group had 1 follow-up phone call with the physiotherapist 1 month after the initial meeting (similarly to review and adjust the health plan as needed), and no further contact or support from the physiotherapist during the 6-month follow-up period.

Measures and analysis. The primary outcome measure was pain intensity during the previous week assessed with a 0–100 subscale from the Fibromyalgia Impact Questionnaire (FIQ-pain). Secondary outcome measures included overall health status (via FIQ-total with 10 subscales), global fatigue (via FIQ-fatigue subscale), multidimensional fatigue (via Multidimensional Fatigue Inventory, a 20-item questionnaire rated on a 1-5 Likert scale), clinical manifestations of stress (via Stress and Crisis Inventory, a 35-item questionnaire rated on a 0-4 Likert scale), self-efficacy (via General Self-Efficacy Scale, a 10-item questionnaire rated on a 1-4 Likert scale), health-related quality of life (via Short Form 36, specifically the Physical Component Summary composite score), leisure-time physical activity (via Leisure Time Physical Activity Instrument), and physical function (via 1-min chair-stand test). Additional demographic data on age, pain localization, pharmacological treatment, tobacco use, country of birth, level of education, family status, economic status, work status, sick-leave, and disability pension were collected via a questionnaire.

Between-group differences for changes in outcomes from baseline to 6-month follow-up were calculated using the Mann–Whitney U test for continuous data, and Pearson’s χ² or Fisher’s exact test for categorical data. Significance level was set at 5% with no adjustment for multiple comparisons. All analyses were made according to intention-to-treat by originally assigned group; missing cases were not included in the analysis.

Main results. Participants consisted of primarily middle-age, middle income, educated (> 12 years of education) females, with > 60% of participants working at least part-time (between-group differences in baseline data and demographic data not detailed in the article). A total of 29 participants were lost to follow-up. In the intervention group, lost-to-follow up participants were older, performed fewer hours of physical activity, and had lower mental fatigue at baseline, compared with those who were lost to follow-up in the active control group.

In between-group analyses, there were no significant differences in the primary outcome (pain intensity) from baseline to 6-month follow-up. The only significant difference in secondary outcomes was seen in global fatigue – the active control group improved significantly compared with the intervention group (P = .004).

In the intervention group, 87% of participants used the digital platform. Among these users, 35% contacted the physiotherapist (75% of these communications were health- or study-related issues, 25% were issues with the digital platform), 33% were contacted by the physiotherapist (96% of these communications were about the health plan and physical activity), and 32% never had any contact with the physiotherapist. There was a significant difference in the primary outcome (pain intensity) from baseline to 6-month follow-up between platform users and non-users (P = .03, mean change [SD] 3.8 [19.66] mm vs –20.5 [6.36] mm, respectively).

Conclusion. No significant differences were found between the groups after 6 months (except for a significant decrease in global fatigue in the active control group compared with the intervention group). Further development of interventions to support persons with CWP to maintain regular physical activity is needed.

Commentary

Chronic widespread pain is a disorder characterized by diffuse body pain persisting for at least 3 months.^1-2 It has been associated with lost work productivity, mental ill health, and reduced quality of life. The development of clinically effective and cost-effective pain management strategies for CWP is challenging given the syndrome complexity and heterogenous symptomology. Thus, multimodal, multidisciplinary management is widely advocated, often a combination of education and self-management, with integration of physical, non-pharmacological and pharmacological treatments.^1-3 Of note, physical exercise and cognitive behavioral therapy are 2 non-pharmacological treatments that hold some promise based on available evidence.

The pervasiveness of technology in nearly all aspects of daily life has corresponded with the development of implementation of a wide range of technology-based interventions for health purposes.⁴ Examples of electronic health or eHealth modalities include internet-based, telephone supported, interactive voice-response, videoconferencing, mobile apps, and virtual reality. While the use of technology in chronic pain management interventions has increased in recent years, the literature is still limited, heterogenous, and provides limited evidence on the efficacy of eHealth/digital interventions, let alone which specific modalities are most effective.^4-9

This study adds to the literature as a randomized controlled trial evaluating the effectiveness of a person-centered intervention for individuals with CWP delivered with digital eHealth support compared with standard telephone follow-up. Results showed no significant difference in the primary outcome of pain intensity and nearly all secondary outcomes between the intervention group (supported by the digital platform) and the active control group (supported by a follow-up phone call). Further, intervention participants who did not use the platform improved significantly more in pain intensity than those who used the platform.

While these results imply that digital support does not contribute to improvements in the outcomes measured, it is important these findings are interpreted with caution given the limitations of the study design as well as limitations with the intervention itself. Importantly, while this study was designed as a randomized controlled trial, the authors indicated that it was not possible to blind the participants or the physiotherapist to group allocation, which may have impacted their behaviors while in the study. In addition, as the authors note, an intervention aimed at increasing physical activity should ideally include an objective measure of activity and this was lacking in this study. The use of an actigraphy device for example would have provided objective, continuous data on movement and could have helped assess an important outcome measure – whether participants reached their physical activity goals or had increased their overall physical activity. In the analysis, there was no adjustment for multiple comparisons or use of imputation methods to handle missing values. Further, it was unclear whether differences in baseline data were evaluated and taken into consideration in between-group analyses. Lastly, results are only attributable to the eHealth mode used in this study (digital web-based with limited mechanisms of behavior change and engagement built-in) and thus should not be generalized to all digital/eHealth interventions persons with CWP.

Applications for Clinical Practice

While the results of this study failed to demonstrate significant differences between a physical activity-promoting intervention for persons with CWP with digital follow-up vs telephone follow-up, it remains important to consider person-centered principles when offering CWP management support. In this spirit, clinicians should consider a management approach that takes into account the individual’s knowledge, resources, and barriers, and also actively involves the patient in treatment planning to enhance the patient’s self-efficacy to manage their health. In addition, individual preference for a specific (or combination of) eHealth/digital modality should be considered and used to guide a comprehensive management plan, as well as used as a complementary modality to face-to-face care/support.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

I will never forget the first time I cared for a patient who tested positive for COVID-19. It was March 2020, and I was evaluating a patient in the emergency department (ED). At the time we knew very little about this virus and how it is transmitted. We had all seen the images from Wuhan, China, and had appropriate fear of the lethality of the virus, but there was not yet a clear understanding as to how best to keep health care practitioners safe as they cared for patients with COVID-19.

That evening I received a page that a middle-aged man who had tested positive for COVID-19 was in the ED with fever, cough, and hypoxia. As a hospitalist, my role is to care for these patients, those admitted to stay overnight in the hospital. Before going to see the patient, I watched a video on how to properly don personal protective equipment (PPE). I walked to the ED and suited up with a surgical mask, goggles, disposable gown, and gloves. I was very conscious of the amount of time I spent in that patient’s room, and tried to stand at the foot of the bed as much as possible so as to maximize the distance between our faces when we talked.

Upon finishing my assessment, I took off my PPE and exited the room but kept wondering if I had done so correctly. That night when I came home, I slept in the guest bedroom to minimize the risk of transmission of the virus to my wife. For the next 7 days I was terrified that I had been exposed to the virus, worried that I hadn’t worn my mask properly, or that I exposed myself to contamination when taking off my goggles and gown. I was hyperaware of my breathing and temperature, wondering if that scratch in my throat was the first sign of something worse. I never did develop any symptoms of illness but the amount of stress I felt that week was enormous.

Over the subsequent weeks I became much more comfortable with putting on and taking off PPE since the volume of COVID patients kept increasing to the point that more than 80% of the hospital patient census consisted of COVID-19 infections. Those patient interactions became less awkward once I could stop worrying about the PPE and focus on providing patient care.

Unfortunately, patient after patient entered the hospital, all with the same symptoms: cough, fever, and hypoxia. Medically there was little decision-making necessary as care was mostly supportive with supplemental oxygen to give these patients time to recover. Instead, I focused on understanding each patient’s symptoms and thinking about what could be offered to relieve bothersome symptoms. These patients were isolated in their hospital rooms – denied visitors and their interactions with hospital staff involved layers and layers of protective barrier. I sought to overcome those physical barriers through personal connection – learning about a patient’s hobbies, asking about their families, or reminiscing about one of their favorite trips.

Despite this supportive care, many patients ended up intubated in the intensive care unit. Many eventually improved, and we celebrated those individuals – a victory at a time. We even counted the COVID discharges with a running tally; first 10, then a few dozen, and eventually the number climbed into the triple digits. But not every patient was so fortunate. Hearing about a 40-something who passed away hit too close to home – what if that were me?

The hospitalists I work with rose to the occasion. We feared the virus but still showed up for work because the patients needed us and we had job obligations to honor. Everyone else was stuck at home during lockdown but we still got in our cars and drove to the hospital, suited up in our PPE, and cared for terrified patients that were struggling to breathe.

There was a satisfaction in having a job to do and being able to contribute during this time of global crisis. Staying busy gave our minds something to focus on and helped us feel a sense of purpose. Some of us stayed late to coordinate staffing. Others helped to disseminate practice guidelines and clinical knowledge. While others lent a hand wherever they could to pitch in. That sense of camaraderie served as plenty of motivation.

During the early stages of the pandemic, there was a sense that this crisis that would end after a few months and life would return to normal. By May, we experienced a dramatic decline in the number of hospitalized patients with COVID-19, which resulted in a real sense of optimism. But soon it became apparent that this pandemic was not going away anytime soon.

Cases nationwide began rising again over the summer. We saw a steady trickle of new admissions at our hospital month after month until the fall when the rate of admissions accelerated again. The hospital reactivated our surge plan, increased staffing, and confronted the new surge with growing dread. That first surge was all endorphins – but fatigue set in by the time the second wave hit. The volunteerism and sense of “we are in this together” just did not exist anymore. The stories about health care heroes in the broader community waned and the outside world seemingly had moved on from thinking about the pandemic.

Yet we remained, caring for patients with cough, fever, and low oxygen saturation. It was like living through a movie we had already seen before. We knew what we were supposed to do and we followed the script. But now it felt too much like a routine.

It has been a very long 14 months since I first cared for a patient with COVID-19. For much of this time it felt like we were just stuck on a treadmill, passing the time but not making any significant progress towards a post-COVID future state. How many times over this year did we push that date forward in our minds when “life would go back to normal”?

Now, we have reason for hope. More than 100 million Americans have been vaccinated and that number rises daily. The vaccines are remarkably effective, they are making a real difference in reducing the number of patients with COVID-19 at the hospital, and our level of daily anxiety is lower. There is still much uncertainty about the future, but at least we can feel proud of our service over the last year — proud of showing up and donning that PPE. And so, we continue one patient at a time.

Corresponding author: James A. Colbert, MD, Attending Hospitalist, Newton-Wellesley Hospital, 2014 Washington St, Newton, MA, 02462, Senior Medical Director, Blue Cross Blue Shield of Massachusetts; [email protected].

Financial disclosures: None.

I will never forget the first time I cared for a patient who tested positive for COVID-19. It was March 2020, and I was evaluating a patient in the emergency department (ED). At the time we knew very little about this virus and how it is transmitted. We had all seen the images from Wuhan, China, and had appropriate fear of the lethality of the virus, but there was not yet a clear understanding as to how best to keep health care practitioners safe as they cared for patients with COVID-19.

That evening I received a page that a middle-aged man who had tested positive for COVID-19 was in the ED with fever, cough, and hypoxia. As a hospitalist, my role is to care for these patients, those admitted to stay overnight in the hospital. Before going to see the patient, I watched a video on how to properly don personal protective equipment (PPE). I walked to the ED and suited up with a surgical mask, goggles, disposable gown, and gloves. I was very conscious of the amount of time I spent in that patient’s room, and tried to stand at the foot of the bed as much as possible so as to maximize the distance between our faces when we talked.

Upon finishing my assessment, I took off my PPE and exited the room but kept wondering if I had done so correctly. That night when I came home, I slept in the guest bedroom to minimize the risk of transmission of the virus to my wife. For the next 7 days I was terrified that I had been exposed to the virus, worried that I hadn’t worn my mask properly, or that I exposed myself to contamination when taking off my goggles and gown. I was hyperaware of my breathing and temperature, wondering if that scratch in my throat was the first sign of something worse. I never did develop any symptoms of illness but the amount of stress I felt that week was enormous.

Over the subsequent weeks I became much more comfortable with putting on and taking off PPE since the volume of COVID patients kept increasing to the point that more than 80% of the hospital patient census consisted of COVID-19 infections. Those patient interactions became less awkward once I could stop worrying about the PPE and focus on providing patient care.

Unfortunately, patient after patient entered the hospital, all with the same symptoms: cough, fever, and hypoxia. Medically there was little decision-making necessary as care was mostly supportive with supplemental oxygen to give these patients time to recover. Instead, I focused on understanding each patient’s symptoms and thinking about what could be offered to relieve bothersome symptoms. These patients were isolated in their hospital rooms – denied visitors and their interactions with hospital staff involved layers and layers of protective barrier. I sought to overcome those physical barriers through personal connection – learning about a patient’s hobbies, asking about their families, or reminiscing about one of their favorite trips.

Despite this supportive care, many patients ended up intubated in the intensive care unit. Many eventually improved, and we celebrated those individuals – a victory at a time. We even counted the COVID discharges with a running tally; first 10, then a few dozen, and eventually the number climbed into the triple digits. But not every patient was so fortunate. Hearing about a 40-something who passed away hit too close to home – what if that were me?

The hospitalists I work with rose to the occasion. We feared the virus but still showed up for work because the patients needed us and we had job obligations to honor. Everyone else was stuck at home during lockdown but we still got in our cars and drove to the hospital, suited up in our PPE, and cared for terrified patients that were struggling to breathe.

There was a satisfaction in having a job to do and being able to contribute during this time of global crisis. Staying busy gave our minds something to focus on and helped us feel a sense of purpose. Some of us stayed late to coordinate staffing. Others helped to disseminate practice guidelines and clinical knowledge. While others lent a hand wherever they could to pitch in. That sense of camaraderie served as plenty of motivation.

During the early stages of the pandemic, there was a sense that this crisis that would end after a few months and life would return to normal. By May, we experienced a dramatic decline in the number of hospitalized patients with COVID-19, which resulted in a real sense of optimism. But soon it became apparent that this pandemic was not going away anytime soon.

Cases nationwide began rising again over the summer. We saw a steady trickle of new admissions at our hospital month after month until the fall when the rate of admissions accelerated again. The hospital reactivated our surge plan, increased staffing, and confronted the new surge with growing dread. That first surge was all endorphins – but fatigue set in by the time the second wave hit. The volunteerism and sense of “we are in this together” just did not exist anymore. The stories about health care heroes in the broader community waned and the outside world seemingly had moved on from thinking about the pandemic.

Yet we remained, caring for patients with cough, fever, and low oxygen saturation. It was like living through a movie we had already seen before. We knew what we were supposed to do and we followed the script. But now it felt too much like a routine.

It has been a very long 14 months since I first cared for a patient with COVID-19. For much of this time it felt like we were just stuck on a treadmill, passing the time but not making any significant progress towards a post-COVID future state. How many times over this year did we push that date forward in our minds when “life would go back to normal”?

Now, we have reason for hope. More than 100 million Americans have been vaccinated and that number rises daily. The vaccines are remarkably effective, they are making a real difference in reducing the number of patients with COVID-19 at the hospital, and our level of daily anxiety is lower. There is still much uncertainty about the future, but at least we can feel proud of our service over the last year — proud of showing up and donning that PPE. And so, we continue one patient at a time.

Corresponding author: James A. Colbert, MD, Attending Hospitalist, Newton-Wellesley Hospital, 2014 Washington St, Newton, MA, 02462, Senior Medical Director, Blue Cross Blue Shield of Massachusetts; [email protected].

Financial disclosures: None.

I will never forget the first time I cared for a patient who tested positive for COVID-19. It was March 2020, and I was evaluating a patient in the emergency department (ED). At the time we knew very little about this virus and how it is transmitted. We had all seen the images from Wuhan, China, and had appropriate fear of the lethality of the virus, but there was not yet a clear understanding as to how best to keep health care practitioners safe as they cared for patients with COVID-19.

That evening I received a page that a middle-aged man who had tested positive for COVID-19 was in the ED with fever, cough, and hypoxia. As a hospitalist, my role is to care for these patients, those admitted to stay overnight in the hospital. Before going to see the patient, I watched a video on how to properly don personal protective equipment (PPE). I walked to the ED and suited up with a surgical mask, goggles, disposable gown, and gloves. I was very conscious of the amount of time I spent in that patient’s room, and tried to stand at the foot of the bed as much as possible so as to maximize the distance between our faces when we talked.

Upon finishing my assessment, I took off my PPE and exited the room but kept wondering if I had done so correctly. That night when I came home, I slept in the guest bedroom to minimize the risk of transmission of the virus to my wife. For the next 7 days I was terrified that I had been exposed to the virus, worried that I hadn’t worn my mask properly, or that I exposed myself to contamination when taking off my goggles and gown. I was hyperaware of my breathing and temperature, wondering if that scratch in my throat was the first sign of something worse. I never did develop any symptoms of illness but the amount of stress I felt that week was enormous.

Over the subsequent weeks I became much more comfortable with putting on and taking off PPE since the volume of COVID patients kept increasing to the point that more than 80% of the hospital patient census consisted of COVID-19 infections. Those patient interactions became less awkward once I could stop worrying about the PPE and focus on providing patient care.

Unfortunately, patient after patient entered the hospital, all with the same symptoms: cough, fever, and hypoxia. Medically there was little decision-making necessary as care was mostly supportive with supplemental oxygen to give these patients time to recover. Instead, I focused on understanding each patient’s symptoms and thinking about what could be offered to relieve bothersome symptoms. These patients were isolated in their hospital rooms – denied visitors and their interactions with hospital staff involved layers and layers of protective barrier. I sought to overcome those physical barriers through personal connection – learning about a patient’s hobbies, asking about their families, or reminiscing about one of their favorite trips.

Despite this supportive care, many patients ended up intubated in the intensive care unit. Many eventually improved, and we celebrated those individuals – a victory at a time. We even counted the COVID discharges with a running tally; first 10, then a few dozen, and eventually the number climbed into the triple digits. But not every patient was so fortunate. Hearing about a 40-something who passed away hit too close to home – what if that were me?

The hospitalists I work with rose to the occasion. We feared the virus but still showed up for work because the patients needed us and we had job obligations to honor. Everyone else was stuck at home during lockdown but we still got in our cars and drove to the hospital, suited up in our PPE, and cared for terrified patients that were struggling to breathe.

There was a satisfaction in having a job to do and being able to contribute during this time of global crisis. Staying busy gave our minds something to focus on and helped us feel a sense of purpose. Some of us stayed late to coordinate staffing. Others helped to disseminate practice guidelines and clinical knowledge. While others lent a hand wherever they could to pitch in. That sense of camaraderie served as plenty of motivation.

During the early stages of the pandemic, there was a sense that this crisis that would end after a few months and life would return to normal. By May, we experienced a dramatic decline in the number of hospitalized patients with COVID-19, which resulted in a real sense of optimism. But soon it became apparent that this pandemic was not going away anytime soon.

Cases nationwide began rising again over the summer. We saw a steady trickle of new admissions at our hospital month after month until the fall when the rate of admissions accelerated again. The hospital reactivated our surge plan, increased staffing, and confronted the new surge with growing dread. That first surge was all endorphins – but fatigue set in by the time the second wave hit. The volunteerism and sense of “we are in this together” just did not exist anymore. The stories about health care heroes in the broader community waned and the outside world seemingly had moved on from thinking about the pandemic.

Yet we remained, caring for patients with cough, fever, and low oxygen saturation. It was like living through a movie we had already seen before. We knew what we were supposed to do and we followed the script. But now it felt too much like a routine.

It has been a very long 14 months since I first cared for a patient with COVID-19. For much of this time it felt like we were just stuck on a treadmill, passing the time but not making any significant progress towards a post-COVID future state. How many times over this year did we push that date forward in our minds when “life would go back to normal”?

Now, we have reason for hope. More than 100 million Americans have been vaccinated and that number rises daily. The vaccines are remarkably effective, they are making a real difference in reducing the number of patients with COVID-19 at the hospital, and our level of daily anxiety is lower. There is still much uncertainty about the future, but at least we can feel proud of our service over the last year — proud of showing up and donning that PPE. And so, we continue one patient at a time.

Corresponding author: James A. Colbert, MD, Attending Hospitalist, Newton-Wellesley Hospital, 2014 Washington St, Newton, MA, 02462, Senior Medical Director, Blue Cross Blue Shield of Massachusetts; [email protected].

Financial disclosures: None.