Key clinical point: Patients with multiple sclerosis (MS) are at an increased risk of cardiovascular and cerebrovascular diseases that traditional risk factors do not fully explain.

Major finding: Compared with people without MS, patients with MS had increased risks for coronary syndrome (hazard ratio [HR], 1.28), cerebrovascular disease (HR, 1.59), any macrovascular disease (HR, 1.32), all-cause mortality (HR, 3.46), and cardiovascular disease mortality (HR, 1.47).

Study details: This population-based, retrospective matched cohort study conducted in England included 12,251 patients with MS and 72,572 people without MS.

Disclosures: The presenting author had no disclosures. Two coauthors received research funding/support from various organizations.

Citation: Palladino R et al. JAMA Neurol. 2020 May 04. doi: 10.1001/jamaneurol.2020.0664. 

Key clinical point: Patients with multiple sclerosis (MS) are at an increased risk of cardiovascular and cerebrovascular diseases that traditional risk factors do not fully explain.

Major finding: Compared with people without MS, patients with MS had increased risks for coronary syndrome (hazard ratio [HR], 1.28), cerebrovascular disease (HR, 1.59), any macrovascular disease (HR, 1.32), all-cause mortality (HR, 3.46), and cardiovascular disease mortality (HR, 1.47).

Study details: This population-based, retrospective matched cohort study conducted in England included 12,251 patients with MS and 72,572 people without MS.

Disclosures: The presenting author had no disclosures. Two coauthors received research funding/support from various organizations.

Citation: Palladino R et al. JAMA Neurol. 2020 May 04. doi: 10.1001/jamaneurol.2020.0664. 

Key clinical point: Patients with multiple sclerosis (MS) are at an increased risk of cardiovascular and cerebrovascular diseases that traditional risk factors do not fully explain.

Major finding: Compared with people without MS, patients with MS had increased risks for coronary syndrome (hazard ratio [HR], 1.28), cerebrovascular disease (HR, 1.59), any macrovascular disease (HR, 1.32), all-cause mortality (HR, 3.46), and cardiovascular disease mortality (HR, 1.47).

Study details: This population-based, retrospective matched cohort study conducted in England included 12,251 patients with MS and 72,572 people without MS.

Disclosures: The presenting author had no disclosures. Two coauthors received research funding/support from various organizations.

Citation: Palladino R et al. JAMA Neurol. 2020 May 04. doi: 10.1001/jamaneurol.2020.0664. 

Key findings in metastatic breast cancer, presented at the ASCO 2020 Virtual Annual Meeting, ranged across all tumor subtypes.

Arguably, the top news in breast cancer was a plenary presentation addressing the role of locoregional therapy in advanced disease. Dr. Harold Burstein, of Dana-Farber Cancer Institute, comments that this study indicates systemic therapy as the mainstay treatment for woman with newly diagnosed advanced disease and a tumor in the breast.

In triple-negative breast cancer, Dr. Burstein highlights two studies. The KEYNOTE-355 study validates the addition of a checkpoint inhibitor in first-line therapy in women whose tumors are PD-L1 positive. The intriguing results of the SWOG S1416 trial, Dr. Burstein comments, suggest the use of PARP inhibition may extend beyond BRCA1 and BRCA2 breast cancers.

In HER2-positive breast cancer, an update of the HER2CLIMB study indicates that the combination of tucatinib, trastuzumab, and capecitabine continues to benefit women with HER2-positive disease. Dr. Burstein expects this combination will be a new standard of care, particularly in women with brain metastases.

As for ER-positive breast cancer, Dr. Burstein reviews the BYLieve trial. Results of this study suggest alpelisib has activity in women with a PIK3CA mutation who have already received a CDK4/6 inhibitor.

Harold J. Burstein, Md, PhD

Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts. Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships.

Key findings in metastatic breast cancer, presented at the ASCO 2020 Virtual Annual Meeting, ranged across all tumor subtypes.

Arguably, the top news in breast cancer was a plenary presentation addressing the role of locoregional therapy in advanced disease. Dr. Harold Burstein, of Dana-Farber Cancer Institute, comments that this study indicates systemic therapy as the mainstay treatment for woman with newly diagnosed advanced disease and a tumor in the breast.

In triple-negative breast cancer, Dr. Burstein highlights two studies. The KEYNOTE-355 study validates the addition of a checkpoint inhibitor in first-line therapy in women whose tumors are PD-L1 positive. The intriguing results of the SWOG S1416 trial, Dr. Burstein comments, suggest the use of PARP inhibition may extend beyond BRCA1 and BRCA2 breast cancers.

In HER2-positive breast cancer, an update of the HER2CLIMB study indicates that the combination of tucatinib, trastuzumab, and capecitabine continues to benefit women with HER2-positive disease. Dr. Burstein expects this combination will be a new standard of care, particularly in women with brain metastases.

As for ER-positive breast cancer, Dr. Burstein reviews the BYLieve trial. Results of this study suggest alpelisib has activity in women with a PIK3CA mutation who have already received a CDK4/6 inhibitor.

Harold J. Burstein, Md, PhD

Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts. Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships.

Key findings in metastatic breast cancer, presented at the ASCO 2020 Virtual Annual Meeting, ranged across all tumor subtypes.

Arguably, the top news in breast cancer was a plenary presentation addressing the role of locoregional therapy in advanced disease. Dr. Harold Burstein, of Dana-Farber Cancer Institute, comments that this study indicates systemic therapy as the mainstay treatment for woman with newly diagnosed advanced disease and a tumor in the breast.

In triple-negative breast cancer, Dr. Burstein highlights two studies. The KEYNOTE-355 study validates the addition of a checkpoint inhibitor in first-line therapy in women whose tumors are PD-L1 positive. The intriguing results of the SWOG S1416 trial, Dr. Burstein comments, suggest the use of PARP inhibition may extend beyond BRCA1 and BRCA2 breast cancers.

In HER2-positive breast cancer, an update of the HER2CLIMB study indicates that the combination of tucatinib, trastuzumab, and capecitabine continues to benefit women with HER2-positive disease. Dr. Burstein expects this combination will be a new standard of care, particularly in women with brain metastases.

As for ER-positive breast cancer, Dr. Burstein reviews the BYLieve trial. Results of this study suggest alpelisib has activity in women with a PIK3CA mutation who have already received a CDK4/6 inhibitor.

Harold J. Burstein, Md, PhD

Professor, Department of Medicine, Harvard Medical School; Institute Physician, Dana-Farber Cancer Institute, Boston, Massachusetts. Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships.

Intranasal butorphanol is a fast-acting and effective acute rescue therapy for patients with the toughest cases of intractable chronic itch, Shawn G. Kwatra, MD, reported at the virtual annual meeting of the American Academy of Dermatology.

Dr. Kwatra, a dermatologist at Johns Hopkins University, Baltimore, where he heads a specialized pruritus clinic, presented a retrospective study of 16 such patients treated with inhaled butorphanol. All had been responsive to a minimum of four antipruritic medications.

This is one of the largest-ever reported series of patients treated with intranasal butorphanol as acute rescue therapy for intractable itch, and it provides a strong signal of efficacy, he said in an interview.

Indeed, 11 of the 16 patients reported marked improvement in their itch after introduction of short-term treatment with butorphanol nasal spray, 1 reported no improvement, and 4 were lost to follow-up.

Itch, Dermatology Life Quality Index (DLQI), and Beck Depression Inventory scores were formally measured prior to introduction of short-term inhaled butorphanol and again at follow-up appointments at 4-6 weeks. The mean self-reported itch numeric rating scale score improved from a mean of 9.8 out of a possible 10 at baseline to 4.6 at follow-up. The reduction in itch was accompanied by major improvements in quality of life: the mean DLQI score dropped from 20.2 to 10.8, while the Beck Depression Inventory score went from 22.1 – typically interpreted as an indicator of moderate depression – to 14.2.

Three patients reported insomnia and/or lightheadedness they attributed to inhaled butorphanol.

The patients with chronic refractory itch had a wide range of associated underlying diagnoses. These included primary sclerosing cholangitis, trigeminal trophic syndrome, brachioradial pruritus, neuropathic pruritus, prurigo nodularis, chronic idiopathic urticaria, chronic aquagenic pruritus, atopic dermatitis, and itch induced by programmed death–1 immune checkpoint inhibitor therapy. It will take large randomized, controlled trials to determine which of these types of chronic pruritus benefit most from intranasal butorphanol, according to Dr. Kwatra.

Since butorphanol is a narcotic analgesic ill-suited to applications other than as short-term acute rescue therapy, there is a pressing unmet need for new therapies specifically targeting chronic itch as a symptom, he added. Several promising agents are advancing through the drug development pipeline.

Dr. Kwatra reported having no financial conflicts regarding this study, conducted free of commercial support.
 

bjancin@mdedge.com

Intranasal butorphanol is a fast-acting and effective acute rescue therapy for patients with the toughest cases of intractable chronic itch, Shawn G. Kwatra, MD, reported at the virtual annual meeting of the American Academy of Dermatology.

Dr. Kwatra, a dermatologist at Johns Hopkins University, Baltimore, where he heads a specialized pruritus clinic, presented a retrospective study of 16 such patients treated with inhaled butorphanol. All had been responsive to a minimum of four antipruritic medications.

This is one of the largest-ever reported series of patients treated with intranasal butorphanol as acute rescue therapy for intractable itch, and it provides a strong signal of efficacy, he said in an interview.

Indeed, 11 of the 16 patients reported marked improvement in their itch after introduction of short-term treatment with butorphanol nasal spray, 1 reported no improvement, and 4 were lost to follow-up.

Itch, Dermatology Life Quality Index (DLQI), and Beck Depression Inventory scores were formally measured prior to introduction of short-term inhaled butorphanol and again at follow-up appointments at 4-6 weeks. The mean self-reported itch numeric rating scale score improved from a mean of 9.8 out of a possible 10 at baseline to 4.6 at follow-up. The reduction in itch was accompanied by major improvements in quality of life: the mean DLQI score dropped from 20.2 to 10.8, while the Beck Depression Inventory score went from 22.1 – typically interpreted as an indicator of moderate depression – to 14.2.

Three patients reported insomnia and/or lightheadedness they attributed to inhaled butorphanol.

The patients with chronic refractory itch had a wide range of associated underlying diagnoses. These included primary sclerosing cholangitis, trigeminal trophic syndrome, brachioradial pruritus, neuropathic pruritus, prurigo nodularis, chronic idiopathic urticaria, chronic aquagenic pruritus, atopic dermatitis, and itch induced by programmed death–1 immune checkpoint inhibitor therapy. It will take large randomized, controlled trials to determine which of these types of chronic pruritus benefit most from intranasal butorphanol, according to Dr. Kwatra.

Since butorphanol is a narcotic analgesic ill-suited to applications other than as short-term acute rescue therapy, there is a pressing unmet need for new therapies specifically targeting chronic itch as a symptom, he added. Several promising agents are advancing through the drug development pipeline.

Dr. Kwatra reported having no financial conflicts regarding this study, conducted free of commercial support.
 

bjancin@mdedge.com

Intranasal butorphanol is a fast-acting and effective acute rescue therapy for patients with the toughest cases of intractable chronic itch, Shawn G. Kwatra, MD, reported at the virtual annual meeting of the American Academy of Dermatology.

Dr. Kwatra, a dermatologist at Johns Hopkins University, Baltimore, where he heads a specialized pruritus clinic, presented a retrospective study of 16 such patients treated with inhaled butorphanol. All had been responsive to a minimum of four antipruritic medications.

This is one of the largest-ever reported series of patients treated with intranasal butorphanol as acute rescue therapy for intractable itch, and it provides a strong signal of efficacy, he said in an interview.

Indeed, 11 of the 16 patients reported marked improvement in their itch after introduction of short-term treatment with butorphanol nasal spray, 1 reported no improvement, and 4 were lost to follow-up.

Itch, Dermatology Life Quality Index (DLQI), and Beck Depression Inventory scores were formally measured prior to introduction of short-term inhaled butorphanol and again at follow-up appointments at 4-6 weeks. The mean self-reported itch numeric rating scale score improved from a mean of 9.8 out of a possible 10 at baseline to 4.6 at follow-up. The reduction in itch was accompanied by major improvements in quality of life: the mean DLQI score dropped from 20.2 to 10.8, while the Beck Depression Inventory score went from 22.1 – typically interpreted as an indicator of moderate depression – to 14.2.

Three patients reported insomnia and/or lightheadedness they attributed to inhaled butorphanol.

The patients with chronic refractory itch had a wide range of associated underlying diagnoses. These included primary sclerosing cholangitis, trigeminal trophic syndrome, brachioradial pruritus, neuropathic pruritus, prurigo nodularis, chronic idiopathic urticaria, chronic aquagenic pruritus, atopic dermatitis, and itch induced by programmed death–1 immune checkpoint inhibitor therapy. It will take large randomized, controlled trials to determine which of these types of chronic pruritus benefit most from intranasal butorphanol, according to Dr. Kwatra.

Since butorphanol is a narcotic analgesic ill-suited to applications other than as short-term acute rescue therapy, there is a pressing unmet need for new therapies specifically targeting chronic itch as a symptom, he added. Several promising agents are advancing through the drug development pipeline.

Dr. Kwatra reported having no financial conflicts regarding this study, conducted free of commercial support.
 

bjancin@mdedge.com

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

sworcester@mdedge.com

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

sworcester@mdedge.com

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

sworcester@mdedge.com

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Despite mounting evidence that low-dose CT screening reduces lung cancer mortality in people at high risk, the uptake of screening in the United States has been slow, and some researchers caution that the risks involved need to be better understood.

It has been almost 10 years since the landmark National Lung Screening Trial (NLST) provided the scientific evidence used by the United States Preventive Services Task Force to recommend annual screening for adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit in the previous 15 years.

But just 4.2% of Americans who qualified for screening in 2018 were tested, according to an American Lung Association report. If everyone at high risk had been tested, 48,000 American lives could have been saved.

Final results from the NELSON trial, published earlier this year, support those from NLST.

Mortality was 24% lower with low-dose CT screening than with no screening in the NELSON cohort, which consisted of 13,195 men and 2594 women at high risk for lung cancer because they were current or former smokers.

“With the NELSON results, the efficacy of low-dose CT screening for lung cancer is confirmed,” wrote the authors of an editorial accompanying the NELSON results. “Our job is no longer to assess whether low-dose CT screening for lung cancer works: it does. Our job is to identify the target population in which it will be acceptable and cost-effective.”

That sentiment is echoed by Michael Gould, MD, from Kaiser Permanente Southern California.

“Lo and behold, we have confirmation of NLST results from NELSON,” Dr. Gould said in an interview. “Now that we have consistent data from the NELSON confirmatory trial, can we finally believe NLST?”

Even though NELSON confirms the benefits of screening in clinical trials, many questions remain about how lung cancer screening translates into everyday practice, said Dr. Gould, who had been scheduled to discuss the trials and the state of lung screening at the American Thoracic Society 2020 International Conference, which will now run virtually in August.

For starters, the target population needs more scrutiny. Research has shown that, outside of clinical trials, the harms of screening can sometimes outweigh the benefits.

In 2018, the rate of overdiagnosis was shown to be 67.2% in the Danish Lung Cancer Screening Trial (DLCST).

And 56% of people screened with low-dose CT had false-positive results that required follow-up testing and procedures, according to a 2017 study of current and former heavy smokers. That rate is more than double the 18.5% false-positive rate in NLST.

“Only 20% of NLST participants were over age 65,” Dr. Gould said. “The NELSON cohort was younger.”

And although the USPSTF recommends lung screening in high-risk people, “there were some in the NLST cohort whose risk was not particularly high.” Others in the trial, he said, had a high risk, but some of those had one or more comorbid conditions, “so the risk was unbalanced.

“Risk is more complicated than simply saying that anyone who meets the NLST criteria should get scanned,” he added.

Weighing risks and benefits needs to be done on a patient-by-patient basis, Dr. Gould said. “Do they have the ability to tolerate surgery? What’s important to them? We can’t just say, ‘you have a 30-pack-year history, go get a test’.”

Often, he said, it’s the people who have the most to gain from screening who are also at highest risk from biopsies and surgical and nonsurgical treatments because of comorbidities.

The NLST population might also have cast a wider net for those eligible for screening; NELSON had a lower threshold for amount smoked (30 vs. 15 pack-years). “NLST points to scanning a bigger population and lighter smokers,” Dr. Gould said.
 

Psychological risks of screening

Neither the NLST nor NELSON reported relevant psychological aspects of harm from CT screening for lung cancer, two researchers reported in a letter responding to the NELSON findings.

The trial-participation request letters, which were sent to 606,409 people in the general population, “in order to identify 15,792 persons (2.6%) who were eligible to participate, may have caused fear,” wrote Jes Lindholt, MD, DMSc, and Rikke Søgaard, PhD, from Odense University Hospital in Denmark.

“That raises the question: Do people want to be screened? I can’t understand why the US and Britain consider it so definitive to start a screening program,” Dr. Lindholt said in an interview.

In addition to a psychological cost, he questioned the financial cost-benefit ratio of a screening program. “What strikes me is that they haven’t done any cost analysis on any of these randomized trials.”

“Of the 203 men who got the diagnosis of lung cancer, 160 (78.8%) died from lung cancer. Whether screening actually improved or prolonged their remaining lifetime should be considered,” Dr. Lindholt and Dr. Søgaard wrote.
 

Challenges of implementation

Despite the extensive trials, there are still questions about how to implement screening in the real world. “Did NLST select patients who were, on average, healthier and less likely to have complications?” Dr. Gould asked.

Everyday practice might not find the same favorable outcomes as NLST. “Can the results of the NTLST be replicated in real-world settings? Not yet,” he said. Hospitals and health systems are struggling to implement screening.

Follow-up and tracking are not where they should be. General practitioners don’t have the same resources as the NLST researchers had, he explained. They were able to remind patients to come back for another test and call them with the results, all under the umbrella of implementation, “and they’re still not on target.”

Getting people scanned is key, said Michael Barry, MD, from Massachusetts General Hospital in Boston, who is a current member of the USPSTF and is working on new lung cancer screening recommendations to be published this summer.

“We have an implementation problem,” he said. “The heavier smokers are being way underscreened.”

People need to have more information to review the pros and cons of screening, Dr. Barry said. “We’ve got large trials that show that benefits outweigh the harms, but we could benefit from implementation research. This is an issue for many screening tasks.”

Eight million Americans meet the eligibility requirements for lung cancer screening with low-dose CT, according to a 2019 report from the American College of Radiology.

Screening tests are covered by Medicare, but getting people to the clinic has not been easy. In 2018, Saved by the Scan, a big-budget national advertising campaign launched by the ALA, featured ex-smokers who survived lung cancer because of early detection with a low-dose CT scan, as reported by Medscape Medical News.

And many people being scanned are not part of the USPSTF target group. In 2017, lung cancer screening was reported “by 12.5% of smokers who met USPSTF criteria and 7.9% of smokers aged 55-80 years who did not meet USPSTF criteria,” according to a recent analysis of data from the Behavioral Risk Factor Surveillance System published by the Centers for Disease Control and Prevention.

The CDC report concludes that some people are being screened without needing screening, and that “avoidance of screening inconsistent with USPSTF criteria could reduce the potential for harms such as overdiagnosis and overtreatment.”

Dr. Gould said he agrees that this factor needs to be looked at. “There is underutilization in those who need screening, and maybe overscreening in those who aren’t at risk.”

There are also epidemiologic data that show that black Americans are at higher risk at a younger age for the same level of smoking. “So should there be a lower threshold for smoking and lower age, particularly in the African American population?” Dr. Gould asked.

The NELSON trial had significant results in a population younger than that in NLST, he pointed out. “That needs to be considered.”
 

Smokers dismiss medical advice

People in the high-risk group need to better understand the benefits of screening, said Christine D. Berg, MD, an NLST researcher from the National Cancer Institute.

“We know the uptake of lung cancer screening has been slow,” she said.

She described encouraging her neighbor, a heavy smoker, to get screened. “But she said she didn’t want to know if she had lung cancer, so she didn’t go.”

“Now she’s dead,” Dr. Berg continued. Unfortunately, “what we see is that those who continue to smoke, and smoke heavily, are not likely to heed medical advice.”

The fear of finding out you have lung cancer needs to be overcome, she said. Smokers need to understand that they can add a decade to their lives if lung cancer is detected early.

Some places in the United States have better screening rates than others. “We see a lot of variation from state to state,” she said. For instance, in Massachusetts, 12.3% of high-risk people have been screened; in Nevada, the rate is just 0.5%.

There are many reasons for that. First, there are logistics. Screening covered by Medicare must be done in a certified center “with good equipment and that can track results,” Dr. Berg said. That might be one hurdle. But the greater hurdle is the patients themselves.

There are studies that point to risks associated with invasive procedures, such as biopsy after screening, which can lead to complications, even when no cancer is found. “My answer to that is, if you need a biopsy, check the data. The Society of Thoracic Surgeons has a database of all the complications, and it’s publicly accessible. You can find hospitals in your region that report data,” she explained, and “that have highest volume and lowest complication rates.”

Second, imaging has improved since the NLST trial. “We have a better ability to estimate cancer in the nodules we find,” Dr. Berg explained. Nodules that previously needed a biopsy to confirm malignancy can now be assessed with AI and machine learning.

“I think the probability of false positives and problems from biopsy have changed dramatically over the last 10 years,” she said.

And we are catching more lung cancer earlier and saving lives. Overall, early detection is increasing, and late-stage detection is decreasing. “We’re bending the curve, making progress,” she said.

In 2019, the 5-year survival rate for lung cancer was 21.7%, up from 17.2% a decade earlier, according to the ALA. Much of that is because of early diagnosis, when the disease is still curable, which could be related to increased screening.

“NELSON showed benefit to CT screening and is useful in helping convince some of the skeptics,” Dr. Berg said.

Diagnosis is also improving with new technologies. Electronic health records can be scanned to identify patients at increased risk, and patient portals can send reminders, notifications, and other educational information to encourage patients to discuss options with their doctor, which could improve the national lung cancer prognosis, Dr. Gould said.

At the end of the day, it still comes down to the patient and doctor having a conversation about the risks and benefits.

“But we have to get to that point,” Dr. Gould said. “We need to continue to develop tools to facilitate that conversation. It’s complicated, and there’s a lot of information to weigh.”

“We’re still working out how to do that,” he added.

Dr. Barry, Dr. Gould, and Dr. Berg have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Despite mounting evidence that low-dose CT screening reduces lung cancer mortality in people at high risk, the uptake of screening in the United States has been slow, and some researchers caution that the risks involved need to be better understood.

It has been almost 10 years since the landmark National Lung Screening Trial (NLST) provided the scientific evidence used by the United States Preventive Services Task Force to recommend annual screening for adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit in the previous 15 years.

But just 4.2% of Americans who qualified for screening in 2018 were tested, according to an American Lung Association report. If everyone at high risk had been tested, 48,000 American lives could have been saved.

Final results from the NELSON trial, published earlier this year, support those from NLST.

Mortality was 24% lower with low-dose CT screening than with no screening in the NELSON cohort, which consisted of 13,195 men and 2594 women at high risk for lung cancer because they were current or former smokers.

“With the NELSON results, the efficacy of low-dose CT screening for lung cancer is confirmed,” wrote the authors of an editorial accompanying the NELSON results. “Our job is no longer to assess whether low-dose CT screening for lung cancer works: it does. Our job is to identify the target population in which it will be acceptable and cost-effective.”

That sentiment is echoed by Michael Gould, MD, from Kaiser Permanente Southern California.

“Lo and behold, we have confirmation of NLST results from NELSON,” Dr. Gould said in an interview. “Now that we have consistent data from the NELSON confirmatory trial, can we finally believe NLST?”

Even though NELSON confirms the benefits of screening in clinical trials, many questions remain about how lung cancer screening translates into everyday practice, said Dr. Gould, who had been scheduled to discuss the trials and the state of lung screening at the American Thoracic Society 2020 International Conference, which will now run virtually in August.

For starters, the target population needs more scrutiny. Research has shown that, outside of clinical trials, the harms of screening can sometimes outweigh the benefits.

In 2018, the rate of overdiagnosis was shown to be 67.2% in the Danish Lung Cancer Screening Trial (DLCST).

And 56% of people screened with low-dose CT had false-positive results that required follow-up testing and procedures, according to a 2017 study of current and former heavy smokers. That rate is more than double the 18.5% false-positive rate in NLST.

“Only 20% of NLST participants were over age 65,” Dr. Gould said. “The NELSON cohort was younger.”

And although the USPSTF recommends lung screening in high-risk people, “there were some in the NLST cohort whose risk was not particularly high.” Others in the trial, he said, had a high risk, but some of those had one or more comorbid conditions, “so the risk was unbalanced.

“Risk is more complicated than simply saying that anyone who meets the NLST criteria should get scanned,” he added.

Weighing risks and benefits needs to be done on a patient-by-patient basis, Dr. Gould said. “Do they have the ability to tolerate surgery? What’s important to them? We can’t just say, ‘you have a 30-pack-year history, go get a test’.”

Often, he said, it’s the people who have the most to gain from screening who are also at highest risk from biopsies and surgical and nonsurgical treatments because of comorbidities.

The NLST population might also have cast a wider net for those eligible for screening; NELSON had a lower threshold for amount smoked (30 vs. 15 pack-years). “NLST points to scanning a bigger population and lighter smokers,” Dr. Gould said.
 

Psychological risks of screening

Neither the NLST nor NELSON reported relevant psychological aspects of harm from CT screening for lung cancer, two researchers reported in a letter responding to the NELSON findings.

The trial-participation request letters, which were sent to 606,409 people in the general population, “in order to identify 15,792 persons (2.6%) who were eligible to participate, may have caused fear,” wrote Jes Lindholt, MD, DMSc, and Rikke Søgaard, PhD, from Odense University Hospital in Denmark.

“That raises the question: Do people want to be screened? I can’t understand why the US and Britain consider it so definitive to start a screening program,” Dr. Lindholt said in an interview.

In addition to a psychological cost, he questioned the financial cost-benefit ratio of a screening program. “What strikes me is that they haven’t done any cost analysis on any of these randomized trials.”

“Of the 203 men who got the diagnosis of lung cancer, 160 (78.8%) died from lung cancer. Whether screening actually improved or prolonged their remaining lifetime should be considered,” Dr. Lindholt and Dr. Søgaard wrote.
 

Challenges of implementation

Despite the extensive trials, there are still questions about how to implement screening in the real world. “Did NLST select patients who were, on average, healthier and less likely to have complications?” Dr. Gould asked.

Everyday practice might not find the same favorable outcomes as NLST. “Can the results of the NTLST be replicated in real-world settings? Not yet,” he said. Hospitals and health systems are struggling to implement screening.

Follow-up and tracking are not where they should be. General practitioners don’t have the same resources as the NLST researchers had, he explained. They were able to remind patients to come back for another test and call them with the results, all under the umbrella of implementation, “and they’re still not on target.”

Getting people scanned is key, said Michael Barry, MD, from Massachusetts General Hospital in Boston, who is a current member of the USPSTF and is working on new lung cancer screening recommendations to be published this summer.

“We have an implementation problem,” he said. “The heavier smokers are being way underscreened.”

People need to have more information to review the pros and cons of screening, Dr. Barry said. “We’ve got large trials that show that benefits outweigh the harms, but we could benefit from implementation research. This is an issue for many screening tasks.”

Eight million Americans meet the eligibility requirements for lung cancer screening with low-dose CT, according to a 2019 report from the American College of Radiology.

Screening tests are covered by Medicare, but getting people to the clinic has not been easy. In 2018, Saved by the Scan, a big-budget national advertising campaign launched by the ALA, featured ex-smokers who survived lung cancer because of early detection with a low-dose CT scan, as reported by Medscape Medical News.

And many people being scanned are not part of the USPSTF target group. In 2017, lung cancer screening was reported “by 12.5% of smokers who met USPSTF criteria and 7.9% of smokers aged 55-80 years who did not meet USPSTF criteria,” according to a recent analysis of data from the Behavioral Risk Factor Surveillance System published by the Centers for Disease Control and Prevention.

The CDC report concludes that some people are being screened without needing screening, and that “avoidance of screening inconsistent with USPSTF criteria could reduce the potential for harms such as overdiagnosis and overtreatment.”

Dr. Gould said he agrees that this factor needs to be looked at. “There is underutilization in those who need screening, and maybe overscreening in those who aren’t at risk.”

There are also epidemiologic data that show that black Americans are at higher risk at a younger age for the same level of smoking. “So should there be a lower threshold for smoking and lower age, particularly in the African American population?” Dr. Gould asked.

The NELSON trial had significant results in a population younger than that in NLST, he pointed out. “That needs to be considered.”
 

Smokers dismiss medical advice

People in the high-risk group need to better understand the benefits of screening, said Christine D. Berg, MD, an NLST researcher from the National Cancer Institute.

“We know the uptake of lung cancer screening has been slow,” she said.

She described encouraging her neighbor, a heavy smoker, to get screened. “But she said she didn’t want to know if she had lung cancer, so she didn’t go.”

“Now she’s dead,” Dr. Berg continued. Unfortunately, “what we see is that those who continue to smoke, and smoke heavily, are not likely to heed medical advice.”

The fear of finding out you have lung cancer needs to be overcome, she said. Smokers need to understand that they can add a decade to their lives if lung cancer is detected early.

Some places in the United States have better screening rates than others. “We see a lot of variation from state to state,” she said. For instance, in Massachusetts, 12.3% of high-risk people have been screened; in Nevada, the rate is just 0.5%.

There are many reasons for that. First, there are logistics. Screening covered by Medicare must be done in a certified center “with good equipment and that can track results,” Dr. Berg said. That might be one hurdle. But the greater hurdle is the patients themselves.

There are studies that point to risks associated with invasive procedures, such as biopsy after screening, which can lead to complications, even when no cancer is found. “My answer to that is, if you need a biopsy, check the data. The Society of Thoracic Surgeons has a database of all the complications, and it’s publicly accessible. You can find hospitals in your region that report data,” she explained, and “that have highest volume and lowest complication rates.”

Second, imaging has improved since the NLST trial. “We have a better ability to estimate cancer in the nodules we find,” Dr. Berg explained. Nodules that previously needed a biopsy to confirm malignancy can now be assessed with AI and machine learning.

“I think the probability of false positives and problems from biopsy have changed dramatically over the last 10 years,” she said.

And we are catching more lung cancer earlier and saving lives. Overall, early detection is increasing, and late-stage detection is decreasing. “We’re bending the curve, making progress,” she said.

In 2019, the 5-year survival rate for lung cancer was 21.7%, up from 17.2% a decade earlier, according to the ALA. Much of that is because of early diagnosis, when the disease is still curable, which could be related to increased screening.

“NELSON showed benefit to CT screening and is useful in helping convince some of the skeptics,” Dr. Berg said.

Diagnosis is also improving with new technologies. Electronic health records can be scanned to identify patients at increased risk, and patient portals can send reminders, notifications, and other educational information to encourage patients to discuss options with their doctor, which could improve the national lung cancer prognosis, Dr. Gould said.

At the end of the day, it still comes down to the patient and doctor having a conversation about the risks and benefits.

“But we have to get to that point,” Dr. Gould said. “We need to continue to develop tools to facilitate that conversation. It’s complicated, and there’s a lot of information to weigh.”

“We’re still working out how to do that,” he added.

Dr. Barry, Dr. Gould, and Dr. Berg have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Despite mounting evidence that low-dose CT screening reduces lung cancer mortality in people at high risk, the uptake of screening in the United States has been slow, and some researchers caution that the risks involved need to be better understood.

It has been almost 10 years since the landmark National Lung Screening Trial (NLST) provided the scientific evidence used by the United States Preventive Services Task Force to recommend annual screening for adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit in the previous 15 years.

But just 4.2% of Americans who qualified for screening in 2018 were tested, according to an American Lung Association report. If everyone at high risk had been tested, 48,000 American lives could have been saved.

Final results from the NELSON trial, published earlier this year, support those from NLST.

Mortality was 24% lower with low-dose CT screening than with no screening in the NELSON cohort, which consisted of 13,195 men and 2594 women at high risk for lung cancer because they were current or former smokers.

“With the NELSON results, the efficacy of low-dose CT screening for lung cancer is confirmed,” wrote the authors of an editorial accompanying the NELSON results. “Our job is no longer to assess whether low-dose CT screening for lung cancer works: it does. Our job is to identify the target population in which it will be acceptable and cost-effective.”

That sentiment is echoed by Michael Gould, MD, from Kaiser Permanente Southern California.

“Lo and behold, we have confirmation of NLST results from NELSON,” Dr. Gould said in an interview. “Now that we have consistent data from the NELSON confirmatory trial, can we finally believe NLST?”

Even though NELSON confirms the benefits of screening in clinical trials, many questions remain about how lung cancer screening translates into everyday practice, said Dr. Gould, who had been scheduled to discuss the trials and the state of lung screening at the American Thoracic Society 2020 International Conference, which will now run virtually in August.

For starters, the target population needs more scrutiny. Research has shown that, outside of clinical trials, the harms of screening can sometimes outweigh the benefits.

In 2018, the rate of overdiagnosis was shown to be 67.2% in the Danish Lung Cancer Screening Trial (DLCST).

And 56% of people screened with low-dose CT had false-positive results that required follow-up testing and procedures, according to a 2017 study of current and former heavy smokers. That rate is more than double the 18.5% false-positive rate in NLST.

“Only 20% of NLST participants were over age 65,” Dr. Gould said. “The NELSON cohort was younger.”

And although the USPSTF recommends lung screening in high-risk people, “there were some in the NLST cohort whose risk was not particularly high.” Others in the trial, he said, had a high risk, but some of those had one or more comorbid conditions, “so the risk was unbalanced.

“Risk is more complicated than simply saying that anyone who meets the NLST criteria should get scanned,” he added.

Weighing risks and benefits needs to be done on a patient-by-patient basis, Dr. Gould said. “Do they have the ability to tolerate surgery? What’s important to them? We can’t just say, ‘you have a 30-pack-year history, go get a test’.”

Often, he said, it’s the people who have the most to gain from screening who are also at highest risk from biopsies and surgical and nonsurgical treatments because of comorbidities.

The NLST population might also have cast a wider net for those eligible for screening; NELSON had a lower threshold for amount smoked (30 vs. 15 pack-years). “NLST points to scanning a bigger population and lighter smokers,” Dr. Gould said.
 

Psychological risks of screening

Neither the NLST nor NELSON reported relevant psychological aspects of harm from CT screening for lung cancer, two researchers reported in a letter responding to the NELSON findings.

The trial-participation request letters, which were sent to 606,409 people in the general population, “in order to identify 15,792 persons (2.6%) who were eligible to participate, may have caused fear,” wrote Jes Lindholt, MD, DMSc, and Rikke Søgaard, PhD, from Odense University Hospital in Denmark.

“That raises the question: Do people want to be screened? I can’t understand why the US and Britain consider it so definitive to start a screening program,” Dr. Lindholt said in an interview.

In addition to a psychological cost, he questioned the financial cost-benefit ratio of a screening program. “What strikes me is that they haven’t done any cost analysis on any of these randomized trials.”

“Of the 203 men who got the diagnosis of lung cancer, 160 (78.8%) died from lung cancer. Whether screening actually improved or prolonged their remaining lifetime should be considered,” Dr. Lindholt and Dr. Søgaard wrote.
 

Challenges of implementation

Despite the extensive trials, there are still questions about how to implement screening in the real world. “Did NLST select patients who were, on average, healthier and less likely to have complications?” Dr. Gould asked.

Everyday practice might not find the same favorable outcomes as NLST. “Can the results of the NTLST be replicated in real-world settings? Not yet,” he said. Hospitals and health systems are struggling to implement screening.

Follow-up and tracking are not where they should be. General practitioners don’t have the same resources as the NLST researchers had, he explained. They were able to remind patients to come back for another test and call them with the results, all under the umbrella of implementation, “and they’re still not on target.”

Getting people scanned is key, said Michael Barry, MD, from Massachusetts General Hospital in Boston, who is a current member of the USPSTF and is working on new lung cancer screening recommendations to be published this summer.

“We have an implementation problem,” he said. “The heavier smokers are being way underscreened.”

People need to have more information to review the pros and cons of screening, Dr. Barry said. “We’ve got large trials that show that benefits outweigh the harms, but we could benefit from implementation research. This is an issue for many screening tasks.”

Eight million Americans meet the eligibility requirements for lung cancer screening with low-dose CT, according to a 2019 report from the American College of Radiology.

Screening tests are covered by Medicare, but getting people to the clinic has not been easy. In 2018, Saved by the Scan, a big-budget national advertising campaign launched by the ALA, featured ex-smokers who survived lung cancer because of early detection with a low-dose CT scan, as reported by Medscape Medical News.

And many people being scanned are not part of the USPSTF target group. In 2017, lung cancer screening was reported “by 12.5% of smokers who met USPSTF criteria and 7.9% of smokers aged 55-80 years who did not meet USPSTF criteria,” according to a recent analysis of data from the Behavioral Risk Factor Surveillance System published by the Centers for Disease Control and Prevention.

The CDC report concludes that some people are being screened without needing screening, and that “avoidance of screening inconsistent with USPSTF criteria could reduce the potential for harms such as overdiagnosis and overtreatment.”

Dr. Gould said he agrees that this factor needs to be looked at. “There is underutilization in those who need screening, and maybe overscreening in those who aren’t at risk.”

There are also epidemiologic data that show that black Americans are at higher risk at a younger age for the same level of smoking. “So should there be a lower threshold for smoking and lower age, particularly in the African American population?” Dr. Gould asked.

The NELSON trial had significant results in a population younger than that in NLST, he pointed out. “That needs to be considered.”
 

Smokers dismiss medical advice

People in the high-risk group need to better understand the benefits of screening, said Christine D. Berg, MD, an NLST researcher from the National Cancer Institute.

“We know the uptake of lung cancer screening has been slow,” she said.

She described encouraging her neighbor, a heavy smoker, to get screened. “But she said she didn’t want to know if she had lung cancer, so she didn’t go.”

“Now she’s dead,” Dr. Berg continued. Unfortunately, “what we see is that those who continue to smoke, and smoke heavily, are not likely to heed medical advice.”

The fear of finding out you have lung cancer needs to be overcome, she said. Smokers need to understand that they can add a decade to their lives if lung cancer is detected early.

Some places in the United States have better screening rates than others. “We see a lot of variation from state to state,” she said. For instance, in Massachusetts, 12.3% of high-risk people have been screened; in Nevada, the rate is just 0.5%.

There are many reasons for that. First, there are logistics. Screening covered by Medicare must be done in a certified center “with good equipment and that can track results,” Dr. Berg said. That might be one hurdle. But the greater hurdle is the patients themselves.

There are studies that point to risks associated with invasive procedures, such as biopsy after screening, which can lead to complications, even when no cancer is found. “My answer to that is, if you need a biopsy, check the data. The Society of Thoracic Surgeons has a database of all the complications, and it’s publicly accessible. You can find hospitals in your region that report data,” she explained, and “that have highest volume and lowest complication rates.”

Second, imaging has improved since the NLST trial. “We have a better ability to estimate cancer in the nodules we find,” Dr. Berg explained. Nodules that previously needed a biopsy to confirm malignancy can now be assessed with AI and machine learning.

“I think the probability of false positives and problems from biopsy have changed dramatically over the last 10 years,” she said.

And we are catching more lung cancer earlier and saving lives. Overall, early detection is increasing, and late-stage detection is decreasing. “We’re bending the curve, making progress,” she said.

In 2019, the 5-year survival rate for lung cancer was 21.7%, up from 17.2% a decade earlier, according to the ALA. Much of that is because of early diagnosis, when the disease is still curable, which could be related to increased screening.

“NELSON showed benefit to CT screening and is useful in helping convince some of the skeptics,” Dr. Berg said.

Diagnosis is also improving with new technologies. Electronic health records can be scanned to identify patients at increased risk, and patient portals can send reminders, notifications, and other educational information to encourage patients to discuss options with their doctor, which could improve the national lung cancer prognosis, Dr. Gould said.

At the end of the day, it still comes down to the patient and doctor having a conversation about the risks and benefits.

“But we have to get to that point,” Dr. Gould said. “We need to continue to develop tools to facilitate that conversation. It’s complicated, and there’s a lot of information to weigh.”

“We’re still working out how to do that,” he added.

Dr. Barry, Dr. Gould, and Dr. Berg have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Key clinical point: Relapse rates are comparable for patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod, dimethyl fumarate, or teriflunomide.

Major finding: After 2 years of treatment initiation, the estimated mean annualized relapse rates were 0.13 (95% confidence interval, 0.04-0.43) for fingolimod, 0.09 (95% confidence interval, 0.03-0.26) for dimethyl fumarate, and 0.11 (95% confidence interval, 0.04-0.35) for teriflunomide.

Study details: The study used inverse probability weighing to compare the efficacy of fingolimod (n=295), dimethyl fumarate (n=227), and teriflunomide (n=107) treatment for at least 24 months in patients with RRMS identified from the Austrian MS Treatment Registry.

Disclosures: The study was funded by Kepler Universitätsklinikum Linz. S Kalcher and E Kvas declared no conflicts of interest. Other authors reported ties with one or more pharmaceutical companies.

Citation: Guger M et al. J Neurol. 2020 Apr 3. doi: 10.1007/s00415-020-09811-6.

Key clinical point: Relapse rates are comparable for patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod, dimethyl fumarate, or teriflunomide.

Major finding: After 2 years of treatment initiation, the estimated mean annualized relapse rates were 0.13 (95% confidence interval, 0.04-0.43) for fingolimod, 0.09 (95% confidence interval, 0.03-0.26) for dimethyl fumarate, and 0.11 (95% confidence interval, 0.04-0.35) for teriflunomide.

Study details: The study used inverse probability weighing to compare the efficacy of fingolimod (n=295), dimethyl fumarate (n=227), and teriflunomide (n=107) treatment for at least 24 months in patients with RRMS identified from the Austrian MS Treatment Registry.

Disclosures: The study was funded by Kepler Universitätsklinikum Linz. S Kalcher and E Kvas declared no conflicts of interest. Other authors reported ties with one or more pharmaceutical companies.

Citation: Guger M et al. J Neurol. 2020 Apr 3. doi: 10.1007/s00415-020-09811-6.

Key clinical point: Relapse rates are comparable for patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod, dimethyl fumarate, or teriflunomide.

Major finding: After 2 years of treatment initiation, the estimated mean annualized relapse rates were 0.13 (95% confidence interval, 0.04-0.43) for fingolimod, 0.09 (95% confidence interval, 0.03-0.26) for dimethyl fumarate, and 0.11 (95% confidence interval, 0.04-0.35) for teriflunomide.

Study details: The study used inverse probability weighing to compare the efficacy of fingolimod (n=295), dimethyl fumarate (n=227), and teriflunomide (n=107) treatment for at least 24 months in patients with RRMS identified from the Austrian MS Treatment Registry.

Disclosures: The study was funded by Kepler Universitätsklinikum Linz. S Kalcher and E Kvas declared no conflicts of interest. Other authors reported ties with one or more pharmaceutical companies.

Citation: Guger M et al. J Neurol. 2020 Apr 3. doi: 10.1007/s00415-020-09811-6.

Key clinical point: The correlation of muscle strength in the lower extremity and trunk with walking performance is stronger in patients with multiple sclerosis (MS) having mild disability than in those having moderate disability.

Major finding: The mild vs. moderate disability group exhibited stronger Pearson correlations of muscle strength to Timed 25-Foot Walk (P less than .001) and 6-minute walk test (P less than .001). For Timed 25-Foot Walk, ankle dorsiflexion (P = .002), knee extension (P = .001), and hip abduction (P = .046) had significantly higher beta coefficients in the mild than moderate disability group.

Study details: A cross-sectional study analyzed data of patients with MS having mild disability (Expanded Disability Status scale [EDSS], 0-3.5; n=36) and moderate disability (EDSS, 4.0-5.5; n=36).

Disclosures: Dr J Kittelson received consulting fees for work on advisory and steering committees for CPC Clinical Research, Bayer Healthcare, Janssen Pharmaceuticals, and Pfizer and for work on data and safety monitoring committees from the Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Pfizer, Genentech, and BioMarin Pharmaceuticals. Dr MM Mañago, J Callesen, U Dalgas, and M Schenkman declared no conflicts of interest. The study did not receive any external funding.

Citation: Mañago MM et al. Mult Scler Relat Disord. 2020 Mar 13. doi: 10.1016/j.msard.2020.102052

Key clinical point: The correlation of muscle strength in the lower extremity and trunk with walking performance is stronger in patients with multiple sclerosis (MS) having mild disability than in those having moderate disability.

Major finding: The mild vs. moderate disability group exhibited stronger Pearson correlations of muscle strength to Timed 25-Foot Walk (P less than .001) and 6-minute walk test (P less than .001). For Timed 25-Foot Walk, ankle dorsiflexion (P = .002), knee extension (P = .001), and hip abduction (P = .046) had significantly higher beta coefficients in the mild than moderate disability group.

Study details: A cross-sectional study analyzed data of patients with MS having mild disability (Expanded Disability Status scale [EDSS], 0-3.5; n=36) and moderate disability (EDSS, 4.0-5.5; n=36).

Disclosures: Dr J Kittelson received consulting fees for work on advisory and steering committees for CPC Clinical Research, Bayer Healthcare, Janssen Pharmaceuticals, and Pfizer and for work on data and safety monitoring committees from the Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Pfizer, Genentech, and BioMarin Pharmaceuticals. Dr MM Mañago, J Callesen, U Dalgas, and M Schenkman declared no conflicts of interest. The study did not receive any external funding.

Citation: Mañago MM et al. Mult Scler Relat Disord. 2020 Mar 13. doi: 10.1016/j.msard.2020.102052

Key clinical point: The correlation of muscle strength in the lower extremity and trunk with walking performance is stronger in patients with multiple sclerosis (MS) having mild disability than in those having moderate disability.

Major finding: The mild vs. moderate disability group exhibited stronger Pearson correlations of muscle strength to Timed 25-Foot Walk (P less than .001) and 6-minute walk test (P less than .001). For Timed 25-Foot Walk, ankle dorsiflexion (P = .002), knee extension (P = .001), and hip abduction (P = .046) had significantly higher beta coefficients in the mild than moderate disability group.

Study details: A cross-sectional study analyzed data of patients with MS having mild disability (Expanded Disability Status scale [EDSS], 0-3.5; n=36) and moderate disability (EDSS, 4.0-5.5; n=36).

Disclosures: Dr J Kittelson received consulting fees for work on advisory and steering committees for CPC Clinical Research, Bayer Healthcare, Janssen Pharmaceuticals, and Pfizer and for work on data and safety monitoring committees from the Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Pfizer, Genentech, and BioMarin Pharmaceuticals. Dr MM Mañago, J Callesen, U Dalgas, and M Schenkman declared no conflicts of interest. The study did not receive any external funding.

Citation: Mañago MM et al. Mult Scler Relat Disord. 2020 Mar 13. doi: 10.1016/j.msard.2020.102052

Here are the stories our MDedge editors across specialties think you need to know about today:

A ‘Fraternity of People Who Are Struggling’

Kathleen Ronan spent a week in a New Jersey hospital, including 5 days in the ICU, battling the novel coronavirus.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, 51, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article. “It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her. Read more.

The evolution of ‘COVIDists’

At the start of the pandemic earlier this year hospitalists at Baystate Health in Western Massachusetts realized the necessity of a new model of care for COVID-19 patients. Challenges included a massive surge of COVID-19 patients, a limited supply of PPE, an inadequate number of intensivists for managing the anticipated ventilated patients, and the potential of losing some of our workforce if they became infected. Hospitalists there came up with an elaborate plan to manage the disease burden and the strain on resources effectively.

A focused group of 10 hospitalists who volunteered to take care of COVID-19 patients with a particular interest in the pandemic and experience in critical care were selected, and the term “COVIDists” was coined to refer to them. The group underwent rapid training in various treatment protocols and ongoing clinical trials.

All the hospitalized COVID-19 patients were grouped together to COVID units, and the COVIDists were deployed to those units geographically. COVIDists were given lighter than usual patient loads to deal with the extra time needed for donning and doffing of PPE and for coordination with specialists. COVIDists were almost the only clinicians physically visiting the patients in most cases, and they became the “eyes and ears” of specialists since the specialists were advised to minimize exposure and pursue telemedicine consults. Read more.

How low should you go?

Cardiovascular risk continues to reduce as systolic blood pressure decreases right down to levels as low as 90 mm Hg, according to a new study.

Researchers analyzed data from a cohort of 1,457 participants (mean age, 58 years) who did not have any traditional cardiovascular risk factors and had a systolic blood pressure level between 90 and 129 mm Hg at baseline. Results showed that, during a mean follow-up of 14.5 years, there was an increase in traditional cardiovascular risk factors, coronary artery calcium, and incident cardiovascular events with increasing systolic blood pressure levels.

“We modeled systolic blood pressure on a continuous scale and saw the risk increasing in a linear fashion as blood pressure increased and this occurred right down to 90 mm Hg. We didn’t see any nadir or J-point where there may be an increased risk at lower pressures,” said lead author Seamus Whelton, MD, assistant professor of medicine at the division of cardiology at Johns Hopkins Medicine, Baltimore.

“From an individual level we can now say that in healthy individuals, a systolic pressure in the 90s is not too low. It is a positive thing. And it is recommended to try and keep systolic pressure at these levels if possible by maintaining a healthy lifestyle,” Dr. Whelton said in an interview. Read more.
 

Asthma tops spending on avoidable pediatric inpatient stays

Asthma costs nearly equaled potentially avoidable hospital bills for diabetes, gastroenteritis, and UTIs combined in a study of in-patient stays among children aged 3 months to 17 years.

Indeed, hospital charges for the treatment of children with asthma made up nearly half of all potentially avoidable pediatric inpatient costs in 2017, according to the Agency for Healthcare Research and Quality.

The cost of potentially avoidable visits for asthma that year was $278 million, versus $284 million combined for the other three conditions, Kimberly W. McDermott, PhD, and H. Joanna Jiang, PhD, reported in an AHRQ statistical brief.

The state inpatient databases of the AHRQ’s Healthcare Cost and Utilization Project included 1.4 million inpatient stays among children aged 3 months to 17 years in 2017, of which 8% (108,300) were deemed potentially preventable.

Rates of potentially avoidable stays for asthma (159 per 100,000 population), gastroenteritis (90 per 100,000), and UTIs (41 per 100,000) were highest for children aged 0-4 years and generally decreased with age, but diabetes stays increased with age, rising from 12 per 100,000 in children aged 5-9 years to 38 per 100,000 for those 15-17 years old, the researchers said. Read more.

Adding monoclonal antibodies to Botox for migraine prevention

Adjunctive preventive therapy with a calcitonin gene–related peptide monoclonal antibody (CGRP-mAb) medication is safe and effective in patients with chronic migraine who have only achieved a partial response to onabotulinumtoxinA (Botox) treatment.

Investigators found the CGRP-mAbs significantly reduced the number of headache days and pain severity with adverse event rates similar to those reported in previous trials of these medications.

Although Botox is associated with significant clinical improvement in chronic migraine, it often fails to adequately control headache frequency and additional medications are needed. Three CGRP-mAbs have recently been approved for migraine prevention, with results from clinical trials demonstrating they are effective for both chronic and episodic migraine. Patients treated with Botox had been excluded from these earlier trials, however. Read more.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

A ‘Fraternity of People Who Are Struggling’

Kathleen Ronan spent a week in a New Jersey hospital, including 5 days in the ICU, battling the novel coronavirus.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, 51, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article. “It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her. Read more.

The evolution of ‘COVIDists’

At the start of the pandemic earlier this year hospitalists at Baystate Health in Western Massachusetts realized the necessity of a new model of care for COVID-19 patients. Challenges included a massive surge of COVID-19 patients, a limited supply of PPE, an inadequate number of intensivists for managing the anticipated ventilated patients, and the potential of losing some of our workforce if they became infected. Hospitalists there came up with an elaborate plan to manage the disease burden and the strain on resources effectively.

A focused group of 10 hospitalists who volunteered to take care of COVID-19 patients with a particular interest in the pandemic and experience in critical care were selected, and the term “COVIDists” was coined to refer to them. The group underwent rapid training in various treatment protocols and ongoing clinical trials.

All the hospitalized COVID-19 patients were grouped together to COVID units, and the COVIDists were deployed to those units geographically. COVIDists were given lighter than usual patient loads to deal with the extra time needed for donning and doffing of PPE and for coordination with specialists. COVIDists were almost the only clinicians physically visiting the patients in most cases, and they became the “eyes and ears” of specialists since the specialists were advised to minimize exposure and pursue telemedicine consults. Read more.

How low should you go?

Cardiovascular risk continues to reduce as systolic blood pressure decreases right down to levels as low as 90 mm Hg, according to a new study.

Researchers analyzed data from a cohort of 1,457 participants (mean age, 58 years) who did not have any traditional cardiovascular risk factors and had a systolic blood pressure level between 90 and 129 mm Hg at baseline. Results showed that, during a mean follow-up of 14.5 years, there was an increase in traditional cardiovascular risk factors, coronary artery calcium, and incident cardiovascular events with increasing systolic blood pressure levels.

“We modeled systolic blood pressure on a continuous scale and saw the risk increasing in a linear fashion as blood pressure increased and this occurred right down to 90 mm Hg. We didn’t see any nadir or J-point where there may be an increased risk at lower pressures,” said lead author Seamus Whelton, MD, assistant professor of medicine at the division of cardiology at Johns Hopkins Medicine, Baltimore.

“From an individual level we can now say that in healthy individuals, a systolic pressure in the 90s is not too low. It is a positive thing. And it is recommended to try and keep systolic pressure at these levels if possible by maintaining a healthy lifestyle,” Dr. Whelton said in an interview. Read more.
 

Asthma tops spending on avoidable pediatric inpatient stays

Asthma costs nearly equaled potentially avoidable hospital bills for diabetes, gastroenteritis, and UTIs combined in a study of in-patient stays among children aged 3 months to 17 years.

Indeed, hospital charges for the treatment of children with asthma made up nearly half of all potentially avoidable pediatric inpatient costs in 2017, according to the Agency for Healthcare Research and Quality.

The cost of potentially avoidable visits for asthma that year was $278 million, versus $284 million combined for the other three conditions, Kimberly W. McDermott, PhD, and H. Joanna Jiang, PhD, reported in an AHRQ statistical brief.

The state inpatient databases of the AHRQ’s Healthcare Cost and Utilization Project included 1.4 million inpatient stays among children aged 3 months to 17 years in 2017, of which 8% (108,300) were deemed potentially preventable.

Rates of potentially avoidable stays for asthma (159 per 100,000 population), gastroenteritis (90 per 100,000), and UTIs (41 per 100,000) were highest for children aged 0-4 years and generally decreased with age, but diabetes stays increased with age, rising from 12 per 100,000 in children aged 5-9 years to 38 per 100,000 for those 15-17 years old, the researchers said. Read more.

Adding monoclonal antibodies to Botox for migraine prevention

Adjunctive preventive therapy with a calcitonin gene–related peptide monoclonal antibody (CGRP-mAb) medication is safe and effective in patients with chronic migraine who have only achieved a partial response to onabotulinumtoxinA (Botox) treatment.

Investigators found the CGRP-mAbs significantly reduced the number of headache days and pain severity with adverse event rates similar to those reported in previous trials of these medications.

Although Botox is associated with significant clinical improvement in chronic migraine, it often fails to adequately control headache frequency and additional medications are needed. Three CGRP-mAbs have recently been approved for migraine prevention, with results from clinical trials demonstrating they are effective for both chronic and episodic migraine. Patients treated with Botox had been excluded from these earlier trials, however. Read more.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

A ‘Fraternity of People Who Are Struggling’

Kathleen Ronan spent a week in a New Jersey hospital, including 5 days in the ICU, battling the novel coronavirus.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, 51, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article. “It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her. Read more.

The evolution of ‘COVIDists’

At the start of the pandemic earlier this year hospitalists at Baystate Health in Western Massachusetts realized the necessity of a new model of care for COVID-19 patients. Challenges included a massive surge of COVID-19 patients, a limited supply of PPE, an inadequate number of intensivists for managing the anticipated ventilated patients, and the potential of losing some of our workforce if they became infected. Hospitalists there came up with an elaborate plan to manage the disease burden and the strain on resources effectively.

A focused group of 10 hospitalists who volunteered to take care of COVID-19 patients with a particular interest in the pandemic and experience in critical care were selected, and the term “COVIDists” was coined to refer to them. The group underwent rapid training in various treatment protocols and ongoing clinical trials.

All the hospitalized COVID-19 patients were grouped together to COVID units, and the COVIDists were deployed to those units geographically. COVIDists were given lighter than usual patient loads to deal with the extra time needed for donning and doffing of PPE and for coordination with specialists. COVIDists were almost the only clinicians physically visiting the patients in most cases, and they became the “eyes and ears” of specialists since the specialists were advised to minimize exposure and pursue telemedicine consults. Read more.

How low should you go?

Cardiovascular risk continues to reduce as systolic blood pressure decreases right down to levels as low as 90 mm Hg, according to a new study.

Researchers analyzed data from a cohort of 1,457 participants (mean age, 58 years) who did not have any traditional cardiovascular risk factors and had a systolic blood pressure level between 90 and 129 mm Hg at baseline. Results showed that, during a mean follow-up of 14.5 years, there was an increase in traditional cardiovascular risk factors, coronary artery calcium, and incident cardiovascular events with increasing systolic blood pressure levels.

“We modeled systolic blood pressure on a continuous scale and saw the risk increasing in a linear fashion as blood pressure increased and this occurred right down to 90 mm Hg. We didn’t see any nadir or J-point where there may be an increased risk at lower pressures,” said lead author Seamus Whelton, MD, assistant professor of medicine at the division of cardiology at Johns Hopkins Medicine, Baltimore.

“From an individual level we can now say that in healthy individuals, a systolic pressure in the 90s is not too low. It is a positive thing. And it is recommended to try and keep systolic pressure at these levels if possible by maintaining a healthy lifestyle,” Dr. Whelton said in an interview. Read more.
 

Asthma tops spending on avoidable pediatric inpatient stays

Asthma costs nearly equaled potentially avoidable hospital bills for diabetes, gastroenteritis, and UTIs combined in a study of in-patient stays among children aged 3 months to 17 years.

Indeed, hospital charges for the treatment of children with asthma made up nearly half of all potentially avoidable pediatric inpatient costs in 2017, according to the Agency for Healthcare Research and Quality.

The cost of potentially avoidable visits for asthma that year was $278 million, versus $284 million combined for the other three conditions, Kimberly W. McDermott, PhD, and H. Joanna Jiang, PhD, reported in an AHRQ statistical brief.

The state inpatient databases of the AHRQ’s Healthcare Cost and Utilization Project included 1.4 million inpatient stays among children aged 3 months to 17 years in 2017, of which 8% (108,300) were deemed potentially preventable.

Rates of potentially avoidable stays for asthma (159 per 100,000 population), gastroenteritis (90 per 100,000), and UTIs (41 per 100,000) were highest for children aged 0-4 years and generally decreased with age, but diabetes stays increased with age, rising from 12 per 100,000 in children aged 5-9 years to 38 per 100,000 for those 15-17 years old, the researchers said. Read more.

Adding monoclonal antibodies to Botox for migraine prevention

Adjunctive preventive therapy with a calcitonin gene–related peptide monoclonal antibody (CGRP-mAb) medication is safe and effective in patients with chronic migraine who have only achieved a partial response to onabotulinumtoxinA (Botox) treatment.

Investigators found the CGRP-mAbs significantly reduced the number of headache days and pain severity with adverse event rates similar to those reported in previous trials of these medications.

Although Botox is associated with significant clinical improvement in chronic migraine, it often fails to adequately control headache frequency and additional medications are needed. Three CGRP-mAbs have recently been approved for migraine prevention, with results from clinical trials demonstrating they are effective for both chronic and episodic migraine. Patients treated with Botox had been excluded from these earlier trials, however. Read more.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

By the time she was discharged from a suburban New Jersey hospital on April 10, Kathleen Ronan thought the worst was behind her. For a week before her husband rushed her to the emergency department (ED), incoherent and struggling to breathe, the novel coronavirus had ravaged her body. She tried to treat her fevers with acetaminophen and ice packs. Despite taking enough Tylenol to risk liver damage and packing herself on ice like the catch of the day, Ronan’s fever continued to rise. By the time her temperature reached 104.5° F, Ronan knew the time had come for more drastic measures.

A team of masked and gowned nurses greeted her at a triage tent outside the ED, and from there, everything becomes hazy for Ronan. She was immediately rushed to the hospital’s special COVID-19 intensive care unit (ICU), where she spent 5 days. But she has few distinct memories from this time. What she does remember is the exhaustion, the pain, the loneliness, and the fear. Her family couldn’t visit, and though Ronan works as a home health nurse, her brain was so addled with fever that she couldn’t make sense of what was happening. After a week in the hospital, 5 days of which were spent in the ICU, 51-year-old Ronan was discharged.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, who had supplemented long days on her feet caring for others as a nurse with regular trips to the gym, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article.

“It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

Nor is PICS simply a set of side effects that will go away on their own. It includes ongoing cognitive difficulties and physical weakness, both of which can lead to employment problems. Beyond that, depression and anxiety can exacerbate – and be exacerbated by – these challenges. Psychologist Jim Jackson, PsyD, assistant director of the ICU Recovery Center at Vanderbilt University Medical Center, Nashville, Tennessee, recently spoke with a former ICU patient who has struggled since her discharge 30 years ago.

“Her life essentially stopped with her critical care stay. She hasn’t been able to move forward,” he said. “She’s part of a whole fraternity of people who are struggling.”

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her.
 

Surviving the ICU

Although the new coronavirus has pushed the world’s critical care system to its limits, it was an outbreak in 1952 that inspired the creation of intensive care units. That summer, a wave of paralytic polio swept over Copenhagen, Denmark, and anesthesiologist Bjørn Ibsen, MD, PhD, used mechanical ventilation — physically operated by medical and dental students – to help 316 children breathe for weeks at a time while their small bodies worked to fight off the virus. The effort halved the mortality rate from polio that affected breathing, from 80% to 40%.

In these wards, dedicated to the very sickest, each patient was assigned his or her own nurse. Over the next decade, hospitals in the United Kingdom and the United States established their own ICUs to treat patients with a variety of conditions. Although it helped improve survival, mortality rates in critical care units remained stubbornly high, owing to the patients’ severe underlying illnesses.

“We thought we were doing a good job if the patient survived, but we had no idea what happened after discharge,” said Carla Sevin, MD, medical director of Vanderbilt’s ICU Recovery Center. Nor did their efforts to find out always bring answers. “We struggled to get people to come in for support — they were debilitated, physically burdened, and weak.”

Through further advances in life support, by the early 2000s, the average mortality rates in American ICUs had dropped to 8% to 19%. As the number of critical care survivors began to climb, clinical researchers noticed that the lives of these patients and their families were profoundly altered by their severe illness.

As Dale Needham, MD, PhD, began his pulmonology and critical care residency in Toronto, Canada, in 2005, a group of physicians there began a 5-year longitudinal study to assess long-term outcomes of patients who developed acute respiratory distress syndrome (ARDS). Although ARDS is an acute condition, the investigators found that patients felt effects for years. Younger patients recovered better than older ones, but none of the patients› physical functioning was equivalent to that of age-matched control persons. Even 5 years later, former ICU patients only reached 76% of expected physical functioning, according to results published in the New England Journal of Medicine. The study was a wake-up call.

At a meeting in Chicago in 2010, Needham, now an intensivist at Johns Hopkins Hospital in Baltimore, Maryland, gathered an interdisciplinary group of colleagues, including patients and caregivers, to clarify the phenomena they were seeing. What emerged from that meeting, published in 2012 in Critical Care Medicine, were the diagnostic criteria for PICS: According to the new definition, PICS is characterized by new or worsening physical and neuropsychiatric deficits that range from forgetfulness and loss of motivation to physical weakness and insomnia.

The issue, Needham says, is that although the trouble starts in the ICU, it only becomes clear once patients leave. “ICU doctors aren’t the ones dealing with this,” Needham said. “We need to build stronger bridges between critical care and other professions.” That’s where PICS comes in, a definition that exists explicitly to alert healthcare providers about the constellation of challenges many of these individuals face as they try to reenter “normal” life.
 

Defining the problem

As an ICU nurse at the Mayo Clinic in Rochester, Minnesota, Annie Johnson, ACNP-BC, knew lots about helping hospitalized patients, but she says she didn’t know anything about what to do after discharge – at least not until her own mother became a patient.

On the first day of retirement in October 2014, Johnson’s mother flatlined. Quick-thinking paramedics resuscitated her, and after several days in critical care, she was discharged. Since then, her heart has remained healthy. Johnson’s sister, who spent time worrying over her mother at the hospital, also had lingering effects. Both have since struggled, plagued by nightmares, flashbacks, and insomnia.

Johnson initially believed her mom’s and sister’s neuropsychiatric, post-ICU struggles were unique to her family. It was only a year later, at a seminar she was attending, that she first heard the words “post–intensive care syndrome.” Suddenly, Johnson had a name for her family’s experiences, and she began to create support groups and resources to help other families like hers.

“I thought of all the patients I had treated over the years who had been on ventilators for days and days and days. And if this happened to my mom after 48 hours, what must they be going through?” she asked.

Once physicians formally defined PICS, the Society for Critical Care Medicine helped create programs to educate ICU staff, patients, and families about potential post-discharge challenges. Researchers also began to investigate factors affecting post-ICU functioning. Follow-up studies of patients with delirium (ranging from general confusion about time and place to extreme agitation and violence) showed they had striking cognitive deficits. Problems with short-term memory, flexible thinking, and motivation plagued patients for years after their critical illness, similar to the physical deficiencies seen after ARDS. Delirium was one of the strongest risk factors for neuropsychiatric problems.

“Delirium is basically a stress test for the brain,” said Babar Khan, MD, a critical care specialist at Indiana University’s Regenstrief Institute, in Bloomington. But whether delirium accentuates preexisting cognitive difficulties or creates them afresh isn’t yet clear.

Sophia Wang, MD, a geriatric psychiatrist at Indiana University who works with many critical care patients, says patients who had experienced delirium in the ICU showed significant defects in memory and executive functioning long after their hospital stay. She points to a 2015 study that followed 47 ICU patients for a year post discharge. Among those who experienced delirium, brain volumes, as measured by MRI, were smaller at 3 months, something associated with cognitive problems at 1 year. Many struggled at work, and unemployment was common. Depression and posttraumatic stress compounded these difficulties. Among those with acute respiratory distress, ICU patients who are young, female, and unemployed are most likely to suffer from posttraumatic stress disorder after they are discharge.

Critical care medicine may have given these patients a second chance at life, Wang says, but the life they return to often looks nothing like the one they had before their illness.

Prolonged mechanical ventilation and the heavy sedation that often accompanies it are predictors of PICS severity. Some of these links could be explained by the gravity of the illness that landed someone in critical care, but others are more likely to be iatrogenic, says Gerald Weinhouse, MD, a pulmonology and critical care physician and co-director of the Critical Illness Recovery Program at the Brigham and Women’s Hospital in Boston. The involvement of loved ones at the patient’s bedside, however, improved the entire family’s outcome.

When Weinhouse saw those data, he and his colleagues founded a peer support program for ICU survivors. In a study published in 2019 in Critical Care Medicine, they identified six different models for peer support for those with PICS and their families, including both online and in-person approaches. An ongoing challenge for physicians, Weinhouse says, is getting patients to engage with these programs, given that their calendars are crowded with medical appointments and that they suffer from increased physical and mental disability.

Studies such as these led critical care physicians to form the ICU Liberation Collaborative to rethink critical care medicine. At Vanderbilt, Sevin and Jackson headed up one of the world’s first post-ICU clinics, which uses an interdisciplinary team to help patients maximize their functioning. They redesigned their critical care unit in a way that allows families to spend the night and that encourages patient mobility. Both Needham and Weinhouse continue tracking patient outcomes.

Even before the novel coronavirus struck, the United States — and the world — had begun to realize that graduating from the ICU was only the start of what was often an extensive recovery.
 

The long road back

When COVID-19 patients began flooding intensive care wards around the world, physicians scrambled to meet their complex and desperate acute medical needs. Over the past few months, physicians have focused on keeping these patients alive. “We’ve never seen anything like it ― not even during polio — with the sheer number of patients, all with respiratory distress,” Needham said.

But he and his colleagues know this is only the beginning.

“We’re aware that survivorship issues are coming. There’s going to be a wave of sick people who survived the coronavirus but are going to need more help,” Weinhouse said.

Intensivists have been drawing on PICS research in their fight to help COVID-19 patients. Work from the past few years has shown that although sedation is required during intubation itself, not everyone needs it while on a ventilator. Titrating down sedating medication helps reduce delirium, Wang says. Such medication has been shown to contribute to later cognitive problems. Needham’s studies showing that prolonged bedrest by ICU patients causes muscular atrophy has led him to encourage patients to move as much as possible. With the help of physical therapists, many patients on ventilators can be awake, alert, and moving around the ward.

One of the biggest challenges critical-care coronavirus patients face is prolonged isolation. The constant presence of a familiar face helps orient confused and delirious patients and provides emotional support during a frightening time. But because the immediate need for infection control outweighs these benefits, few hospitals allow visitors, especially for COVID-19 patients.

To address this, some units have been using video technology to allow loved ones to call in. At Johns Hopkins, physicians have also been relying on the expertise of occupational therapists (OTs). Needham says that one OT found that rubbing the hand and back of an agitated, delirious patient helped soothe and calm him better than many medications.

Ronan, who spent 5 days in intensive care, echoes that problem. She says she found the relative lack of human contact to be one of the most challenging parts of being in a bed on a COVID-19 ward. Separated from her husband and daughter, suffering from high fever and severe illness, she lost all track of time.

Her return home was difficult, too. Although her job as a home health nurse had prepared her on some level for the challenges she would face after discharge, Ronan says the hospital provided little practical help.

“Everything is so much harder at home, even little things like going to the bathroom,” she said. “I feel like I’m trying to bail out a sinking ship with a teacup.”

Khan and other physicians, aware of the challenges Ronan and others face once home, aim to create post-ICU clinics specifically for COVID-19 patients. They want to build what Khan calls a “one-stop shop” for all the support patients need to recover. Some of that can be provided via telehealth, which may also help ease the physical burden.

Because there’s so much physicians don’t know about the coronavirus, Johnson says, such clinics are not only a chance to help the sickest COVID-19 patients, they will also help researchers learn more about the virus and improve critical care for other illnesses.

Today, nearly 2 months after discharge, Ronan is back on the job but struggles with a persistent cough — likely due to the lung damage she sustained while ill. She has constant fatigue, as well as ongoing upset stomach from all the medications she took to reduce fever and body aches. When she dons a mask for work, the tangible reminder of her hospital stay sends her into a panic attack. Physically, she’s weaker than before.

Researchers are still trying to understand everything that Ronan and other COVID-19 patients need to move on with their lives after being in the ICU. Mysteries abound, but the ground laid by Sevin, Needham, Weinhouse, and others has provided a solid foundation on which to build.
 

This article first appeared on Medscape.com.

By the time she was discharged from a suburban New Jersey hospital on April 10, Kathleen Ronan thought the worst was behind her. For a week before her husband rushed her to the emergency department (ED), incoherent and struggling to breathe, the novel coronavirus had ravaged her body. She tried to treat her fevers with acetaminophen and ice packs. Despite taking enough Tylenol to risk liver damage and packing herself on ice like the catch of the day, Ronan’s fever continued to rise. By the time her temperature reached 104.5° F, Ronan knew the time had come for more drastic measures.

A team of masked and gowned nurses greeted her at a triage tent outside the ED, and from there, everything becomes hazy for Ronan. She was immediately rushed to the hospital’s special COVID-19 intensive care unit (ICU), where she spent 5 days. But she has few distinct memories from this time. What she does remember is the exhaustion, the pain, the loneliness, and the fear. Her family couldn’t visit, and though Ronan works as a home health nurse, her brain was so addled with fever that she couldn’t make sense of what was happening. After a week in the hospital, 5 days of which were spent in the ICU, 51-year-old Ronan was discharged.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, who had supplemented long days on her feet caring for others as a nurse with regular trips to the gym, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article.

“It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

Nor is PICS simply a set of side effects that will go away on their own. It includes ongoing cognitive difficulties and physical weakness, both of which can lead to employment problems. Beyond that, depression and anxiety can exacerbate – and be exacerbated by – these challenges. Psychologist Jim Jackson, PsyD, assistant director of the ICU Recovery Center at Vanderbilt University Medical Center, Nashville, Tennessee, recently spoke with a former ICU patient who has struggled since her discharge 30 years ago.

“Her life essentially stopped with her critical care stay. She hasn’t been able to move forward,” he said. “She’s part of a whole fraternity of people who are struggling.”

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her.
 

Surviving the ICU

Although the new coronavirus has pushed the world’s critical care system to its limits, it was an outbreak in 1952 that inspired the creation of intensive care units. That summer, a wave of paralytic polio swept over Copenhagen, Denmark, and anesthesiologist Bjørn Ibsen, MD, PhD, used mechanical ventilation — physically operated by medical and dental students – to help 316 children breathe for weeks at a time while their small bodies worked to fight off the virus. The effort halved the mortality rate from polio that affected breathing, from 80% to 40%.

In these wards, dedicated to the very sickest, each patient was assigned his or her own nurse. Over the next decade, hospitals in the United Kingdom and the United States established their own ICUs to treat patients with a variety of conditions. Although it helped improve survival, mortality rates in critical care units remained stubbornly high, owing to the patients’ severe underlying illnesses.

“We thought we were doing a good job if the patient survived, but we had no idea what happened after discharge,” said Carla Sevin, MD, medical director of Vanderbilt’s ICU Recovery Center. Nor did their efforts to find out always bring answers. “We struggled to get people to come in for support — they were debilitated, physically burdened, and weak.”

Through further advances in life support, by the early 2000s, the average mortality rates in American ICUs had dropped to 8% to 19%. As the number of critical care survivors began to climb, clinical researchers noticed that the lives of these patients and their families were profoundly altered by their severe illness.

As Dale Needham, MD, PhD, began his pulmonology and critical care residency in Toronto, Canada, in 2005, a group of physicians there began a 5-year longitudinal study to assess long-term outcomes of patients who developed acute respiratory distress syndrome (ARDS). Although ARDS is an acute condition, the investigators found that patients felt effects for years. Younger patients recovered better than older ones, but none of the patients› physical functioning was equivalent to that of age-matched control persons. Even 5 years later, former ICU patients only reached 76% of expected physical functioning, according to results published in the New England Journal of Medicine. The study was a wake-up call.

At a meeting in Chicago in 2010, Needham, now an intensivist at Johns Hopkins Hospital in Baltimore, Maryland, gathered an interdisciplinary group of colleagues, including patients and caregivers, to clarify the phenomena they were seeing. What emerged from that meeting, published in 2012 in Critical Care Medicine, were the diagnostic criteria for PICS: According to the new definition, PICS is characterized by new or worsening physical and neuropsychiatric deficits that range from forgetfulness and loss of motivation to physical weakness and insomnia.

The issue, Needham says, is that although the trouble starts in the ICU, it only becomes clear once patients leave. “ICU doctors aren’t the ones dealing with this,” Needham said. “We need to build stronger bridges between critical care and other professions.” That’s where PICS comes in, a definition that exists explicitly to alert healthcare providers about the constellation of challenges many of these individuals face as they try to reenter “normal” life.
 

Defining the problem

As an ICU nurse at the Mayo Clinic in Rochester, Minnesota, Annie Johnson, ACNP-BC, knew lots about helping hospitalized patients, but she says she didn’t know anything about what to do after discharge – at least not until her own mother became a patient.

On the first day of retirement in October 2014, Johnson’s mother flatlined. Quick-thinking paramedics resuscitated her, and after several days in critical care, she was discharged. Since then, her heart has remained healthy. Johnson’s sister, who spent time worrying over her mother at the hospital, also had lingering effects. Both have since struggled, plagued by nightmares, flashbacks, and insomnia.

Johnson initially believed her mom’s and sister’s neuropsychiatric, post-ICU struggles were unique to her family. It was only a year later, at a seminar she was attending, that she first heard the words “post–intensive care syndrome.” Suddenly, Johnson had a name for her family’s experiences, and she began to create support groups and resources to help other families like hers.

“I thought of all the patients I had treated over the years who had been on ventilators for days and days and days. And if this happened to my mom after 48 hours, what must they be going through?” she asked.

Once physicians formally defined PICS, the Society for Critical Care Medicine helped create programs to educate ICU staff, patients, and families about potential post-discharge challenges. Researchers also began to investigate factors affecting post-ICU functioning. Follow-up studies of patients with delirium (ranging from general confusion about time and place to extreme agitation and violence) showed they had striking cognitive deficits. Problems with short-term memory, flexible thinking, and motivation plagued patients for years after their critical illness, similar to the physical deficiencies seen after ARDS. Delirium was one of the strongest risk factors for neuropsychiatric problems.

“Delirium is basically a stress test for the brain,” said Babar Khan, MD, a critical care specialist at Indiana University’s Regenstrief Institute, in Bloomington. But whether delirium accentuates preexisting cognitive difficulties or creates them afresh isn’t yet clear.

Sophia Wang, MD, a geriatric psychiatrist at Indiana University who works with many critical care patients, says patients who had experienced delirium in the ICU showed significant defects in memory and executive functioning long after their hospital stay. She points to a 2015 study that followed 47 ICU patients for a year post discharge. Among those who experienced delirium, brain volumes, as measured by MRI, were smaller at 3 months, something associated with cognitive problems at 1 year. Many struggled at work, and unemployment was common. Depression and posttraumatic stress compounded these difficulties. Among those with acute respiratory distress, ICU patients who are young, female, and unemployed are most likely to suffer from posttraumatic stress disorder after they are discharge.

Critical care medicine may have given these patients a second chance at life, Wang says, but the life they return to often looks nothing like the one they had before their illness.

Prolonged mechanical ventilation and the heavy sedation that often accompanies it are predictors of PICS severity. Some of these links could be explained by the gravity of the illness that landed someone in critical care, but others are more likely to be iatrogenic, says Gerald Weinhouse, MD, a pulmonology and critical care physician and co-director of the Critical Illness Recovery Program at the Brigham and Women’s Hospital in Boston. The involvement of loved ones at the patient’s bedside, however, improved the entire family’s outcome.

When Weinhouse saw those data, he and his colleagues founded a peer support program for ICU survivors. In a study published in 2019 in Critical Care Medicine, they identified six different models for peer support for those with PICS and their families, including both online and in-person approaches. An ongoing challenge for physicians, Weinhouse says, is getting patients to engage with these programs, given that their calendars are crowded with medical appointments and that they suffer from increased physical and mental disability.

Studies such as these led critical care physicians to form the ICU Liberation Collaborative to rethink critical care medicine. At Vanderbilt, Sevin and Jackson headed up one of the world’s first post-ICU clinics, which uses an interdisciplinary team to help patients maximize their functioning. They redesigned their critical care unit in a way that allows families to spend the night and that encourages patient mobility. Both Needham and Weinhouse continue tracking patient outcomes.

Even before the novel coronavirus struck, the United States — and the world — had begun to realize that graduating from the ICU was only the start of what was often an extensive recovery.
 

The long road back

When COVID-19 patients began flooding intensive care wards around the world, physicians scrambled to meet their complex and desperate acute medical needs. Over the past few months, physicians have focused on keeping these patients alive. “We’ve never seen anything like it ― not even during polio — with the sheer number of patients, all with respiratory distress,” Needham said.

But he and his colleagues know this is only the beginning.

“We’re aware that survivorship issues are coming. There’s going to be a wave of sick people who survived the coronavirus but are going to need more help,” Weinhouse said.

Intensivists have been drawing on PICS research in their fight to help COVID-19 patients. Work from the past few years has shown that although sedation is required during intubation itself, not everyone needs it while on a ventilator. Titrating down sedating medication helps reduce delirium, Wang says. Such medication has been shown to contribute to later cognitive problems. Needham’s studies showing that prolonged bedrest by ICU patients causes muscular atrophy has led him to encourage patients to move as much as possible. With the help of physical therapists, many patients on ventilators can be awake, alert, and moving around the ward.

One of the biggest challenges critical-care coronavirus patients face is prolonged isolation. The constant presence of a familiar face helps orient confused and delirious patients and provides emotional support during a frightening time. But because the immediate need for infection control outweighs these benefits, few hospitals allow visitors, especially for COVID-19 patients.

To address this, some units have been using video technology to allow loved ones to call in. At Johns Hopkins, physicians have also been relying on the expertise of occupational therapists (OTs). Needham says that one OT found that rubbing the hand and back of an agitated, delirious patient helped soothe and calm him better than many medications.

Ronan, who spent 5 days in intensive care, echoes that problem. She says she found the relative lack of human contact to be one of the most challenging parts of being in a bed on a COVID-19 ward. Separated from her husband and daughter, suffering from high fever and severe illness, she lost all track of time.

Her return home was difficult, too. Although her job as a home health nurse had prepared her on some level for the challenges she would face after discharge, Ronan says the hospital provided little practical help.

“Everything is so much harder at home, even little things like going to the bathroom,” she said. “I feel like I’m trying to bail out a sinking ship with a teacup.”

Khan and other physicians, aware of the challenges Ronan and others face once home, aim to create post-ICU clinics specifically for COVID-19 patients. They want to build what Khan calls a “one-stop shop” for all the support patients need to recover. Some of that can be provided via telehealth, which may also help ease the physical burden.

Because there’s so much physicians don’t know about the coronavirus, Johnson says, such clinics are not only a chance to help the sickest COVID-19 patients, they will also help researchers learn more about the virus and improve critical care for other illnesses.

Today, nearly 2 months after discharge, Ronan is back on the job but struggles with a persistent cough — likely due to the lung damage she sustained while ill. She has constant fatigue, as well as ongoing upset stomach from all the medications she took to reduce fever and body aches. When she dons a mask for work, the tangible reminder of her hospital stay sends her into a panic attack. Physically, she’s weaker than before.

Researchers are still trying to understand everything that Ronan and other COVID-19 patients need to move on with their lives after being in the ICU. Mysteries abound, but the ground laid by Sevin, Needham, Weinhouse, and others has provided a solid foundation on which to build.
 

This article first appeared on Medscape.com.

By the time she was discharged from a suburban New Jersey hospital on April 10, Kathleen Ronan thought the worst was behind her. For a week before her husband rushed her to the emergency department (ED), incoherent and struggling to breathe, the novel coronavirus had ravaged her body. She tried to treat her fevers with acetaminophen and ice packs. Despite taking enough Tylenol to risk liver damage and packing herself on ice like the catch of the day, Ronan’s fever continued to rise. By the time her temperature reached 104.5° F, Ronan knew the time had come for more drastic measures.

A team of masked and gowned nurses greeted her at a triage tent outside the ED, and from there, everything becomes hazy for Ronan. She was immediately rushed to the hospital’s special COVID-19 intensive care unit (ICU), where she spent 5 days. But she has few distinct memories from this time. What she does remember is the exhaustion, the pain, the loneliness, and the fear. Her family couldn’t visit, and though Ronan works as a home health nurse, her brain was so addled with fever that she couldn’t make sense of what was happening. After a week in the hospital, 5 days of which were spent in the ICU, 51-year-old Ronan was discharged.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, who had supplemented long days on her feet caring for others as a nurse with regular trips to the gym, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article.

“It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

Nor is PICS simply a set of side effects that will go away on their own. It includes ongoing cognitive difficulties and physical weakness, both of which can lead to employment problems. Beyond that, depression and anxiety can exacerbate – and be exacerbated by – these challenges. Psychologist Jim Jackson, PsyD, assistant director of the ICU Recovery Center at Vanderbilt University Medical Center, Nashville, Tennessee, recently spoke with a former ICU patient who has struggled since her discharge 30 years ago.

“Her life essentially stopped with her critical care stay. She hasn’t been able to move forward,” he said. “She’s part of a whole fraternity of people who are struggling.”

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her.
 

Surviving the ICU

Although the new coronavirus has pushed the world’s critical care system to its limits, it was an outbreak in 1952 that inspired the creation of intensive care units. That summer, a wave of paralytic polio swept over Copenhagen, Denmark, and anesthesiologist Bjørn Ibsen, MD, PhD, used mechanical ventilation — physically operated by medical and dental students – to help 316 children breathe for weeks at a time while their small bodies worked to fight off the virus. The effort halved the mortality rate from polio that affected breathing, from 80% to 40%.

In these wards, dedicated to the very sickest, each patient was assigned his or her own nurse. Over the next decade, hospitals in the United Kingdom and the United States established their own ICUs to treat patients with a variety of conditions. Although it helped improve survival, mortality rates in critical care units remained stubbornly high, owing to the patients’ severe underlying illnesses.

“We thought we were doing a good job if the patient survived, but we had no idea what happened after discharge,” said Carla Sevin, MD, medical director of Vanderbilt’s ICU Recovery Center. Nor did their efforts to find out always bring answers. “We struggled to get people to come in for support — they were debilitated, physically burdened, and weak.”

Through further advances in life support, by the early 2000s, the average mortality rates in American ICUs had dropped to 8% to 19%. As the number of critical care survivors began to climb, clinical researchers noticed that the lives of these patients and their families were profoundly altered by their severe illness.

As Dale Needham, MD, PhD, began his pulmonology and critical care residency in Toronto, Canada, in 2005, a group of physicians there began a 5-year longitudinal study to assess long-term outcomes of patients who developed acute respiratory distress syndrome (ARDS). Although ARDS is an acute condition, the investigators found that patients felt effects for years. Younger patients recovered better than older ones, but none of the patients› physical functioning was equivalent to that of age-matched control persons. Even 5 years later, former ICU patients only reached 76% of expected physical functioning, according to results published in the New England Journal of Medicine. The study was a wake-up call.

At a meeting in Chicago in 2010, Needham, now an intensivist at Johns Hopkins Hospital in Baltimore, Maryland, gathered an interdisciplinary group of colleagues, including patients and caregivers, to clarify the phenomena they were seeing. What emerged from that meeting, published in 2012 in Critical Care Medicine, were the diagnostic criteria for PICS: According to the new definition, PICS is characterized by new or worsening physical and neuropsychiatric deficits that range from forgetfulness and loss of motivation to physical weakness and insomnia.

The issue, Needham says, is that although the trouble starts in the ICU, it only becomes clear once patients leave. “ICU doctors aren’t the ones dealing with this,” Needham said. “We need to build stronger bridges between critical care and other professions.” That’s where PICS comes in, a definition that exists explicitly to alert healthcare providers about the constellation of challenges many of these individuals face as they try to reenter “normal” life.
 

Defining the problem

As an ICU nurse at the Mayo Clinic in Rochester, Minnesota, Annie Johnson, ACNP-BC, knew lots about helping hospitalized patients, but she says she didn’t know anything about what to do after discharge – at least not until her own mother became a patient.

On the first day of retirement in October 2014, Johnson’s mother flatlined. Quick-thinking paramedics resuscitated her, and after several days in critical care, she was discharged. Since then, her heart has remained healthy. Johnson’s sister, who spent time worrying over her mother at the hospital, also had lingering effects. Both have since struggled, plagued by nightmares, flashbacks, and insomnia.

Johnson initially believed her mom’s and sister’s neuropsychiatric, post-ICU struggles were unique to her family. It was only a year later, at a seminar she was attending, that she first heard the words “post–intensive care syndrome.” Suddenly, Johnson had a name for her family’s experiences, and she began to create support groups and resources to help other families like hers.

“I thought of all the patients I had treated over the years who had been on ventilators for days and days and days. And if this happened to my mom after 48 hours, what must they be going through?” she asked.

Once physicians formally defined PICS, the Society for Critical Care Medicine helped create programs to educate ICU staff, patients, and families about potential post-discharge challenges. Researchers also began to investigate factors affecting post-ICU functioning. Follow-up studies of patients with delirium (ranging from general confusion about time and place to extreme agitation and violence) showed they had striking cognitive deficits. Problems with short-term memory, flexible thinking, and motivation plagued patients for years after their critical illness, similar to the physical deficiencies seen after ARDS. Delirium was one of the strongest risk factors for neuropsychiatric problems.

“Delirium is basically a stress test for the brain,” said Babar Khan, MD, a critical care specialist at Indiana University’s Regenstrief Institute, in Bloomington. But whether delirium accentuates preexisting cognitive difficulties or creates them afresh isn’t yet clear.

Sophia Wang, MD, a geriatric psychiatrist at Indiana University who works with many critical care patients, says patients who had experienced delirium in the ICU showed significant defects in memory and executive functioning long after their hospital stay. She points to a 2015 study that followed 47 ICU patients for a year post discharge. Among those who experienced delirium, brain volumes, as measured by MRI, were smaller at 3 months, something associated with cognitive problems at 1 year. Many struggled at work, and unemployment was common. Depression and posttraumatic stress compounded these difficulties. Among those with acute respiratory distress, ICU patients who are young, female, and unemployed are most likely to suffer from posttraumatic stress disorder after they are discharge.

Critical care medicine may have given these patients a second chance at life, Wang says, but the life they return to often looks nothing like the one they had before their illness.

Prolonged mechanical ventilation and the heavy sedation that often accompanies it are predictors of PICS severity. Some of these links could be explained by the gravity of the illness that landed someone in critical care, but others are more likely to be iatrogenic, says Gerald Weinhouse, MD, a pulmonology and critical care physician and co-director of the Critical Illness Recovery Program at the Brigham and Women’s Hospital in Boston. The involvement of loved ones at the patient’s bedside, however, improved the entire family’s outcome.

When Weinhouse saw those data, he and his colleagues founded a peer support program for ICU survivors. In a study published in 2019 in Critical Care Medicine, they identified six different models for peer support for those with PICS and their families, including both online and in-person approaches. An ongoing challenge for physicians, Weinhouse says, is getting patients to engage with these programs, given that their calendars are crowded with medical appointments and that they suffer from increased physical and mental disability.

Studies such as these led critical care physicians to form the ICU Liberation Collaborative to rethink critical care medicine. At Vanderbilt, Sevin and Jackson headed up one of the world’s first post-ICU clinics, which uses an interdisciplinary team to help patients maximize their functioning. They redesigned their critical care unit in a way that allows families to spend the night and that encourages patient mobility. Both Needham and Weinhouse continue tracking patient outcomes.

Even before the novel coronavirus struck, the United States — and the world — had begun to realize that graduating from the ICU was only the start of what was often an extensive recovery.
 

The long road back

When COVID-19 patients began flooding intensive care wards around the world, physicians scrambled to meet their complex and desperate acute medical needs. Over the past few months, physicians have focused on keeping these patients alive. “We’ve never seen anything like it ― not even during polio — with the sheer number of patients, all with respiratory distress,” Needham said.

But he and his colleagues know this is only the beginning.

“We’re aware that survivorship issues are coming. There’s going to be a wave of sick people who survived the coronavirus but are going to need more help,” Weinhouse said.

Intensivists have been drawing on PICS research in their fight to help COVID-19 patients. Work from the past few years has shown that although sedation is required during intubation itself, not everyone needs it while on a ventilator. Titrating down sedating medication helps reduce delirium, Wang says. Such medication has been shown to contribute to later cognitive problems. Needham’s studies showing that prolonged bedrest by ICU patients causes muscular atrophy has led him to encourage patients to move as much as possible. With the help of physical therapists, many patients on ventilators can be awake, alert, and moving around the ward.

One of the biggest challenges critical-care coronavirus patients face is prolonged isolation. The constant presence of a familiar face helps orient confused and delirious patients and provides emotional support during a frightening time. But because the immediate need for infection control outweighs these benefits, few hospitals allow visitors, especially for COVID-19 patients.

To address this, some units have been using video technology to allow loved ones to call in. At Johns Hopkins, physicians have also been relying on the expertise of occupational therapists (OTs). Needham says that one OT found that rubbing the hand and back of an agitated, delirious patient helped soothe and calm him better than many medications.

Ronan, who spent 5 days in intensive care, echoes that problem. She says she found the relative lack of human contact to be one of the most challenging parts of being in a bed on a COVID-19 ward. Separated from her husband and daughter, suffering from high fever and severe illness, she lost all track of time.

Her return home was difficult, too. Although her job as a home health nurse had prepared her on some level for the challenges she would face after discharge, Ronan says the hospital provided little practical help.

“Everything is so much harder at home, even little things like going to the bathroom,” she said. “I feel like I’m trying to bail out a sinking ship with a teacup.”

Khan and other physicians, aware of the challenges Ronan and others face once home, aim to create post-ICU clinics specifically for COVID-19 patients. They want to build what Khan calls a “one-stop shop” for all the support patients need to recover. Some of that can be provided via telehealth, which may also help ease the physical burden.

Because there’s so much physicians don’t know about the coronavirus, Johnson says, such clinics are not only a chance to help the sickest COVID-19 patients, they will also help researchers learn more about the virus and improve critical care for other illnesses.

Today, nearly 2 months after discharge, Ronan is back on the job but struggles with a persistent cough — likely due to the lung damage she sustained while ill. She has constant fatigue, as well as ongoing upset stomach from all the medications she took to reduce fever and body aches. When she dons a mask for work, the tangible reminder of her hospital stay sends her into a panic attack. Physically, she’s weaker than before.

Researchers are still trying to understand everything that Ronan and other COVID-19 patients need to move on with their lives after being in the ICU. Mysteries abound, but the ground laid by Sevin, Needham, Weinhouse, and others has provided a solid foundation on which to build.
 

This article first appeared on Medscape.com.

Cardiovascular risk continues to reduce as systolic blood pressure decreases right down to levels as low as 90 mm Hg, a new study has shown.

The study analyzed data from a cohort of 1,457 participants (mean age, 58 years) who did not have any traditional cardiovascular risk factors and had a systolic blood pressure level between 90 and 129 mm Hg at baseline. Results showed that, during a mean follow-up of 14.5 years, there was an increase in traditional cardiovascular risk factors, coronary artery calcium, and incident cardiovascular events with increasing systolic blood pressure levels.

“We modeled systolic blood pressure on a continuous scale and saw the risk increasing in a linear fashion as blood pressure increased and this occurred right down to 90 mm Hg. We didn’t see any nadir or J-point where there may be an increased risk at lower pressures,” said lead author Seamus Whelton, MD.

Dr. Whelton is assistant professor of medicine at the division of cardiology at Johns Hopkins Medicine, Baltimore. He is the son of Paul Whelton, MD, chair of the 2017 American College of Cardiology/American Heart Association hypertension guideline writing committee.

“From an individual level we can now say that in healthy individuals, a systolic pressure in the 90s is not too low. It is a positive thing. And it is recommended to try and keep systolic pressure at these levels if possible by maintaining a healthy lifestyle,” Dr. Whelton said in an interview. “At a population level this finding could lead to stronger recommendations on interventions to prevent increasing blood pressure such as healthier diets, reducing sodium intake, and increasing exercise. Small changes in blood pressure on a population level will lead to large changes in cardiovascular risk on a population a level.”

The study was published online in JAMA Cardiology on June 10.

The researchers noted that populations in nonindustrialized countries have little to no increase in systolic blood pressure levels with age, while systolic blood pressure levels typically increase with age in countries with industrialized diets and lifestyles. This has important implications, because atherosclerosis is a slowly progressive disease and the lower an individual’s lifetime exposure to cardiovascular risk factors, such as increased systolic blood pressure, the lower their probable risk for a future cardiovascular event, they wrote.

While the association between systolic blood pressure level, coronary artery calcium, and atherosclerotic cardiovascular disease is well established at higher blood pressure levels, optimal systolic pressure levels for a healthy adult and whether there is a J-shaped relationship or lower limit of systolic pressure necessary to maintain adequate organ perfusion has been uncertain, they explained.

In addition, prior studies have typically used a reference systolic pressure of less than 115-120 mm Hg to define a normal level, and it is uncertain whether there is a lower level at which the risk for incident cardiovascular disease plateaus or increases.

To investigate this, they analyzed data from the Multi-Ethnic Study of Atherosclerosis, a community-based, multiethnic cohort free from known cardiovascular disease at enrollment. The current analysis included individuals with a systolic blood pressure between 90 and 129 mm Hg without other traditional cardiovascular risk factors including dyslipidemia (LDL cholesterol >160 mg/dL or HDL cholesterol <40 mg/dL), diabetes, or current tobacco use.

Results showed an adjusted hazard ratio for atherosclerotic cardiovascular disease was 1.53 for every 10 mm Hg increase in systolic blood pressure levels.

Compared with people with systolic pressures of 90-99 mm Hg, the adjusted hazard ratio for atherosclerotic cardiovascular disease risk was 3.00 for those with 100-109 mm Hg, 3.10 for those with 110-119 mm Hg, and 4.58 for those with 120-129 mm Hg.

There was also a graded increase in the prevalence of coronary artery calcium starting from systolic blood pressure levels as low as 90 mm Hg.

“Previous research on the J-shaped curve for blood pressure has primarily focused on diastolic pressure. We did control for diastolic pressure in this analysis but that was not the focus,” Dr. Whelton said. “Obviously, there will be a minimum optimum value for both diastolic and systolic pressure. But from this study we can say that for systolic pressure, that minimum recommended value is below 90 mm Hg.”

In terms of implications, the researchers wrote: “Among individuals at low or intermediate atherosclerotic cardiovascular risk, it may be more efficacious to focus on a life-course approach for preventing an increase in systolic blood pressure levels rather than treatment of established hypertension to lower systolic blood pressure levels.”

What is a normal blood pressure?

In an accompanying commentary, Daniel Jones, MD, of the University of Mississippi Medical Center, Jackson, said these new findings support the position that risk imposed by blood pressure level begins well below the current 130/80 mm Hg definition of hypertension and guideline-recommended goal.

The study is “a reminder that even a good execution of treatment of hypertension is far from an ideal way to prevent atherosclerotic cardiovascular disease,” he said.

“A systolic of 130 is not the number we should focus on for patients who are not yet hypertensive, as 130 is not a normal blood pressure,” Dr. Jones added in an audio interview on the JAMA website.

“The findings also suggest that the disease process for atherosclerotic cardiovascular disease begins early in life and support the importance of primordial prevention through a healthy lifestyle, including a healthy diet and levels of physical activity. In addition, the findings highlight the need for a population-based strategy focusing on primordial prevention to reduce the age-related increase in BP reported in all industrialized societies,” Dr. Jones wrote.

He recommended that clinicians encourage a healthy lifestyle in patients and families of patients with cardiovascular disease. “This intervention requires no sophisticated genetic testing or clinical trials to credibly inform a family that the children and grandchildren of a patient with atherosclerotic cardiovascular disease or risk factors will benefit from a healthy lifestyle beginning at the earliest age.

“Clinicians often lose sight of the big picture with regard to blood pressure because they have the patient in front of them. But that patient has children and grandchildren who may share the risk and may be in a better position with regard to prevention of future [coronary artery disease], stroke, and kidney disease,” he said.

Conducting the JAMA audio interview, Clyde Yancy, MD, chief of cardiology at Northwestern University, Chicago, said that “this is very stimulating research. It is not asking the question of what is the target blood pressure for patients with hypertension, but rather: What is the goal blood pressure if you actually want to avoid atherosclerotic cardiovascular disease risk altogether?

“These data have made us understand that there is a difference between the goal blood pressure reduction and treatment thresholds that we respect, the normative blood pressure values we see in a clinical setting, and what is truly normal blood pressure,” Dr. Yancy concluded. “That is a very important nuance, especially when we’re talking about population health. Families and communities need to understand what the true normal is.”

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

Cardiovascular risk continues to reduce as systolic blood pressure decreases right down to levels as low as 90 mm Hg, a new study has shown.

The study analyzed data from a cohort of 1,457 participants (mean age, 58 years) who did not have any traditional cardiovascular risk factors and had a systolic blood pressure level between 90 and 129 mm Hg at baseline. Results showed that, during a mean follow-up of 14.5 years, there was an increase in traditional cardiovascular risk factors, coronary artery calcium, and incident cardiovascular events with increasing systolic blood pressure levels.

“We modeled systolic blood pressure on a continuous scale and saw the risk increasing in a linear fashion as blood pressure increased and this occurred right down to 90 mm Hg. We didn’t see any nadir or J-point where there may be an increased risk at lower pressures,” said lead author Seamus Whelton, MD.

Dr. Whelton is assistant professor of medicine at the division of cardiology at Johns Hopkins Medicine, Baltimore. He is the son of Paul Whelton, MD, chair of the 2017 American College of Cardiology/American Heart Association hypertension guideline writing committee.

“From an individual level we can now say that in healthy individuals, a systolic pressure in the 90s is not too low. It is a positive thing. And it is recommended to try and keep systolic pressure at these levels if possible by maintaining a healthy lifestyle,” Dr. Whelton said in an interview. “At a population level this finding could lead to stronger recommendations on interventions to prevent increasing blood pressure such as healthier diets, reducing sodium intake, and increasing exercise. Small changes in blood pressure on a population level will lead to large changes in cardiovascular risk on a population a level.”

The study was published online in JAMA Cardiology on June 10.

The researchers noted that populations in nonindustrialized countries have little to no increase in systolic blood pressure levels with age, while systolic blood pressure levels typically increase with age in countries with industrialized diets and lifestyles. This has important implications, because atherosclerosis is a slowly progressive disease and the lower an individual’s lifetime exposure to cardiovascular risk factors, such as increased systolic blood pressure, the lower their probable risk for a future cardiovascular event, they wrote.

While the association between systolic blood pressure level, coronary artery calcium, and atherosclerotic cardiovascular disease is well established at higher blood pressure levels, optimal systolic pressure levels for a healthy adult and whether there is a J-shaped relationship or lower limit of systolic pressure necessary to maintain adequate organ perfusion has been uncertain, they explained.

In addition, prior studies have typically used a reference systolic pressure of less than 115-120 mm Hg to define a normal level, and it is uncertain whether there is a lower level at which the risk for incident cardiovascular disease plateaus or increases.

To investigate this, they analyzed data from the Multi-Ethnic Study of Atherosclerosis, a community-based, multiethnic cohort free from known cardiovascular disease at enrollment. The current analysis included individuals with a systolic blood pressure between 90 and 129 mm Hg without other traditional cardiovascular risk factors including dyslipidemia (LDL cholesterol >160 mg/dL or HDL cholesterol <40 mg/dL), diabetes, or current tobacco use.

Results showed an adjusted hazard ratio for atherosclerotic cardiovascular disease was 1.53 for every 10 mm Hg increase in systolic blood pressure levels.

Compared with people with systolic pressures of 90-99 mm Hg, the adjusted hazard ratio for atherosclerotic cardiovascular disease risk was 3.00 for those with 100-109 mm Hg, 3.10 for those with 110-119 mm Hg, and 4.58 for those with 120-129 mm Hg.

There was also a graded increase in the prevalence of coronary artery calcium starting from systolic blood pressure levels as low as 90 mm Hg.

“Previous research on the J-shaped curve for blood pressure has primarily focused on diastolic pressure. We did control for diastolic pressure in this analysis but that was not the focus,” Dr. Whelton said. “Obviously, there will be a minimum optimum value for both diastolic and systolic pressure. But from this study we can say that for systolic pressure, that minimum recommended value is below 90 mm Hg.”

In terms of implications, the researchers wrote: “Among individuals at low or intermediate atherosclerotic cardiovascular risk, it may be more efficacious to focus on a life-course approach for preventing an increase in systolic blood pressure levels rather than treatment of established hypertension to lower systolic blood pressure levels.”

What is a normal blood pressure?

In an accompanying commentary, Daniel Jones, MD, of the University of Mississippi Medical Center, Jackson, said these new findings support the position that risk imposed by blood pressure level begins well below the current 130/80 mm Hg definition of hypertension and guideline-recommended goal.

The study is “a reminder that even a good execution of treatment of hypertension is far from an ideal way to prevent atherosclerotic cardiovascular disease,” he said.

“A systolic of 130 is not the number we should focus on for patients who are not yet hypertensive, as 130 is not a normal blood pressure,” Dr. Jones added in an audio interview on the JAMA website.

“The findings also suggest that the disease process for atherosclerotic cardiovascular disease begins early in life and support the importance of primordial prevention through a healthy lifestyle, including a healthy diet and levels of physical activity. In addition, the findings highlight the need for a population-based strategy focusing on primordial prevention to reduce the age-related increase in BP reported in all industrialized societies,” Dr. Jones wrote.

He recommended that clinicians encourage a healthy lifestyle in patients and families of patients with cardiovascular disease. “This intervention requires no sophisticated genetic testing or clinical trials to credibly inform a family that the children and grandchildren of a patient with atherosclerotic cardiovascular disease or risk factors will benefit from a healthy lifestyle beginning at the earliest age.

“Clinicians often lose sight of the big picture with regard to blood pressure because they have the patient in front of them. But that patient has children and grandchildren who may share the risk and may be in a better position with regard to prevention of future [coronary artery disease], stroke, and kidney disease,” he said.

Conducting the JAMA audio interview, Clyde Yancy, MD, chief of cardiology at Northwestern University, Chicago, said that “this is very stimulating research. It is not asking the question of what is the target blood pressure for patients with hypertension, but rather: What is the goal blood pressure if you actually want to avoid atherosclerotic cardiovascular disease risk altogether?

“These data have made us understand that there is a difference between the goal blood pressure reduction and treatment thresholds that we respect, the normative blood pressure values we see in a clinical setting, and what is truly normal blood pressure,” Dr. Yancy concluded. “That is a very important nuance, especially when we’re talking about population health. Families and communities need to understand what the true normal is.”

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

Cardiovascular risk continues to reduce as systolic blood pressure decreases right down to levels as low as 90 mm Hg, a new study has shown.

The study analyzed data from a cohort of 1,457 participants (mean age, 58 years) who did not have any traditional cardiovascular risk factors and had a systolic blood pressure level between 90 and 129 mm Hg at baseline. Results showed that, during a mean follow-up of 14.5 years, there was an increase in traditional cardiovascular risk factors, coronary artery calcium, and incident cardiovascular events with increasing systolic blood pressure levels.

“We modeled systolic blood pressure on a continuous scale and saw the risk increasing in a linear fashion as blood pressure increased and this occurred right down to 90 mm Hg. We didn’t see any nadir or J-point where there may be an increased risk at lower pressures,” said lead author Seamus Whelton, MD.

Dr. Whelton is assistant professor of medicine at the division of cardiology at Johns Hopkins Medicine, Baltimore. He is the son of Paul Whelton, MD, chair of the 2017 American College of Cardiology/American Heart Association hypertension guideline writing committee.

“From an individual level we can now say that in healthy individuals, a systolic pressure in the 90s is not too low. It is a positive thing. And it is recommended to try and keep systolic pressure at these levels if possible by maintaining a healthy lifestyle,” Dr. Whelton said in an interview. “At a population level this finding could lead to stronger recommendations on interventions to prevent increasing blood pressure such as healthier diets, reducing sodium intake, and increasing exercise. Small changes in blood pressure on a population level will lead to large changes in cardiovascular risk on a population a level.”

The study was published online in JAMA Cardiology on June 10.

The researchers noted that populations in nonindustrialized countries have little to no increase in systolic blood pressure levels with age, while systolic blood pressure levels typically increase with age in countries with industrialized diets and lifestyles. This has important implications, because atherosclerosis is a slowly progressive disease and the lower an individual’s lifetime exposure to cardiovascular risk factors, such as increased systolic blood pressure, the lower their probable risk for a future cardiovascular event, they wrote.

While the association between systolic blood pressure level, coronary artery calcium, and atherosclerotic cardiovascular disease is well established at higher blood pressure levels, optimal systolic pressure levels for a healthy adult and whether there is a J-shaped relationship or lower limit of systolic pressure necessary to maintain adequate organ perfusion has been uncertain, they explained.

In addition, prior studies have typically used a reference systolic pressure of less than 115-120 mm Hg to define a normal level, and it is uncertain whether there is a lower level at which the risk for incident cardiovascular disease plateaus or increases.

To investigate this, they analyzed data from the Multi-Ethnic Study of Atherosclerosis, a community-based, multiethnic cohort free from known cardiovascular disease at enrollment. The current analysis included individuals with a systolic blood pressure between 90 and 129 mm Hg without other traditional cardiovascular risk factors including dyslipidemia (LDL cholesterol >160 mg/dL or HDL cholesterol <40 mg/dL), diabetes, or current tobacco use.

Results showed an adjusted hazard ratio for atherosclerotic cardiovascular disease was 1.53 for every 10 mm Hg increase in systolic blood pressure levels.

Compared with people with systolic pressures of 90-99 mm Hg, the adjusted hazard ratio for atherosclerotic cardiovascular disease risk was 3.00 for those with 100-109 mm Hg, 3.10 for those with 110-119 mm Hg, and 4.58 for those with 120-129 mm Hg.

There was also a graded increase in the prevalence of coronary artery calcium starting from systolic blood pressure levels as low as 90 mm Hg.

“Previous research on the J-shaped curve for blood pressure has primarily focused on diastolic pressure. We did control for diastolic pressure in this analysis but that was not the focus,” Dr. Whelton said. “Obviously, there will be a minimum optimum value for both diastolic and systolic pressure. But from this study we can say that for systolic pressure, that minimum recommended value is below 90 mm Hg.”

In terms of implications, the researchers wrote: “Among individuals at low or intermediate atherosclerotic cardiovascular risk, it may be more efficacious to focus on a life-course approach for preventing an increase in systolic blood pressure levels rather than treatment of established hypertension to lower systolic blood pressure levels.”

What is a normal blood pressure?

In an accompanying commentary, Daniel Jones, MD, of the University of Mississippi Medical Center, Jackson, said these new findings support the position that risk imposed by blood pressure level begins well below the current 130/80 mm Hg definition of hypertension and guideline-recommended goal.

The study is “a reminder that even a good execution of treatment of hypertension is far from an ideal way to prevent atherosclerotic cardiovascular disease,” he said.

“A systolic of 130 is not the number we should focus on for patients who are not yet hypertensive, as 130 is not a normal blood pressure,” Dr. Jones added in an audio interview on the JAMA website.

“The findings also suggest that the disease process for atherosclerotic cardiovascular disease begins early in life and support the importance of primordial prevention through a healthy lifestyle, including a healthy diet and levels of physical activity. In addition, the findings highlight the need for a population-based strategy focusing on primordial prevention to reduce the age-related increase in BP reported in all industrialized societies,” Dr. Jones wrote.

He recommended that clinicians encourage a healthy lifestyle in patients and families of patients with cardiovascular disease. “This intervention requires no sophisticated genetic testing or clinical trials to credibly inform a family that the children and grandchildren of a patient with atherosclerotic cardiovascular disease or risk factors will benefit from a healthy lifestyle beginning at the earliest age.

“Clinicians often lose sight of the big picture with regard to blood pressure because they have the patient in front of them. But that patient has children and grandchildren who may share the risk and may be in a better position with regard to prevention of future [coronary artery disease], stroke, and kidney disease,” he said.

Conducting the JAMA audio interview, Clyde Yancy, MD, chief of cardiology at Northwestern University, Chicago, said that “this is very stimulating research. It is not asking the question of what is the target blood pressure for patients with hypertension, but rather: What is the goal blood pressure if you actually want to avoid atherosclerotic cardiovascular disease risk altogether?

“These data have made us understand that there is a difference between the goal blood pressure reduction and treatment thresholds that we respect, the normative blood pressure values we see in a clinical setting, and what is truly normal blood pressure,” Dr. Yancy concluded. “That is a very important nuance, especially when we’re talking about population health. Families and communities need to understand what the true normal is.”

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