Noninvasive testing allows for routine risk stratification and long-term monitoring of patients with nonalcoholic fatty liver disease (NAFLD), offering a safer, more practical approach than biopsy, according to a recent Clinical Practice Update Expert Review by the American Gastroenterological Association.

The update, published online in Gastroenterology, includes eight best practice advice statements.

“The health care burden of longitudinal management of patients with NAFLD is significant. The emergence and utilization of noninvasive testing (NIT) in gastroenterology practices has the potential to significantly enhance the care of patients with NAFLD by improving detection of patients with advanced fibrosis who are at increased risk for cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), thereby facilitating timely clinical management,” wrote authors who were led by Julia J. Wattacheril, MD, MPH, of the Columbia University–New York Presbyterian Hospital nonalcoholic fatty liver disease program and center for liver disease and transplantation.

“In this Expert Review, we have provided clinicians with best practice advice for optimal utilization of NITs in patients with NAFLD,” the authors wrote.

Consensus best practice for implementing NITs in practice are scarce, giving rise to the present clinical practice update. The expert panel reviewed available evidence for these tests during longitudinal care of patients with advanced fibrosis as a means of predicting liver-related outcomes and informing treatment decisions.

The first statement encourages use of NITs for risk stratification during the diagnosis of NAFLD, typically in the form of clinical calculators like fibrosis 4 index (FIB-4), vibration controlled transient elastography (VCTE), shear wave

elastography (SWE), or magnetic resonance elastography (MRE), all of which have been validated in NAFLD.

“Ultrasound-based 3-dimensional elastography (Velacur) and iron-corrected T1 magnetic resonance imaging, although used less frequently, are emerging technologies,” the panelists noted.

Second, the update suggests that patients with a FIB-4 less than 1.3 are unlikely to have advanced hepatic fibrosis, based on this threshold’s strong negative predictive value (NPV).

Still, clinicians should remember that this FIB-4 threshold may be less reliable among patients younger than 35 years or older than 65 years, making it necessary to also consider other clinical measurements, according to the update. The third best practice advice encourages use of two or more NITs among patients with a FIB-4 score greater than 1.3.

The fourth piece of best practice advice suggests that clinicians follow manufacturer’s specifications when implementing NITs, as misuse may lead to “discordant results and adverse events.”

Fifth, to increase the positive predictive value (PPV) for detecting advanced fibrosis, NITs are best interpreted in the context of relevant clinical data, such as physical exam and endoscopy findings.

Next, the document encourages use of liver biopsy when NIT findings are discordant or indeterminate, conflict with findings from other test modalities, or if alternative, non–NAFLD etiologies are suspected.

The penultimate best practice advice suggests use of NITs for serial longitudinal disease monitoring, with signs of progression or regression used to guide clinical decisions.

“Additional evidence for longitudinal prediction of fibrosis regression and progression and response to intervention (lifestyle and pharmacologic) is needed in trials and real-world clinical practice,” Dr. Wattacheril and colleagues noted.

Finally, the clinical practice update advises surveillance of liver complications, such as hepatocellular carcinoma, among patients with NIT results that suggest advanced fibrosis (F3) or cirrhosis (F4).

This clinical practice update was commissioned by the AGA Institute. The investigators disclosed relationships with AstraZeneca, BMS, Novo Nordisk, and others.
 

Noninvasive testing allows for routine risk stratification and long-term monitoring of patients with nonalcoholic fatty liver disease (NAFLD), offering a safer, more practical approach than biopsy, according to a recent Clinical Practice Update Expert Review by the American Gastroenterological Association.

The update, published online in Gastroenterology, includes eight best practice advice statements.

“The health care burden of longitudinal management of patients with NAFLD is significant. The emergence and utilization of noninvasive testing (NIT) in gastroenterology practices has the potential to significantly enhance the care of patients with NAFLD by improving detection of patients with advanced fibrosis who are at increased risk for cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), thereby facilitating timely clinical management,” wrote authors who were led by Julia J. Wattacheril, MD, MPH, of the Columbia University–New York Presbyterian Hospital nonalcoholic fatty liver disease program and center for liver disease and transplantation.

“In this Expert Review, we have provided clinicians with best practice advice for optimal utilization of NITs in patients with NAFLD,” the authors wrote.

Consensus best practice for implementing NITs in practice are scarce, giving rise to the present clinical practice update. The expert panel reviewed available evidence for these tests during longitudinal care of patients with advanced fibrosis as a means of predicting liver-related outcomes and informing treatment decisions.

The first statement encourages use of NITs for risk stratification during the diagnosis of NAFLD, typically in the form of clinical calculators like fibrosis 4 index (FIB-4), vibration controlled transient elastography (VCTE), shear wave

elastography (SWE), or magnetic resonance elastography (MRE), all of which have been validated in NAFLD.

“Ultrasound-based 3-dimensional elastography (Velacur) and iron-corrected T1 magnetic resonance imaging, although used less frequently, are emerging technologies,” the panelists noted.

Second, the update suggests that patients with a FIB-4 less than 1.3 are unlikely to have advanced hepatic fibrosis, based on this threshold’s strong negative predictive value (NPV).

Still, clinicians should remember that this FIB-4 threshold may be less reliable among patients younger than 35 years or older than 65 years, making it necessary to also consider other clinical measurements, according to the update. The third best practice advice encourages use of two or more NITs among patients with a FIB-4 score greater than 1.3.

The fourth piece of best practice advice suggests that clinicians follow manufacturer’s specifications when implementing NITs, as misuse may lead to “discordant results and adverse events.”

Fifth, to increase the positive predictive value (PPV) for detecting advanced fibrosis, NITs are best interpreted in the context of relevant clinical data, such as physical exam and endoscopy findings.

Next, the document encourages use of liver biopsy when NIT findings are discordant or indeterminate, conflict with findings from other test modalities, or if alternative, non–NAFLD etiologies are suspected.

The penultimate best practice advice suggests use of NITs for serial longitudinal disease monitoring, with signs of progression or regression used to guide clinical decisions.

“Additional evidence for longitudinal prediction of fibrosis regression and progression and response to intervention (lifestyle and pharmacologic) is needed in trials and real-world clinical practice,” Dr. Wattacheril and colleagues noted.

Finally, the clinical practice update advises surveillance of liver complications, such as hepatocellular carcinoma, among patients with NIT results that suggest advanced fibrosis (F3) or cirrhosis (F4).

This clinical practice update was commissioned by the AGA Institute. The investigators disclosed relationships with AstraZeneca, BMS, Novo Nordisk, and others.
 

Noninvasive testing allows for routine risk stratification and long-term monitoring of patients with nonalcoholic fatty liver disease (NAFLD), offering a safer, more practical approach than biopsy, according to a recent Clinical Practice Update Expert Review by the American Gastroenterological Association.

The update, published online in Gastroenterology, includes eight best practice advice statements.

“The health care burden of longitudinal management of patients with NAFLD is significant. The emergence and utilization of noninvasive testing (NIT) in gastroenterology practices has the potential to significantly enhance the care of patients with NAFLD by improving detection of patients with advanced fibrosis who are at increased risk for cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), thereby facilitating timely clinical management,” wrote authors who were led by Julia J. Wattacheril, MD, MPH, of the Columbia University–New York Presbyterian Hospital nonalcoholic fatty liver disease program and center for liver disease and transplantation.

“In this Expert Review, we have provided clinicians with best practice advice for optimal utilization of NITs in patients with NAFLD,” the authors wrote.

Consensus best practice for implementing NITs in practice are scarce, giving rise to the present clinical practice update. The expert panel reviewed available evidence for these tests during longitudinal care of patients with advanced fibrosis as a means of predicting liver-related outcomes and informing treatment decisions.

The first statement encourages use of NITs for risk stratification during the diagnosis of NAFLD, typically in the form of clinical calculators like fibrosis 4 index (FIB-4), vibration controlled transient elastography (VCTE), shear wave

elastography (SWE), or magnetic resonance elastography (MRE), all of which have been validated in NAFLD.

“Ultrasound-based 3-dimensional elastography (Velacur) and iron-corrected T1 magnetic resonance imaging, although used less frequently, are emerging technologies,” the panelists noted.

Second, the update suggests that patients with a FIB-4 less than 1.3 are unlikely to have advanced hepatic fibrosis, based on this threshold’s strong negative predictive value (NPV).

Still, clinicians should remember that this FIB-4 threshold may be less reliable among patients younger than 35 years or older than 65 years, making it necessary to also consider other clinical measurements, according to the update. The third best practice advice encourages use of two or more NITs among patients with a FIB-4 score greater than 1.3.

The fourth piece of best practice advice suggests that clinicians follow manufacturer’s specifications when implementing NITs, as misuse may lead to “discordant results and adverse events.”

Fifth, to increase the positive predictive value (PPV) for detecting advanced fibrosis, NITs are best interpreted in the context of relevant clinical data, such as physical exam and endoscopy findings.

Next, the document encourages use of liver biopsy when NIT findings are discordant or indeterminate, conflict with findings from other test modalities, or if alternative, non–NAFLD etiologies are suspected.

The penultimate best practice advice suggests use of NITs for serial longitudinal disease monitoring, with signs of progression or regression used to guide clinical decisions.

“Additional evidence for longitudinal prediction of fibrosis regression and progression and response to intervention (lifestyle and pharmacologic) is needed in trials and real-world clinical practice,” Dr. Wattacheril and colleagues noted.

Finally, the clinical practice update advises surveillance of liver complications, such as hepatocellular carcinoma, among patients with NIT results that suggest advanced fibrosis (F3) or cirrhosis (F4).

This clinical practice update was commissioned by the AGA Institute. The investigators disclosed relationships with AstraZeneca, BMS, Novo Nordisk, and others.
 

Changes in proteins and antibodies suggesting immune dysregulation may be detectable in serum years before clinical manifestation of complicated Crohn’s disease, shows a study recently published in Clinical Gastroenterology and Hepatology.

These preclinical signatures could one day play a role in screening for complicated Crohn’s disease (CD) and in mapping underlying disease pathways, potentially opening doors to new preventive approaches, wrote study authors who were led by Joseph A. Murray, MD, of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn.

“Mounting evidence suggests that the diagnosis of CD is preceded by a lengthy asymptomatic preclinical period,” investigators wrote. “Gaining insight into this phase may allow a better understanding of the primary events that lead to its development and offer potential strategies to predict and prevent the disease including its complications.”

The study, which was a nested case-control study based on the PREDICTS study, included 201 patients with CD who had serum samples archived 2, 4, and 6 years prior to diagnosis, as well as 201 healthy controls who provided serum samples for comparison. Serum samples were analyzed with a comprehensive panel of 1,129 proteomic markers and antimicrobial antibodies.

At time of diagnosis, 47 of the patients with CD (24%) had a complicated phenotype, including stricturing behavior, penetrating behavior, or need for early surgery.

“The unique availability of preclinical samples collected at multiple time points allowed us to examine the sequence of immunological changes and protein biomarkers that occurred before diagnosis,” the investigators wrote. “We also evaluated a wide array of protein biomarkers, utilizing a novel proteomic platform, and applied novel rigorous statistical approaches, which allowed us to discover the potential biomarkers and biologic pathways for the complicated phenotypes even before diagnosis.”

As early as 6 years before diagnosis, patients with complicated CD had significantly higher levels of antimicrobial antibodies than patients with noncomplicated CD, as well as elevations in 22 protein biomarkers indicating immune dysregulation.

Specifically, complicated CD was preceded by elevated anti–Saccharomyces cerevisiae antibodies (ASCA) IgA/IgG, anti-Flagellin antibodies, and other proteins linked with fibrosis, adaptive immunity, and innate immunity. Simultaneously, the same patients had reduced levels of protein biomarkers linked with protection against fibrosis and tissue damage. Network analysis added weight to these findings by demonstrating a significant correlation between ASCA IgA/IgG and protein biomarkers tied to innate immunity and lack of factors for tissue protection.

“Altogether, the hypothesis can be proposed that the combination of increasing levels of inflammatory cytokines, loss of anti-inflammatory proteins, and production of antimicrobial antibodies could accelerate and magnify tissue destruction and fibrosis driving complications at diagnosis in CD,” the investigators wrote. “These data support the concept that complicated CD may not always be the result of the progression of an uncontrolled inflammatory disease but may also be the consequence of a unique pathophysiological process.”

The findings deserve further investigation as they could lead to new clinical tools for screening and intervention. “The serological signature that we identified could help to further select subjects at risk of developing complicated CD who could be preferential candidates for preventative strategies,” investigators wrote.

The investigators disclosed relationships with Janssen, AbbVie, Galapagos, and others.

Changes in proteins and antibodies suggesting immune dysregulation may be detectable in serum years before clinical manifestation of complicated Crohn’s disease, shows a study recently published in Clinical Gastroenterology and Hepatology.

These preclinical signatures could one day play a role in screening for complicated Crohn’s disease (CD) and in mapping underlying disease pathways, potentially opening doors to new preventive approaches, wrote study authors who were led by Joseph A. Murray, MD, of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn.

“Mounting evidence suggests that the diagnosis of CD is preceded by a lengthy asymptomatic preclinical period,” investigators wrote. “Gaining insight into this phase may allow a better understanding of the primary events that lead to its development and offer potential strategies to predict and prevent the disease including its complications.”

The study, which was a nested case-control study based on the PREDICTS study, included 201 patients with CD who had serum samples archived 2, 4, and 6 years prior to diagnosis, as well as 201 healthy controls who provided serum samples for comparison. Serum samples were analyzed with a comprehensive panel of 1,129 proteomic markers and antimicrobial antibodies.

At time of diagnosis, 47 of the patients with CD (24%) had a complicated phenotype, including stricturing behavior, penetrating behavior, or need for early surgery.

“The unique availability of preclinical samples collected at multiple time points allowed us to examine the sequence of immunological changes and protein biomarkers that occurred before diagnosis,” the investigators wrote. “We also evaluated a wide array of protein biomarkers, utilizing a novel proteomic platform, and applied novel rigorous statistical approaches, which allowed us to discover the potential biomarkers and biologic pathways for the complicated phenotypes even before diagnosis.”

As early as 6 years before diagnosis, patients with complicated CD had significantly higher levels of antimicrobial antibodies than patients with noncomplicated CD, as well as elevations in 22 protein biomarkers indicating immune dysregulation.

Specifically, complicated CD was preceded by elevated anti–Saccharomyces cerevisiae antibodies (ASCA) IgA/IgG, anti-Flagellin antibodies, and other proteins linked with fibrosis, adaptive immunity, and innate immunity. Simultaneously, the same patients had reduced levels of protein biomarkers linked with protection against fibrosis and tissue damage. Network analysis added weight to these findings by demonstrating a significant correlation between ASCA IgA/IgG and protein biomarkers tied to innate immunity and lack of factors for tissue protection.

“Altogether, the hypothesis can be proposed that the combination of increasing levels of inflammatory cytokines, loss of anti-inflammatory proteins, and production of antimicrobial antibodies could accelerate and magnify tissue destruction and fibrosis driving complications at diagnosis in CD,” the investigators wrote. “These data support the concept that complicated CD may not always be the result of the progression of an uncontrolled inflammatory disease but may also be the consequence of a unique pathophysiological process.”

The findings deserve further investigation as they could lead to new clinical tools for screening and intervention. “The serological signature that we identified could help to further select subjects at risk of developing complicated CD who could be preferential candidates for preventative strategies,” investigators wrote.

The investigators disclosed relationships with Janssen, AbbVie, Galapagos, and others.

Changes in proteins and antibodies suggesting immune dysregulation may be detectable in serum years before clinical manifestation of complicated Crohn’s disease, shows a study recently published in Clinical Gastroenterology and Hepatology.

These preclinical signatures could one day play a role in screening for complicated Crohn’s disease (CD) and in mapping underlying disease pathways, potentially opening doors to new preventive approaches, wrote study authors who were led by Joseph A. Murray, MD, of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn.

“Mounting evidence suggests that the diagnosis of CD is preceded by a lengthy asymptomatic preclinical period,” investigators wrote. “Gaining insight into this phase may allow a better understanding of the primary events that lead to its development and offer potential strategies to predict and prevent the disease including its complications.”

The study, which was a nested case-control study based on the PREDICTS study, included 201 patients with CD who had serum samples archived 2, 4, and 6 years prior to diagnosis, as well as 201 healthy controls who provided serum samples for comparison. Serum samples were analyzed with a comprehensive panel of 1,129 proteomic markers and antimicrobial antibodies.

At time of diagnosis, 47 of the patients with CD (24%) had a complicated phenotype, including stricturing behavior, penetrating behavior, or need for early surgery.

“The unique availability of preclinical samples collected at multiple time points allowed us to examine the sequence of immunological changes and protein biomarkers that occurred before diagnosis,” the investigators wrote. “We also evaluated a wide array of protein biomarkers, utilizing a novel proteomic platform, and applied novel rigorous statistical approaches, which allowed us to discover the potential biomarkers and biologic pathways for the complicated phenotypes even before diagnosis.”

As early as 6 years before diagnosis, patients with complicated CD had significantly higher levels of antimicrobial antibodies than patients with noncomplicated CD, as well as elevations in 22 protein biomarkers indicating immune dysregulation.

Specifically, complicated CD was preceded by elevated anti–Saccharomyces cerevisiae antibodies (ASCA) IgA/IgG, anti-Flagellin antibodies, and other proteins linked with fibrosis, adaptive immunity, and innate immunity. Simultaneously, the same patients had reduced levels of protein biomarkers linked with protection against fibrosis and tissue damage. Network analysis added weight to these findings by demonstrating a significant correlation between ASCA IgA/IgG and protein biomarkers tied to innate immunity and lack of factors for tissue protection.

“Altogether, the hypothesis can be proposed that the combination of increasing levels of inflammatory cytokines, loss of anti-inflammatory proteins, and production of antimicrobial antibodies could accelerate and magnify tissue destruction and fibrosis driving complications at diagnosis in CD,” the investigators wrote. “These data support the concept that complicated CD may not always be the result of the progression of an uncontrolled inflammatory disease but may also be the consequence of a unique pathophysiological process.”

The findings deserve further investigation as they could lead to new clinical tools for screening and intervention. “The serological signature that we identified could help to further select subjects at risk of developing complicated CD who could be preferential candidates for preventative strategies,” investigators wrote.

The investigators disclosed relationships with Janssen, AbbVie, Galapagos, and others.

The risk of developing breast cancer in individuals with pathogenic cancer syndrome variants may be less elevated in those without a first-degree family history, according to findings from a large population-based cohort study.

Similar results were seen for patients with Lynch syndrome.

The findings suggest that a first-degree family history confers much of the risk that is associated with pathogenic variants associated with hereditary breast, ovarian, and colorectal cancers. Furthermore, to avoid overtreatment in those without a first-degree family history who undergo genetic testing, that history should be considered when discussing potential follow-up care, the investigators argue.

“This difference in penetrance in carrier individuals, if replicated in larger studies, could be sufficient to justify stratifying just individuals with a family history into high-risk groups currently eligible for specialist clinical care,” Leigh Jackson, PhD, of the University of Exeter College of Medicine and Health, Royal Devon and Exeter Hospital, England, and his colleagues noted.

To assess how population penetrance of familial cancer syndromes varies based on family history, researchers analyzed exome sequences and clinical data collected between March 2006 and June 25, 2021, from 454,712 UK Biobank participants with either breast or colorectal cancer, a self-reported family history of breast or colorectal cancer, and a pathogenic/likely pathogenic variant in the major genes associated with hereditary breast cancer or Lynch syndrome.

After researchers controlled for sex, death, recruitment center, screening, and prophylactic surgery, those with a pathogenic BRCA1 (n = 230) or BRCA2 (n = 611) variant had an increased risk of breast cancer, and the risk was higher in those with a first-degree family history (relative hazard, 10.3 and 7.8, respectively), than in those without a first-degree family history (relative hazard, 7.2 and 4.7), the investigators reported.

Penetrance to age 60 years was also higher in those with vs. without a first-degree family history (44.7% and 24.1% vs 22.8% and 17.9%, respectively).

Similarly, patients with Lynch syndrome and a pathogenic MLH1, MSH2, or MSH6 variant (n = 89, 71, and 421, respectively) had an increased risk of colorectal cancer, and that risk was higher in those with vs. without a family history (relative hazard, 35.6, 48.0, and 9.9 vs. 13.0, 15.4, and 7.2). Penetrance to age 60 was higher for those with a pathogenic MLH1 and MSH2 variant with vs. without a family history (30.9% and 38% vs. 20.5% and 8.3%).

The study results were published online in eClinicalMedicine, part of The Lancet Discovery Science.

“The findings of this study suggest that any universal policy of returning pathogenic cancer predisposing genetic variants found incidentally or through direct-to-consumer genetic testing of asymptomatic individuals should consider family history and other factors when counseling patients on the risks and benefits of follow-up care,” the investigators recommended. “It will be very difficult to counsel individuals as to their particular risk profile without further pedigree construction or investigations.

“If penetrance estimates from affected families are used, there is a danger of overmanagement of asymptomatic individuals with no family history of disease. These ‘patients-in-waiting’ may be exposed to unnecessary surveillance or more invasive prophylactic procedures,” they added.

This study was supported by an MRC grant. The authors reported having no competing interests.

The risk of developing breast cancer in individuals with pathogenic cancer syndrome variants may be less elevated in those without a first-degree family history, according to findings from a large population-based cohort study.

Similar results were seen for patients with Lynch syndrome.

The findings suggest that a first-degree family history confers much of the risk that is associated with pathogenic variants associated with hereditary breast, ovarian, and colorectal cancers. Furthermore, to avoid overtreatment in those without a first-degree family history who undergo genetic testing, that history should be considered when discussing potential follow-up care, the investigators argue.

“This difference in penetrance in carrier individuals, if replicated in larger studies, could be sufficient to justify stratifying just individuals with a family history into high-risk groups currently eligible for specialist clinical care,” Leigh Jackson, PhD, of the University of Exeter College of Medicine and Health, Royal Devon and Exeter Hospital, England, and his colleagues noted.

To assess how population penetrance of familial cancer syndromes varies based on family history, researchers analyzed exome sequences and clinical data collected between March 2006 and June 25, 2021, from 454,712 UK Biobank participants with either breast or colorectal cancer, a self-reported family history of breast or colorectal cancer, and a pathogenic/likely pathogenic variant in the major genes associated with hereditary breast cancer or Lynch syndrome.

After researchers controlled for sex, death, recruitment center, screening, and prophylactic surgery, those with a pathogenic BRCA1 (n = 230) or BRCA2 (n = 611) variant had an increased risk of breast cancer, and the risk was higher in those with a first-degree family history (relative hazard, 10.3 and 7.8, respectively), than in those without a first-degree family history (relative hazard, 7.2 and 4.7), the investigators reported.

Penetrance to age 60 years was also higher in those with vs. without a first-degree family history (44.7% and 24.1% vs 22.8% and 17.9%, respectively).

Similarly, patients with Lynch syndrome and a pathogenic MLH1, MSH2, or MSH6 variant (n = 89, 71, and 421, respectively) had an increased risk of colorectal cancer, and that risk was higher in those with vs. without a family history (relative hazard, 35.6, 48.0, and 9.9 vs. 13.0, 15.4, and 7.2). Penetrance to age 60 was higher for those with a pathogenic MLH1 and MSH2 variant with vs. without a family history (30.9% and 38% vs. 20.5% and 8.3%).

The study results were published online in eClinicalMedicine, part of The Lancet Discovery Science.

“The findings of this study suggest that any universal policy of returning pathogenic cancer predisposing genetic variants found incidentally or through direct-to-consumer genetic testing of asymptomatic individuals should consider family history and other factors when counseling patients on the risks and benefits of follow-up care,” the investigators recommended. “It will be very difficult to counsel individuals as to their particular risk profile without further pedigree construction or investigations.

“If penetrance estimates from affected families are used, there is a danger of overmanagement of asymptomatic individuals with no family history of disease. These ‘patients-in-waiting’ may be exposed to unnecessary surveillance or more invasive prophylactic procedures,” they added.

This study was supported by an MRC grant. The authors reported having no competing interests.

The risk of developing breast cancer in individuals with pathogenic cancer syndrome variants may be less elevated in those without a first-degree family history, according to findings from a large population-based cohort study.

Similar results were seen for patients with Lynch syndrome.

The findings suggest that a first-degree family history confers much of the risk that is associated with pathogenic variants associated with hereditary breast, ovarian, and colorectal cancers. Furthermore, to avoid overtreatment in those without a first-degree family history who undergo genetic testing, that history should be considered when discussing potential follow-up care, the investigators argue.

“This difference in penetrance in carrier individuals, if replicated in larger studies, could be sufficient to justify stratifying just individuals with a family history into high-risk groups currently eligible for specialist clinical care,” Leigh Jackson, PhD, of the University of Exeter College of Medicine and Health, Royal Devon and Exeter Hospital, England, and his colleagues noted.

To assess how population penetrance of familial cancer syndromes varies based on family history, researchers analyzed exome sequences and clinical data collected between March 2006 and June 25, 2021, from 454,712 UK Biobank participants with either breast or colorectal cancer, a self-reported family history of breast or colorectal cancer, and a pathogenic/likely pathogenic variant in the major genes associated with hereditary breast cancer or Lynch syndrome.

After researchers controlled for sex, death, recruitment center, screening, and prophylactic surgery, those with a pathogenic BRCA1 (n = 230) or BRCA2 (n = 611) variant had an increased risk of breast cancer, and the risk was higher in those with a first-degree family history (relative hazard, 10.3 and 7.8, respectively), than in those without a first-degree family history (relative hazard, 7.2 and 4.7), the investigators reported.

Penetrance to age 60 years was also higher in those with vs. without a first-degree family history (44.7% and 24.1% vs 22.8% and 17.9%, respectively).

Similarly, patients with Lynch syndrome and a pathogenic MLH1, MSH2, or MSH6 variant (n = 89, 71, and 421, respectively) had an increased risk of colorectal cancer, and that risk was higher in those with vs. without a family history (relative hazard, 35.6, 48.0, and 9.9 vs. 13.0, 15.4, and 7.2). Penetrance to age 60 was higher for those with a pathogenic MLH1 and MSH2 variant with vs. without a family history (30.9% and 38% vs. 20.5% and 8.3%).

The study results were published online in eClinicalMedicine, part of The Lancet Discovery Science.

“The findings of this study suggest that any universal policy of returning pathogenic cancer predisposing genetic variants found incidentally or through direct-to-consumer genetic testing of asymptomatic individuals should consider family history and other factors when counseling patients on the risks and benefits of follow-up care,” the investigators recommended. “It will be very difficult to counsel individuals as to their particular risk profile without further pedigree construction or investigations.

“If penetrance estimates from affected families are used, there is a danger of overmanagement of asymptomatic individuals with no family history of disease. These ‘patients-in-waiting’ may be exposed to unnecessary surveillance or more invasive prophylactic procedures,” they added.

This study was supported by an MRC grant. The authors reported having no competing interests.

The European Commission has authorized the marketing of ritlecitinib to treat adults and adolescents 12 years of age and older with severe alopecia areata. This makes ritlecitinib the first medicine authorized by the EC to treat individuals with severe alopecia areata as young as 12 years of age.

Taken as a once-daily pill, ritlecitinib is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3. In June of 2023, the drug received FDA approval for the treatment of severe alopecia areata in people ages 12 and older in the United States.

According to a press release from Pfizer, which developed the drug, EC approval was based on the pivotal ALLEGRO clinical trial program, which included the ALLEGRO phase 2b/3 study that evaluated ritlecitinib in patients aged 12 years and older with alopecia areata with 50% or more scalp hair loss, including patients with alopecia totalis (total scalp hair loss) and alopecia universalis (total body hair loss). Results from this study showed that 13.4% of adults and adolescents achieved 90% or more scalp hair coverage (Severity of Alopecia Tool score of 10 or less) after 24 weeks of treatment with ritlecitinib 50 mg, compared with 1.5% of those on placebo.

The study also measured Patient Global Impression of Change (PGI-C). At week 24, 49.2% of participants treated with ritlecitinib reported a PGI-C response of “moderate” to “great” improvement in their alopecia areata, compared with 9.2% with placebo.

According to results from an ongoing, long-term phase 3 study of ritlecitinib known as ALLEGRO-LT, the most common adverse reactions reported from use of the drug included diarrhea (9.2%), acne (6.2%), upper respiratory tract infections (6.2%), urticaria (4.6%), rash (3.8%), folliculitis (3.1%), and dizziness (2.3%), the company press release said.





 

The European Commission has authorized the marketing of ritlecitinib to treat adults and adolescents 12 years of age and older with severe alopecia areata. This makes ritlecitinib the first medicine authorized by the EC to treat individuals with severe alopecia areata as young as 12 years of age.

Taken as a once-daily pill, ritlecitinib is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3. In June of 2023, the drug received FDA approval for the treatment of severe alopecia areata in people ages 12 and older in the United States.

According to a press release from Pfizer, which developed the drug, EC approval was based on the pivotal ALLEGRO clinical trial program, which included the ALLEGRO phase 2b/3 study that evaluated ritlecitinib in patients aged 12 years and older with alopecia areata with 50% or more scalp hair loss, including patients with alopecia totalis (total scalp hair loss) and alopecia universalis (total body hair loss). Results from this study showed that 13.4% of adults and adolescents achieved 90% or more scalp hair coverage (Severity of Alopecia Tool score of 10 or less) after 24 weeks of treatment with ritlecitinib 50 mg, compared with 1.5% of those on placebo.

The study also measured Patient Global Impression of Change (PGI-C). At week 24, 49.2% of participants treated with ritlecitinib reported a PGI-C response of “moderate” to “great” improvement in their alopecia areata, compared with 9.2% with placebo.

According to results from an ongoing, long-term phase 3 study of ritlecitinib known as ALLEGRO-LT, the most common adverse reactions reported from use of the drug included diarrhea (9.2%), acne (6.2%), upper respiratory tract infections (6.2%), urticaria (4.6%), rash (3.8%), folliculitis (3.1%), and dizziness (2.3%), the company press release said.





 

The European Commission has authorized the marketing of ritlecitinib to treat adults and adolescents 12 years of age and older with severe alopecia areata. This makes ritlecitinib the first medicine authorized by the EC to treat individuals with severe alopecia areata as young as 12 years of age.

Taken as a once-daily pill, ritlecitinib is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3. In June of 2023, the drug received FDA approval for the treatment of severe alopecia areata in people ages 12 and older in the United States.

According to a press release from Pfizer, which developed the drug, EC approval was based on the pivotal ALLEGRO clinical trial program, which included the ALLEGRO phase 2b/3 study that evaluated ritlecitinib in patients aged 12 years and older with alopecia areata with 50% or more scalp hair loss, including patients with alopecia totalis (total scalp hair loss) and alopecia universalis (total body hair loss). Results from this study showed that 13.4% of adults and adolescents achieved 90% or more scalp hair coverage (Severity of Alopecia Tool score of 10 or less) after 24 weeks of treatment with ritlecitinib 50 mg, compared with 1.5% of those on placebo.

The study also measured Patient Global Impression of Change (PGI-C). At week 24, 49.2% of participants treated with ritlecitinib reported a PGI-C response of “moderate” to “great” improvement in their alopecia areata, compared with 9.2% with placebo.

According to results from an ongoing, long-term phase 3 study of ritlecitinib known as ALLEGRO-LT, the most common adverse reactions reported from use of the drug included diarrhea (9.2%), acne (6.2%), upper respiratory tract infections (6.2%), urticaria (4.6%), rash (3.8%), folliculitis (3.1%), and dizziness (2.3%), the company press release said.





 

Recorded Aug. 26, 2023. This transcript has been edited for clarity.

Robert A. Harrington, MD: I’m here with my good friend, Manesh Patel, from Duke University. We’re at the European Society of Cardiology (ESC) congress in Amsterdam, and I pulled Manesh into the studio for a conversation about something that’s really topical right now: sudden cardiac death in athletes.

What I hope to do [in this interview] is really pick Manesh’s brain on how we are thinking about this. Are we going to think about treatment issues? Are we going to think about prevention issues? Are we thinking about screening? We’ll try to make it practical.

Dr. Manesh Patel is chief of cardiovascular medicine at Duke University and also the director of the Duke Heart Center. Manesh, thanks for joining me here.
 

Bronny James and Damar Hamlin

Manesh R. Patel, MD: Excited to be here, Bob. Always.

Harrington: [Recently,] a news article comes out about the cause of Bronny James’ sudden cardiac death. Let me put this into a bigger societal context.

Last winter, Damar Hamlin, from the Buffalo Bills, suffered a traumatic injury on the field, and with that, had cardiac arrest. He’s back playing football – great to see. You and I are involved with the American Heart Association. He’s been very supportive of our efforts around things like CPR. He’s been terrific. It’s great to see him playing.

We know a little less about Bronny James. The news articles say the cause is both functional and anatomical, and it seems to be congenital, but we don’t have any details beyond this. Let’s not focus on the people; let’s focus on the topic.

Patel: I’m excited that we’re having the conversation. First and foremost, we’re excited that, with what we’ve seen on a national stage, these two individuals are doing well. They survived sudden cardiac death, which is a testament to all the things that we’ll talk about.

There are many important questions, like, is this increasing? Is this something we can prevent? And what are those things that might be happening to athletes?

Harrington: Can we predict it?

Patel: Right. I think the idea of sudden cardiac death in athletes is really a critical one for us to think about because it does concern participation and what we think about that. There are many experts who’ve been studying this for years that I now get to work with.

Harrington: Tell us a little bit about the kind of things you’ve been doing in this area.

Patel: Even before these events in the COVID era, we were wondering about athletes getting myocarditis, just in general, what do we know about that? People like Aaron Baggish, Kim Harmon, Jonathan Drezner, and others have been studying this.

Harrington: You and I did a show on athletes and COVID-19.

Patel: With the American Heart Association (AHA), the Cornell Foundation, and others, we started the Outcomes Registry for Cardiac Conditions in Athletes (ORCCA). This registry is across the United States, and athletes can sign up.

Harrington: Is it voluntary? Do the schools sign them up?

Patel: The athletes sign up. Team trainers and doctors talk to the athletes. We don’t really know the risks of some of these conditions. There’s a lot of gray area – people with certain conditions that were really interesting; aortas that are dilated in tall people.

Harrington: Long QT.

Patel: Long QT. There are certainly things that we know we should be intervening on and others where participation is a question. All of these we are trying to longitudinally put into the registry and follow them over time.

The second thing is understanding from the last Bethesda Conference that we want shared decision-making. There are going to be conditions where you say, “Look, I think your risk is high. You’ve a family history of sudden cardiac death. You have arrhythmias while you’re exercising.”

Harrington: You have a big, thick heart.

Patel: If you have hypertrophic cardiomyopathy, whether you’re an athlete or a 40-year-old adult, we’re going to have the same conversation. I think that holds. There’s a variety or a spectrum where we don’t know. I think the registry is one big step.

Thinking back to when somebody has an event, I would say take the teachable moment with the AHA and others to make sure your communities and your areas have automated external defibrillators (AEDs) and CPR training, and that we get to 100%: 100% response, 100% CPR, 100% defibrillation. I think that’s the first step.
 

Chain of survival

Harrington: Let’s really focus on the chain of survival. It is a chain: If any link is broken, your chance of survival really drops. We’ve had some well-known cases within our AHA community, including somebody who talks about it regularly: Kevin Volpp, from the University of Pennsylvania, a health economist. He had almost the perfect chain of survival. He had sudden cardiac death in a restaurant that was immediately observed, CPR started, EMTs called, and AED on the scene. Impressive.

Patel: That was in Cincinnati, where there are communities that have really worked on these things. I think you’re right. The chain of survival with rapid CPR to build a nation of survivors is key. The people at the AHA are helping us do this; there is a national call to make sure CPR is something that people feel comfortable doing. That they do it in men and women. They do it for anyone that goes down. And realize that it’s CPR that is hands-only. I think that’s an important lesson from Damar’s work, Nancy Brown’s, and AHA’s. Actually, schools in many countries require that to get through primary school.

Harrington: CPR training is a requirement to graduate from high school in some states.

Patel: My son just graduated from high school, and we spent time at his school making sure that everybody had access to CPR training. I think the way to do this is to start with that. Now, getting more specific about teams and athletes, I think most have emergency action plans, but it’s having action plans that work because of where you are and where the AED locations might be, or what the sport is. Having a plan on how you’re going to get that athlete to a place where you can help them recover is an important piece.

From there, I think the conversation for us is about what can we do as a society and as a country to answer some critical questions, including some real-world questions that people are asking: We had COVID-19 and we’re hearing these cases. Is this going up or down, and are these related?

Soon, hopefully the same group I talked about and others will have a publication, working with the NCAA to look at all of the deaths that they observed in NCAA Division I athletes over 20 years, including the sudden cardiac deaths. I won’t share the results because the publication isn’t out, but I think that’s the kind of important information that will help us understand if these rates are going up or down.

Harrington: What’s associated with that risk? Then we can start getting at whether it is something that, when we’re doing assessment for suitability for sports, has risk factors that should warrant more investigation.

Patel: Much like the field of cardiology, we haven’t enough of an evidence base, the right technologies, or the studies to determine how we should do screening, or not screening, across the board. Again, there is variation. There are some countries where anyone participating is going to get an ECG and an echocardiogram. There are other countries, like the United States, where it’s going to be a bit dependent on athlete risk.

Harrington: And where you live.

Patel: And where you live. Unfortunately, again, that brings in the idea that it might not be equitable in how we’re evaluating these individuals. I do think the opportunity to start to standardize that evaluation exists, and it likely comes from the ability to look back and say, “Here are some higher-risk individuals or some higher-risk scenarios.”

Harrington: Isn’t this what we do all the time in clinical medicine?

Patel: It’s going to be applied to a population that maybe is not as studied. I said this to you before we came on. The other thing is to make sure that the shared decision-making allows athletes who feel like they have a chance or want to play. During COVID, we had many college athletes, high school athletes, and kids not able to participate in sports. There was significant depression, feeling of loneliness, and even physical loss. People were actually getting less conditioned quickly. There’s a great benefit to sports participation.

Harrington: We were extrapolating from older data. If I’ve just had this new infection, COVID, and I’ve maybe got some signs of it in my heart, why can’t I exercise? That’s extrapolating from old myocarditis data.

Patel: We’re having to learn and follow it. I think there’s value in following that and getting those data. The second thing I think is really valuable is that we’ve shown that these individuals, if you do have these conversations and follow them, can participate and can be part of understanding the risk just like anything else.

Harrington: Is it sport specific? Are there some sports where maybe the conversation should be a little more intense than in other sports?

Patel: I think what we’ll see is that the conversations may be sport specific, and some may concern the number of athletes tested. At times, it’s pretty complicated. It does look like there are, as you know, different weight-bearing performance athletes, endurance athletes, or what I’ll call burst sports. There will probably be data that will identify certain sports where we may need to pay a bit more attention.

Harrington: What about the contact issues? Damar had a very specific thing, we think, happen to him. Football is a violent, contact-oriented sport, but fortunately we don’t regularly see what happened to Damar.

Patel: We’re talking about sudden cardiac death, but obviously, contact issues and neurologic evaluation is a whole other topic. That’s another big issue that I know many are following, and the NCAA is carefully, too. For Damar, I think we know that it was commotio cordis. At least when that happens, when there’s a ball or a trauma to the chest, those things have to be timed just so to actually lead to this event. Thankfully, it’s not very frequent, but it can happen.

Harrington: Hockey pucks, baseballs, soccer balls, a helmet to the chest ...

Patel: You have to be in a specific cycle of the squeeze. We don’t see that very frequently. I do think the evaluation and treatment, hopefully, makes a difference. One thing that we’re evolving in the screening world is our imaging; it’s getting better. We are not just doing echocardiograms; we are able to do other studies. There’s a mix of imaging and other technologies.

Is screening the answer?

Harrington: Let’s talk about that because screening is the area, I would say, with the most controversy – and a large amount of emotional controversy. Some argue that the data are not good enough to screen, or doctors are saying, “Wait a minute, why are we screening all these kids?” You said you were at your son’s high school doing CPR training. How many athletes are at his high school? There are many, and that’s a pretty small high school. Big communities, big universities, and the professional sports can afford it. Should we be doing this at the community level?

Patel: There have been some data. The Italians have done standard screening for some time, and it’s shown us that if you did echocardiograms in many individuals, you do find some cases that are hypertrophic cardiomyopathy in pathology. The issue is just how much you have to do and the resource utilization. I think as we get to a world where screening studies can happen with smaller technology and AI, that can be democratizing in how we get to athletes.

Harrington: Give an example of that. We were talking outside, you and I, about some of the new stethoscope technology.

Patel: Yes, stethoscopes are going to be one of the examples. We have stethoscopes that have the ability to get sounds and ECG signals, or at least some lead signals.

Harrington: Yes.

Patel: Potentially you can imagine that sound and ECG tracing in an AI environment, at least getting you from “everyone gets a listen with one stethoscope in their gym from their coach,” and it goes to the cloud. When there are enough questions, these are the ones that have to go further. Now, that’s a big study that has to be carried out; I’m not in any way saying we should do that.

Harrington: The technology is coming.

Patel: We start to see that our ability to rapidly do something to meet our athletes or our patients where they are will happen soon. Remember that the performance curve can vary, but once you have a sound where you can start to say that this is a regular flow murmur vs. “I’m worried about this,” especially as you mark it with ECG – that’s one example.

Smaller imaging is another example. For many years, ECGs have been talked about. There are entire courses that we run looking at ECGs in athletes. Remembering that Aaron Baggish and others are publishing that these individuals are large. When we look at their hearts, we see that they’re large, but when you adjust for size, often you can identify that many of them are within what we think are normal. Structurally, there are still many cases where you look at hearts and you’re asking, “Is this a thick heart? Is this noncompaction? Is this some pathology?”

That’s where you need imaging expertise. I think you have to have those individuals. I’m not advocating screening. I’m advocating studying it and that we should be thinking about the population. I don’t see a world where we don’t eventually start to really look to prevent those.

Harrington: Right. Whether it’s understanding that there are certain risk factors associated with this and we have to dedicate screening resources to those individuals, or if we want to do it more broadly on the population level to understand this with deeper dives into certain individuals, we’ve got to study it.

Patel: Some of the experts in sports medicine and sports cardiology have been collecting these data for a while. It’s time that we are there, because with these events we have the opportunity to share more of these data and maybe raise awareness – not in the teachable moment only – to get others to contribute.

I do believe that long term there’s an opportunity. We’ve seen that. We see that the rates, unfortunately, for marathon runners, where people unfortunately have events, seem to be higher. And we’ve seen the studies on troponin leaks in these individuals or evidence that there’s some effect on the heart from these events. We want people to be able to be long-term healthy.
 

Early defibrillation

Harrington: A large amount of work needs to be done. We talked with regard to screening, we’ve talked about CPR. We really need to have a nation of people who can do hands-only CPR. Let’s talk about AEDs, another key part of the chain of survival.

Patel: We have another important study going on, but an important message first: AEDs are critical to survival. We know that CPR is critical, but so is getting people to a defibrillator.

Harrington: Early defibrillation.

Patel: Early defibrillation. Early CPR is one of the biggest markers of making sure we perfuse people to get to early defibrillation, but then you have to get early defibrillation. There’s been a huge push in many communities, again, along with AHA and others, to make sure that AEDs are available not only in the U.S. but around the world. We’re at ESC and we see the push around the world to get AEDs available. They’ve come down in size and come down in cost, and that’s made it much more accessible. That’s really good. They’re still not always there.

We’ve seen really interesting randomized studies with people in some European countries where they have certain areas, just because of the locations, where bystanders will help get an AED  vs. randomizing to the EMS truck. They seem better in some of those variations. Chris Granger, at our institution, with Monique Starks, Dan Mark, and others, is doing a study in North Carolina where we’re testing different ways to potentially get AEDs in communities. We’re randomizing counties to one or two ways of getting AEDs to those individuals.

Harrington: Can you have an app where you just click “Find me an AED”?

Patel: Is there a world where the AED is found or is something bringing you the AED? Are there drones? Are there people driving? Are there ways that an AED is brought to the scene? All of those are going to be critical. It starts with continuing to figure out ways to support the costs of getting AEDs in places. The technology is continuing to evolve.

Harrington: It really is the premedical system stuff that makes the difference. Once EMS arrives with trained individuals who can defibrillate, they can transport you to a medical facility where trained physicians are at. It’s that pre-EMS thing that is so critical.

Patel: We talk often about athletes, but cardiac arrest care in general, and the chain of survival with CPR and AEDs, is critical. I still see patients in the CICU at Duke where, unfortunately, the biggest driver, as you just highlighted in that chain of survival, is how rapid we were in that golden hour. In the first 15 minutes, are you getting CPR, are you getting AED? Are you getting to a system?

Harrington: Are you getting a rapid transport?

Patel: Are you getting a neurologic assessment? Are you getting cooled or not? Those are important things.

Harrington: All right. Let’s try to wrap this up. Teachable moments, we talked about. One of the things about cases in prominent athletes is that it makes it to the newspaper and then it raises awareness. There is a drawing inference from a small group of cases to the broader societal issues. That’s an important topic.

We’ve talked about possible screening options, identifying at-risk individuals and high-risk individuals. A large amount of data has already been accumulated, but there is more work to be done. We focused on how to use those teachable moments to really influence the chain of survival, not just for athletes but for society at large.

I love your point about the Bethesda Conference on shared decision-making. Like with everything else, we have to have that two-way conversation: What are the athlete’s goals, hopes, and aspirations?

Patel: That group of experts, in addition to shared decision-making, gave us a whole list of conditions that we should be aware of and the cutpoints of where we think normal and not normal live for athletes. I think that’s used by many.

Can we build our systems to make research happen faster for the individuals? These athletes are at colleges that are obviously doing so much to make sure they’re okay. The people who are helping with this registry, and others, are going to continue to work to ask whether we can engage them as citizen participants and scientists. I think athletes are going to become some of our best advocates for why you’d want to know about yourself and how to perform CPR.

Harrington: I love the concept of citizen scientists, that we all have an obligation to contribute to the evidence base because we all want to use that evidence.

This has been a terrific conversation. I’ve been joined by my good friend, Dr. Manesh Patel from Duke University. I hope you’ve enjoyed our discussion here at the ESC. We have been taking a little break from the science going on around us to talk about sudden cardiac death in athletes. It really does have implications for broader societal concepts.

Dr. Harrington is the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine and provost for medical affairs of Cornell University, New York, as well as a former president of the American Heart Association. He has disclosed the following relevant financial relationships: Research relationships with Baim Institute (DSMB); CSL (RCT executive committee); Janssen (RCT chair); National Heart, Lung, and Blood Institute (RCT executive committee, DSMB chair); Patient-Centered Outcomes Research Institute (RCT co-chair); Duke Clinical Research Institute. Consulting relationships with Atropos Health; Bitterroot Bio; Bristol Myers Squibb; BridgeBio; Element Science; Edwards Lifesciences; Foresite Labs; Medscape/WebMD Board of Directors for: American Heart Association; College of the Holy Cross; Cytokinetics. Dr. Patel is professor of medicine, Duke University; chief, division of cardiology; director, Duke Heart Center, Duke University Medical Center, Durham, N.C. He has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, adviser, consultant, or trustee for Bayer; Janssen; Novartis (consultant). Received research grant from Bayer; Janssen.

A version of this article appeared on Medscape.com.

Recorded Aug. 26, 2023. This transcript has been edited for clarity.

Robert A. Harrington, MD: I’m here with my good friend, Manesh Patel, from Duke University. We’re at the European Society of Cardiology (ESC) congress in Amsterdam, and I pulled Manesh into the studio for a conversation about something that’s really topical right now: sudden cardiac death in athletes.

What I hope to do [in this interview] is really pick Manesh’s brain on how we are thinking about this. Are we going to think about treatment issues? Are we going to think about prevention issues? Are we thinking about screening? We’ll try to make it practical.

Dr. Manesh Patel is chief of cardiovascular medicine at Duke University and also the director of the Duke Heart Center. Manesh, thanks for joining me here.
 

Bronny James and Damar Hamlin

Manesh R. Patel, MD: Excited to be here, Bob. Always.

Harrington: [Recently,] a news article comes out about the cause of Bronny James’ sudden cardiac death. Let me put this into a bigger societal context.

Last winter, Damar Hamlin, from the Buffalo Bills, suffered a traumatic injury on the field, and with that, had cardiac arrest. He’s back playing football – great to see. You and I are involved with the American Heart Association. He’s been very supportive of our efforts around things like CPR. He’s been terrific. It’s great to see him playing.

We know a little less about Bronny James. The news articles say the cause is both functional and anatomical, and it seems to be congenital, but we don’t have any details beyond this. Let’s not focus on the people; let’s focus on the topic.

Patel: I’m excited that we’re having the conversation. First and foremost, we’re excited that, with what we’ve seen on a national stage, these two individuals are doing well. They survived sudden cardiac death, which is a testament to all the things that we’ll talk about.

There are many important questions, like, is this increasing? Is this something we can prevent? And what are those things that might be happening to athletes?

Harrington: Can we predict it?

Patel: Right. I think the idea of sudden cardiac death in athletes is really a critical one for us to think about because it does concern participation and what we think about that. There are many experts who’ve been studying this for years that I now get to work with.

Harrington: Tell us a little bit about the kind of things you’ve been doing in this area.

Patel: Even before these events in the COVID era, we were wondering about athletes getting myocarditis, just in general, what do we know about that? People like Aaron Baggish, Kim Harmon, Jonathan Drezner, and others have been studying this.

Harrington: You and I did a show on athletes and COVID-19.

Patel: With the American Heart Association (AHA), the Cornell Foundation, and others, we started the Outcomes Registry for Cardiac Conditions in Athletes (ORCCA). This registry is across the United States, and athletes can sign up.

Harrington: Is it voluntary? Do the schools sign them up?

Patel: The athletes sign up. Team trainers and doctors talk to the athletes. We don’t really know the risks of some of these conditions. There’s a lot of gray area – people with certain conditions that were really interesting; aortas that are dilated in tall people.

Harrington: Long QT.

Patel: Long QT. There are certainly things that we know we should be intervening on and others where participation is a question. All of these we are trying to longitudinally put into the registry and follow them over time.

The second thing is understanding from the last Bethesda Conference that we want shared decision-making. There are going to be conditions where you say, “Look, I think your risk is high. You’ve a family history of sudden cardiac death. You have arrhythmias while you’re exercising.”

Harrington: You have a big, thick heart.

Patel: If you have hypertrophic cardiomyopathy, whether you’re an athlete or a 40-year-old adult, we’re going to have the same conversation. I think that holds. There’s a variety or a spectrum where we don’t know. I think the registry is one big step.

Thinking back to when somebody has an event, I would say take the teachable moment with the AHA and others to make sure your communities and your areas have automated external defibrillators (AEDs) and CPR training, and that we get to 100%: 100% response, 100% CPR, 100% defibrillation. I think that’s the first step.
 

Chain of survival

Harrington: Let’s really focus on the chain of survival. It is a chain: If any link is broken, your chance of survival really drops. We’ve had some well-known cases within our AHA community, including somebody who talks about it regularly: Kevin Volpp, from the University of Pennsylvania, a health economist. He had almost the perfect chain of survival. He had sudden cardiac death in a restaurant that was immediately observed, CPR started, EMTs called, and AED on the scene. Impressive.

Patel: That was in Cincinnati, where there are communities that have really worked on these things. I think you’re right. The chain of survival with rapid CPR to build a nation of survivors is key. The people at the AHA are helping us do this; there is a national call to make sure CPR is something that people feel comfortable doing. That they do it in men and women. They do it for anyone that goes down. And realize that it’s CPR that is hands-only. I think that’s an important lesson from Damar’s work, Nancy Brown’s, and AHA’s. Actually, schools in many countries require that to get through primary school.

Harrington: CPR training is a requirement to graduate from high school in some states.

Patel: My son just graduated from high school, and we spent time at his school making sure that everybody had access to CPR training. I think the way to do this is to start with that. Now, getting more specific about teams and athletes, I think most have emergency action plans, but it’s having action plans that work because of where you are and where the AED locations might be, or what the sport is. Having a plan on how you’re going to get that athlete to a place where you can help them recover is an important piece.

From there, I think the conversation for us is about what can we do as a society and as a country to answer some critical questions, including some real-world questions that people are asking: We had COVID-19 and we’re hearing these cases. Is this going up or down, and are these related?

Soon, hopefully the same group I talked about and others will have a publication, working with the NCAA to look at all of the deaths that they observed in NCAA Division I athletes over 20 years, including the sudden cardiac deaths. I won’t share the results because the publication isn’t out, but I think that’s the kind of important information that will help us understand if these rates are going up or down.

Harrington: What’s associated with that risk? Then we can start getting at whether it is something that, when we’re doing assessment for suitability for sports, has risk factors that should warrant more investigation.

Patel: Much like the field of cardiology, we haven’t enough of an evidence base, the right technologies, or the studies to determine how we should do screening, or not screening, across the board. Again, there is variation. There are some countries where anyone participating is going to get an ECG and an echocardiogram. There are other countries, like the United States, where it’s going to be a bit dependent on athlete risk.

Harrington: And where you live.

Patel: And where you live. Unfortunately, again, that brings in the idea that it might not be equitable in how we’re evaluating these individuals. I do think the opportunity to start to standardize that evaluation exists, and it likely comes from the ability to look back and say, “Here are some higher-risk individuals or some higher-risk scenarios.”

Harrington: Isn’t this what we do all the time in clinical medicine?

Patel: It’s going to be applied to a population that maybe is not as studied. I said this to you before we came on. The other thing is to make sure that the shared decision-making allows athletes who feel like they have a chance or want to play. During COVID, we had many college athletes, high school athletes, and kids not able to participate in sports. There was significant depression, feeling of loneliness, and even physical loss. People were actually getting less conditioned quickly. There’s a great benefit to sports participation.

Harrington: We were extrapolating from older data. If I’ve just had this new infection, COVID, and I’ve maybe got some signs of it in my heart, why can’t I exercise? That’s extrapolating from old myocarditis data.

Patel: We’re having to learn and follow it. I think there’s value in following that and getting those data. The second thing I think is really valuable is that we’ve shown that these individuals, if you do have these conversations and follow them, can participate and can be part of understanding the risk just like anything else.

Harrington: Is it sport specific? Are there some sports where maybe the conversation should be a little more intense than in other sports?

Patel: I think what we’ll see is that the conversations may be sport specific, and some may concern the number of athletes tested. At times, it’s pretty complicated. It does look like there are, as you know, different weight-bearing performance athletes, endurance athletes, or what I’ll call burst sports. There will probably be data that will identify certain sports where we may need to pay a bit more attention.

Harrington: What about the contact issues? Damar had a very specific thing, we think, happen to him. Football is a violent, contact-oriented sport, but fortunately we don’t regularly see what happened to Damar.

Patel: We’re talking about sudden cardiac death, but obviously, contact issues and neurologic evaluation is a whole other topic. That’s another big issue that I know many are following, and the NCAA is carefully, too. For Damar, I think we know that it was commotio cordis. At least when that happens, when there’s a ball or a trauma to the chest, those things have to be timed just so to actually lead to this event. Thankfully, it’s not very frequent, but it can happen.

Harrington: Hockey pucks, baseballs, soccer balls, a helmet to the chest ...

Patel: You have to be in a specific cycle of the squeeze. We don’t see that very frequently. I do think the evaluation and treatment, hopefully, makes a difference. One thing that we’re evolving in the screening world is our imaging; it’s getting better. We are not just doing echocardiograms; we are able to do other studies. There’s a mix of imaging and other technologies.

Is screening the answer?

Harrington: Let’s talk about that because screening is the area, I would say, with the most controversy – and a large amount of emotional controversy. Some argue that the data are not good enough to screen, or doctors are saying, “Wait a minute, why are we screening all these kids?” You said you were at your son’s high school doing CPR training. How many athletes are at his high school? There are many, and that’s a pretty small high school. Big communities, big universities, and the professional sports can afford it. Should we be doing this at the community level?

Patel: There have been some data. The Italians have done standard screening for some time, and it’s shown us that if you did echocardiograms in many individuals, you do find some cases that are hypertrophic cardiomyopathy in pathology. The issue is just how much you have to do and the resource utilization. I think as we get to a world where screening studies can happen with smaller technology and AI, that can be democratizing in how we get to athletes.

Harrington: Give an example of that. We were talking outside, you and I, about some of the new stethoscope technology.

Patel: Yes, stethoscopes are going to be one of the examples. We have stethoscopes that have the ability to get sounds and ECG signals, or at least some lead signals.

Harrington: Yes.

Patel: Potentially you can imagine that sound and ECG tracing in an AI environment, at least getting you from “everyone gets a listen with one stethoscope in their gym from their coach,” and it goes to the cloud. When there are enough questions, these are the ones that have to go further. Now, that’s a big study that has to be carried out; I’m not in any way saying we should do that.

Harrington: The technology is coming.

Patel: We start to see that our ability to rapidly do something to meet our athletes or our patients where they are will happen soon. Remember that the performance curve can vary, but once you have a sound where you can start to say that this is a regular flow murmur vs. “I’m worried about this,” especially as you mark it with ECG – that’s one example.

Smaller imaging is another example. For many years, ECGs have been talked about. There are entire courses that we run looking at ECGs in athletes. Remembering that Aaron Baggish and others are publishing that these individuals are large. When we look at their hearts, we see that they’re large, but when you adjust for size, often you can identify that many of them are within what we think are normal. Structurally, there are still many cases where you look at hearts and you’re asking, “Is this a thick heart? Is this noncompaction? Is this some pathology?”

That’s where you need imaging expertise. I think you have to have those individuals. I’m not advocating screening. I’m advocating studying it and that we should be thinking about the population. I don’t see a world where we don’t eventually start to really look to prevent those.

Harrington: Right. Whether it’s understanding that there are certain risk factors associated with this and we have to dedicate screening resources to those individuals, or if we want to do it more broadly on the population level to understand this with deeper dives into certain individuals, we’ve got to study it.

Patel: Some of the experts in sports medicine and sports cardiology have been collecting these data for a while. It’s time that we are there, because with these events we have the opportunity to share more of these data and maybe raise awareness – not in the teachable moment only – to get others to contribute.

I do believe that long term there’s an opportunity. We’ve seen that. We see that the rates, unfortunately, for marathon runners, where people unfortunately have events, seem to be higher. And we’ve seen the studies on troponin leaks in these individuals or evidence that there’s some effect on the heart from these events. We want people to be able to be long-term healthy.
 

Early defibrillation

Harrington: A large amount of work needs to be done. We talked with regard to screening, we’ve talked about CPR. We really need to have a nation of people who can do hands-only CPR. Let’s talk about AEDs, another key part of the chain of survival.

Patel: We have another important study going on, but an important message first: AEDs are critical to survival. We know that CPR is critical, but so is getting people to a defibrillator.

Harrington: Early defibrillation.

Patel: Early defibrillation. Early CPR is one of the biggest markers of making sure we perfuse people to get to early defibrillation, but then you have to get early defibrillation. There’s been a huge push in many communities, again, along with AHA and others, to make sure that AEDs are available not only in the U.S. but around the world. We’re at ESC and we see the push around the world to get AEDs available. They’ve come down in size and come down in cost, and that’s made it much more accessible. That’s really good. They’re still not always there.

We’ve seen really interesting randomized studies with people in some European countries where they have certain areas, just because of the locations, where bystanders will help get an AED  vs. randomizing to the EMS truck. They seem better in some of those variations. Chris Granger, at our institution, with Monique Starks, Dan Mark, and others, is doing a study in North Carolina where we’re testing different ways to potentially get AEDs in communities. We’re randomizing counties to one or two ways of getting AEDs to those individuals.

Harrington: Can you have an app where you just click “Find me an AED”?

Patel: Is there a world where the AED is found or is something bringing you the AED? Are there drones? Are there people driving? Are there ways that an AED is brought to the scene? All of those are going to be critical. It starts with continuing to figure out ways to support the costs of getting AEDs in places. The technology is continuing to evolve.

Harrington: It really is the premedical system stuff that makes the difference. Once EMS arrives with trained individuals who can defibrillate, they can transport you to a medical facility where trained physicians are at. It’s that pre-EMS thing that is so critical.

Patel: We talk often about athletes, but cardiac arrest care in general, and the chain of survival with CPR and AEDs, is critical. I still see patients in the CICU at Duke where, unfortunately, the biggest driver, as you just highlighted in that chain of survival, is how rapid we were in that golden hour. In the first 15 minutes, are you getting CPR, are you getting AED? Are you getting to a system?

Harrington: Are you getting a rapid transport?

Patel: Are you getting a neurologic assessment? Are you getting cooled or not? Those are important things.

Harrington: All right. Let’s try to wrap this up. Teachable moments, we talked about. One of the things about cases in prominent athletes is that it makes it to the newspaper and then it raises awareness. There is a drawing inference from a small group of cases to the broader societal issues. That’s an important topic.

We’ve talked about possible screening options, identifying at-risk individuals and high-risk individuals. A large amount of data has already been accumulated, but there is more work to be done. We focused on how to use those teachable moments to really influence the chain of survival, not just for athletes but for society at large.

I love your point about the Bethesda Conference on shared decision-making. Like with everything else, we have to have that two-way conversation: What are the athlete’s goals, hopes, and aspirations?

Patel: That group of experts, in addition to shared decision-making, gave us a whole list of conditions that we should be aware of and the cutpoints of where we think normal and not normal live for athletes. I think that’s used by many.

Can we build our systems to make research happen faster for the individuals? These athletes are at colleges that are obviously doing so much to make sure they’re okay. The people who are helping with this registry, and others, are going to continue to work to ask whether we can engage them as citizen participants and scientists. I think athletes are going to become some of our best advocates for why you’d want to know about yourself and how to perform CPR.

Harrington: I love the concept of citizen scientists, that we all have an obligation to contribute to the evidence base because we all want to use that evidence.

This has been a terrific conversation. I’ve been joined by my good friend, Dr. Manesh Patel from Duke University. I hope you’ve enjoyed our discussion here at the ESC. We have been taking a little break from the science going on around us to talk about sudden cardiac death in athletes. It really does have implications for broader societal concepts.

Dr. Harrington is the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine and provost for medical affairs of Cornell University, New York, as well as a former president of the American Heart Association. He has disclosed the following relevant financial relationships: Research relationships with Baim Institute (DSMB); CSL (RCT executive committee); Janssen (RCT chair); National Heart, Lung, and Blood Institute (RCT executive committee, DSMB chair); Patient-Centered Outcomes Research Institute (RCT co-chair); Duke Clinical Research Institute. Consulting relationships with Atropos Health; Bitterroot Bio; Bristol Myers Squibb; BridgeBio; Element Science; Edwards Lifesciences; Foresite Labs; Medscape/WebMD Board of Directors for: American Heart Association; College of the Holy Cross; Cytokinetics. Dr. Patel is professor of medicine, Duke University; chief, division of cardiology; director, Duke Heart Center, Duke University Medical Center, Durham, N.C. He has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, adviser, consultant, or trustee for Bayer; Janssen; Novartis (consultant). Received research grant from Bayer; Janssen.

A version of this article appeared on Medscape.com.

Recorded Aug. 26, 2023. This transcript has been edited for clarity.

Robert A. Harrington, MD: I’m here with my good friend, Manesh Patel, from Duke University. We’re at the European Society of Cardiology (ESC) congress in Amsterdam, and I pulled Manesh into the studio for a conversation about something that’s really topical right now: sudden cardiac death in athletes.

What I hope to do [in this interview] is really pick Manesh’s brain on how we are thinking about this. Are we going to think about treatment issues? Are we going to think about prevention issues? Are we thinking about screening? We’ll try to make it practical.

Dr. Manesh Patel is chief of cardiovascular medicine at Duke University and also the director of the Duke Heart Center. Manesh, thanks for joining me here.
 

Bronny James and Damar Hamlin

Manesh R. Patel, MD: Excited to be here, Bob. Always.

Harrington: [Recently,] a news article comes out about the cause of Bronny James’ sudden cardiac death. Let me put this into a bigger societal context.

Last winter, Damar Hamlin, from the Buffalo Bills, suffered a traumatic injury on the field, and with that, had cardiac arrest. He’s back playing football – great to see. You and I are involved with the American Heart Association. He’s been very supportive of our efforts around things like CPR. He’s been terrific. It’s great to see him playing.

We know a little less about Bronny James. The news articles say the cause is both functional and anatomical, and it seems to be congenital, but we don’t have any details beyond this. Let’s not focus on the people; let’s focus on the topic.

Patel: I’m excited that we’re having the conversation. First and foremost, we’re excited that, with what we’ve seen on a national stage, these two individuals are doing well. They survived sudden cardiac death, which is a testament to all the things that we’ll talk about.

There are many important questions, like, is this increasing? Is this something we can prevent? And what are those things that might be happening to athletes?

Harrington: Can we predict it?

Patel: Right. I think the idea of sudden cardiac death in athletes is really a critical one for us to think about because it does concern participation and what we think about that. There are many experts who’ve been studying this for years that I now get to work with.

Harrington: Tell us a little bit about the kind of things you’ve been doing in this area.

Patel: Even before these events in the COVID era, we were wondering about athletes getting myocarditis, just in general, what do we know about that? People like Aaron Baggish, Kim Harmon, Jonathan Drezner, and others have been studying this.

Harrington: You and I did a show on athletes and COVID-19.

Patel: With the American Heart Association (AHA), the Cornell Foundation, and others, we started the Outcomes Registry for Cardiac Conditions in Athletes (ORCCA). This registry is across the United States, and athletes can sign up.

Harrington: Is it voluntary? Do the schools sign them up?

Patel: The athletes sign up. Team trainers and doctors talk to the athletes. We don’t really know the risks of some of these conditions. There’s a lot of gray area – people with certain conditions that were really interesting; aortas that are dilated in tall people.

Harrington: Long QT.

Patel: Long QT. There are certainly things that we know we should be intervening on and others where participation is a question. All of these we are trying to longitudinally put into the registry and follow them over time.

The second thing is understanding from the last Bethesda Conference that we want shared decision-making. There are going to be conditions where you say, “Look, I think your risk is high. You’ve a family history of sudden cardiac death. You have arrhythmias while you’re exercising.”

Harrington: You have a big, thick heart.

Patel: If you have hypertrophic cardiomyopathy, whether you’re an athlete or a 40-year-old adult, we’re going to have the same conversation. I think that holds. There’s a variety or a spectrum where we don’t know. I think the registry is one big step.

Thinking back to when somebody has an event, I would say take the teachable moment with the AHA and others to make sure your communities and your areas have automated external defibrillators (AEDs) and CPR training, and that we get to 100%: 100% response, 100% CPR, 100% defibrillation. I think that’s the first step.
 

Chain of survival

Harrington: Let’s really focus on the chain of survival. It is a chain: If any link is broken, your chance of survival really drops. We’ve had some well-known cases within our AHA community, including somebody who talks about it regularly: Kevin Volpp, from the University of Pennsylvania, a health economist. He had almost the perfect chain of survival. He had sudden cardiac death in a restaurant that was immediately observed, CPR started, EMTs called, and AED on the scene. Impressive.

Patel: That was in Cincinnati, where there are communities that have really worked on these things. I think you’re right. The chain of survival with rapid CPR to build a nation of survivors is key. The people at the AHA are helping us do this; there is a national call to make sure CPR is something that people feel comfortable doing. That they do it in men and women. They do it for anyone that goes down. And realize that it’s CPR that is hands-only. I think that’s an important lesson from Damar’s work, Nancy Brown’s, and AHA’s. Actually, schools in many countries require that to get through primary school.

Harrington: CPR training is a requirement to graduate from high school in some states.

Patel: My son just graduated from high school, and we spent time at his school making sure that everybody had access to CPR training. I think the way to do this is to start with that. Now, getting more specific about teams and athletes, I think most have emergency action plans, but it’s having action plans that work because of where you are and where the AED locations might be, or what the sport is. Having a plan on how you’re going to get that athlete to a place where you can help them recover is an important piece.

From there, I think the conversation for us is about what can we do as a society and as a country to answer some critical questions, including some real-world questions that people are asking: We had COVID-19 and we’re hearing these cases. Is this going up or down, and are these related?

Soon, hopefully the same group I talked about and others will have a publication, working with the NCAA to look at all of the deaths that they observed in NCAA Division I athletes over 20 years, including the sudden cardiac deaths. I won’t share the results because the publication isn’t out, but I think that’s the kind of important information that will help us understand if these rates are going up or down.

Harrington: What’s associated with that risk? Then we can start getting at whether it is something that, when we’re doing assessment for suitability for sports, has risk factors that should warrant more investigation.

Patel: Much like the field of cardiology, we haven’t enough of an evidence base, the right technologies, or the studies to determine how we should do screening, or not screening, across the board. Again, there is variation. There are some countries where anyone participating is going to get an ECG and an echocardiogram. There are other countries, like the United States, where it’s going to be a bit dependent on athlete risk.

Harrington: And where you live.

Patel: And where you live. Unfortunately, again, that brings in the idea that it might not be equitable in how we’re evaluating these individuals. I do think the opportunity to start to standardize that evaluation exists, and it likely comes from the ability to look back and say, “Here are some higher-risk individuals or some higher-risk scenarios.”

Harrington: Isn’t this what we do all the time in clinical medicine?

Patel: It’s going to be applied to a population that maybe is not as studied. I said this to you before we came on. The other thing is to make sure that the shared decision-making allows athletes who feel like they have a chance or want to play. During COVID, we had many college athletes, high school athletes, and kids not able to participate in sports. There was significant depression, feeling of loneliness, and even physical loss. People were actually getting less conditioned quickly. There’s a great benefit to sports participation.

Harrington: We were extrapolating from older data. If I’ve just had this new infection, COVID, and I’ve maybe got some signs of it in my heart, why can’t I exercise? That’s extrapolating from old myocarditis data.

Patel: We’re having to learn and follow it. I think there’s value in following that and getting those data. The second thing I think is really valuable is that we’ve shown that these individuals, if you do have these conversations and follow them, can participate and can be part of understanding the risk just like anything else.

Harrington: Is it sport specific? Are there some sports where maybe the conversation should be a little more intense than in other sports?

Patel: I think what we’ll see is that the conversations may be sport specific, and some may concern the number of athletes tested. At times, it’s pretty complicated. It does look like there are, as you know, different weight-bearing performance athletes, endurance athletes, or what I’ll call burst sports. There will probably be data that will identify certain sports where we may need to pay a bit more attention.

Harrington: What about the contact issues? Damar had a very specific thing, we think, happen to him. Football is a violent, contact-oriented sport, but fortunately we don’t regularly see what happened to Damar.

Patel: We’re talking about sudden cardiac death, but obviously, contact issues and neurologic evaluation is a whole other topic. That’s another big issue that I know many are following, and the NCAA is carefully, too. For Damar, I think we know that it was commotio cordis. At least when that happens, when there’s a ball or a trauma to the chest, those things have to be timed just so to actually lead to this event. Thankfully, it’s not very frequent, but it can happen.

Harrington: Hockey pucks, baseballs, soccer balls, a helmet to the chest ...

Patel: You have to be in a specific cycle of the squeeze. We don’t see that very frequently. I do think the evaluation and treatment, hopefully, makes a difference. One thing that we’re evolving in the screening world is our imaging; it’s getting better. We are not just doing echocardiograms; we are able to do other studies. There’s a mix of imaging and other technologies.

Is screening the answer?

Harrington: Let’s talk about that because screening is the area, I would say, with the most controversy – and a large amount of emotional controversy. Some argue that the data are not good enough to screen, or doctors are saying, “Wait a minute, why are we screening all these kids?” You said you were at your son’s high school doing CPR training. How many athletes are at his high school? There are many, and that’s a pretty small high school. Big communities, big universities, and the professional sports can afford it. Should we be doing this at the community level?

Patel: There have been some data. The Italians have done standard screening for some time, and it’s shown us that if you did echocardiograms in many individuals, you do find some cases that are hypertrophic cardiomyopathy in pathology. The issue is just how much you have to do and the resource utilization. I think as we get to a world where screening studies can happen with smaller technology and AI, that can be democratizing in how we get to athletes.

Harrington: Give an example of that. We were talking outside, you and I, about some of the new stethoscope technology.

Patel: Yes, stethoscopes are going to be one of the examples. We have stethoscopes that have the ability to get sounds and ECG signals, or at least some lead signals.

Harrington: Yes.

Patel: Potentially you can imagine that sound and ECG tracing in an AI environment, at least getting you from “everyone gets a listen with one stethoscope in their gym from their coach,” and it goes to the cloud. When there are enough questions, these are the ones that have to go further. Now, that’s a big study that has to be carried out; I’m not in any way saying we should do that.

Harrington: The technology is coming.

Patel: We start to see that our ability to rapidly do something to meet our athletes or our patients where they are will happen soon. Remember that the performance curve can vary, but once you have a sound where you can start to say that this is a regular flow murmur vs. “I’m worried about this,” especially as you mark it with ECG – that’s one example.

Smaller imaging is another example. For many years, ECGs have been talked about. There are entire courses that we run looking at ECGs in athletes. Remembering that Aaron Baggish and others are publishing that these individuals are large. When we look at their hearts, we see that they’re large, but when you adjust for size, often you can identify that many of them are within what we think are normal. Structurally, there are still many cases where you look at hearts and you’re asking, “Is this a thick heart? Is this noncompaction? Is this some pathology?”

That’s where you need imaging expertise. I think you have to have those individuals. I’m not advocating screening. I’m advocating studying it and that we should be thinking about the population. I don’t see a world where we don’t eventually start to really look to prevent those.

Harrington: Right. Whether it’s understanding that there are certain risk factors associated with this and we have to dedicate screening resources to those individuals, or if we want to do it more broadly on the population level to understand this with deeper dives into certain individuals, we’ve got to study it.

Patel: Some of the experts in sports medicine and sports cardiology have been collecting these data for a while. It’s time that we are there, because with these events we have the opportunity to share more of these data and maybe raise awareness – not in the teachable moment only – to get others to contribute.

I do believe that long term there’s an opportunity. We’ve seen that. We see that the rates, unfortunately, for marathon runners, where people unfortunately have events, seem to be higher. And we’ve seen the studies on troponin leaks in these individuals or evidence that there’s some effect on the heart from these events. We want people to be able to be long-term healthy.
 

Early defibrillation

Harrington: A large amount of work needs to be done. We talked with regard to screening, we’ve talked about CPR. We really need to have a nation of people who can do hands-only CPR. Let’s talk about AEDs, another key part of the chain of survival.

Patel: We have another important study going on, but an important message first: AEDs are critical to survival. We know that CPR is critical, but so is getting people to a defibrillator.

Harrington: Early defibrillation.

Patel: Early defibrillation. Early CPR is one of the biggest markers of making sure we perfuse people to get to early defibrillation, but then you have to get early defibrillation. There’s been a huge push in many communities, again, along with AHA and others, to make sure that AEDs are available not only in the U.S. but around the world. We’re at ESC and we see the push around the world to get AEDs available. They’ve come down in size and come down in cost, and that’s made it much more accessible. That’s really good. They’re still not always there.

We’ve seen really interesting randomized studies with people in some European countries where they have certain areas, just because of the locations, where bystanders will help get an AED  vs. randomizing to the EMS truck. They seem better in some of those variations. Chris Granger, at our institution, with Monique Starks, Dan Mark, and others, is doing a study in North Carolina where we’re testing different ways to potentially get AEDs in communities. We’re randomizing counties to one or two ways of getting AEDs to those individuals.

Harrington: Can you have an app where you just click “Find me an AED”?

Patel: Is there a world where the AED is found or is something bringing you the AED? Are there drones? Are there people driving? Are there ways that an AED is brought to the scene? All of those are going to be critical. It starts with continuing to figure out ways to support the costs of getting AEDs in places. The technology is continuing to evolve.

Harrington: It really is the premedical system stuff that makes the difference. Once EMS arrives with trained individuals who can defibrillate, they can transport you to a medical facility where trained physicians are at. It’s that pre-EMS thing that is so critical.

Patel: We talk often about athletes, but cardiac arrest care in general, and the chain of survival with CPR and AEDs, is critical. I still see patients in the CICU at Duke where, unfortunately, the biggest driver, as you just highlighted in that chain of survival, is how rapid we were in that golden hour. In the first 15 minutes, are you getting CPR, are you getting AED? Are you getting to a system?

Harrington: Are you getting a rapid transport?

Patel: Are you getting a neurologic assessment? Are you getting cooled or not? Those are important things.

Harrington: All right. Let’s try to wrap this up. Teachable moments, we talked about. One of the things about cases in prominent athletes is that it makes it to the newspaper and then it raises awareness. There is a drawing inference from a small group of cases to the broader societal issues. That’s an important topic.

We’ve talked about possible screening options, identifying at-risk individuals and high-risk individuals. A large amount of data has already been accumulated, but there is more work to be done. We focused on how to use those teachable moments to really influence the chain of survival, not just for athletes but for society at large.

I love your point about the Bethesda Conference on shared decision-making. Like with everything else, we have to have that two-way conversation: What are the athlete’s goals, hopes, and aspirations?

Patel: That group of experts, in addition to shared decision-making, gave us a whole list of conditions that we should be aware of and the cutpoints of where we think normal and not normal live for athletes. I think that’s used by many.

Can we build our systems to make research happen faster for the individuals? These athletes are at colleges that are obviously doing so much to make sure they’re okay. The people who are helping with this registry, and others, are going to continue to work to ask whether we can engage them as citizen participants and scientists. I think athletes are going to become some of our best advocates for why you’d want to know about yourself and how to perform CPR.

Harrington: I love the concept of citizen scientists, that we all have an obligation to contribute to the evidence base because we all want to use that evidence.

This has been a terrific conversation. I’ve been joined by my good friend, Dr. Manesh Patel from Duke University. I hope you’ve enjoyed our discussion here at the ESC. We have been taking a little break from the science going on around us to talk about sudden cardiac death in athletes. It really does have implications for broader societal concepts.

Dr. Harrington is the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine and provost for medical affairs of Cornell University, New York, as well as a former president of the American Heart Association. He has disclosed the following relevant financial relationships: Research relationships with Baim Institute (DSMB); CSL (RCT executive committee); Janssen (RCT chair); National Heart, Lung, and Blood Institute (RCT executive committee, DSMB chair); Patient-Centered Outcomes Research Institute (RCT co-chair); Duke Clinical Research Institute. Consulting relationships with Atropos Health; Bitterroot Bio; Bristol Myers Squibb; BridgeBio; Element Science; Edwards Lifesciences; Foresite Labs; Medscape/WebMD Board of Directors for: American Heart Association; College of the Holy Cross; Cytokinetics. Dr. Patel is professor of medicine, Duke University; chief, division of cardiology; director, Duke Heart Center, Duke University Medical Center, Durham, N.C. He has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, adviser, consultant, or trustee for Bayer; Janssen; Novartis (consultant). Received research grant from Bayer; Janssen.

A version of this article appeared on Medscape.com.

Use of dialectical behavior therapy significantly reduced suicide attempts in adolescents with bipolar disorder, compared with standard of care, based on data from 100 individuals aged 12-18 years.

University of Pittsburgh

Bipolar spectrum disorder (BP) is known to substantially increase the risk for suicide in youth, but no psychosocial intervention for this population has targeted suicidal behavior in particular, wrote Tina R. Goldstein, PhD, of the University of Pittsburgh, and colleagues.

Dialectical behavior therapy (DBT) had shown effectiveness for decreasing suicide attempts in adults with borderline personality disorder, and previous studies of DBT have shown reduced suicidal ideation, self-harm, and suicide attempts in suicidal adolescents, but these studies have mainly excluded BP teens, the researchers said.

In a study published in JAMA Psychiatry, the researchers recruited adolescents aged 12-18 years with a diagnosis of BP who were treated at an outpatient clinic between November 2014 and September 2019. Of these, 47 were randomized to 1 year of DBT (a total of 36 sessions) and 53 to standard of care (SOC) psychotherapy. All participants also received medication using a flexible algorithm.

The primary outcomes were suicide attempts over a 1-year period and measurements of mood symptoms and states, specifically depression and hypomania/mania. Secondary analyses included the effect of DBT on individuals with a history of suicide attempt and on improving emotion dysregulation. The mean age of the participants was 16.1 years; 85 were female, and 74% were White.

Participants in both DBT and SOC groups reported similar rates of suicide attempt rates at study enrollment based on the Adolescent Longitudinal Follow-Up Evaluation (ALIFE) with a mean of 2.0 and 1.8 attempts, respectively (P = .80). Based on the Columbia–Suicide Severity Rating Scale Pediatric Version (C-SSRS), participants in the DBT group had slightly more suicide attempts than the SOC group at study enrollment, with a mean of 1.4 and 0.6 attempts, respectively (P = .02).

Controlling for baseline attempts, participants in the DBT group had significantly fewer suicide attempts over the study period, compared with the SOC group as measured by both ALIFE (mean 0.2 vs. 1.1) and C-SSRS (mean 0.04 vs. 0.10, P = .03 for both measures). The incidence rate ratios for reduced suicide attempts were 0.32 for ALIFE and 0.13 for C-SSRS, both significant in favor of DBT, compared with SOC.

Overall, both groups showed similarly significant improvement on measures of mood symptoms and episodes over the study period. The standardized depression rating scale slope was –0.17 and the standardized mania rating scale slope was –0.24.

DBT was significantly more effective than SOC psychotherapy at decreasing suicide attempts over 1 year (ALIFE: incidence rate ratio, 0.32; 95% CI, 0.11-0.96; C-SSRS: IRR, 0.13; 95% CI, 0.02-0.78).

On further analysis, the decrease in suicide attempts in the DBT group was greater over time and among those with a lifetime history of suicide attempts (IRR, 0.23). “Decreased risk of suicide attempt in DBT was mediated by improvement in emotion dysregulation, particularly for those with high baseline emotion dysregulation,” the researchers wrote in their discussion.

The findings were limited by several factors including the mainly female, non-Hispanic White study population, and controlled clinical setting, the researchers noted. Data from a forthcoming community implementation field trial will address some generalizability issues, although more work is needed to address disparities in BP diagnosis and treatment, they added.

However, the results support the potential of DBT for mood management and for reducing suicide attempts in a high-risk adolescent population, especially those with high levels of emotional dysregulation, on par with other established psychosocial treatments, the researchers concluded.
 

More options needed to manage increased risk

“It was important to conduct this study at this time because, while still relatively rare, bipolar spectrum disorders in adolescents confer increased risk for suicide,” Peter L. Loper Jr., MD, of the University of South Carolina, Columbia, said in an interview. The complexity of BP and the increased risk of suicide in these patients challenge clinicians to identify robust evidence-based interventions beyond pharmacotherapy that mitigate this risk, said Dr. Loper, who is triple board certified in pediatrics, general psychiatry, and child & adolescent psychiatry, but was not involved in the study.

The current study findings were not surprising, because DBT has proven effective in decreasing suicidal ideation and suicide attempts in other high-risk adolescent patient populations, Dr. Loper said. “Given the therapeutic content of DBT, with emphasis on mindfulness, distress tolerance, social skills, and emotional regulation, I think it is reasonable to hypothesize that DBT might be a globally applicable intervention, independent of mental health diagnosis or etiology of suicidal ideation,” he said.

The take-home message for clinicians is that the results support the efficacy of DBT as an intervention for adolescents with BP and suicidal ideation, self-injurious behavior, or suicide attempts, said Dr. Loper. For these patients, given their increased suicide risk, “DBT should certainly be recommended as a component of their treatment plan,” he said.

However, barriers to the use of DBT in clinical practice exist, notably access and cost, Dr. Loper noted. “I think that the most prominent barrier in accessing DBT in clinical practice is the availability of certified, structured DBT treatment programs, and particularly those willing to provide services to adolescents,” he said. “Additionally, certified DBT programs, which are the gold standard, are often not covered by third-party payers, making cost yet another potential barrier.”

Looking ahead, Dr. Loper agreed with the study authors that additional research with a more diverse patient population representative of adolescents with bipolar spectrum disorder “is a crucial area of focus.”

The study was funded by the National Institutes of Mental Health through a grant to Dr. Goldstein, who also disclosed royalties from Guilford Press unrelated to the current study. Dr. Loper had no financial conflicts to disclose.
 

Use of dialectical behavior therapy significantly reduced suicide attempts in adolescents with bipolar disorder, compared with standard of care, based on data from 100 individuals aged 12-18 years.

University of Pittsburgh

Bipolar spectrum disorder (BP) is known to substantially increase the risk for suicide in youth, but no psychosocial intervention for this population has targeted suicidal behavior in particular, wrote Tina R. Goldstein, PhD, of the University of Pittsburgh, and colleagues.

Dialectical behavior therapy (DBT) had shown effectiveness for decreasing suicide attempts in adults with borderline personality disorder, and previous studies of DBT have shown reduced suicidal ideation, self-harm, and suicide attempts in suicidal adolescents, but these studies have mainly excluded BP teens, the researchers said.

In a study published in JAMA Psychiatry, the researchers recruited adolescents aged 12-18 years with a diagnosis of BP who were treated at an outpatient clinic between November 2014 and September 2019. Of these, 47 were randomized to 1 year of DBT (a total of 36 sessions) and 53 to standard of care (SOC) psychotherapy. All participants also received medication using a flexible algorithm.

The primary outcomes were suicide attempts over a 1-year period and measurements of mood symptoms and states, specifically depression and hypomania/mania. Secondary analyses included the effect of DBT on individuals with a history of suicide attempt and on improving emotion dysregulation. The mean age of the participants was 16.1 years; 85 were female, and 74% were White.

Participants in both DBT and SOC groups reported similar rates of suicide attempt rates at study enrollment based on the Adolescent Longitudinal Follow-Up Evaluation (ALIFE) with a mean of 2.0 and 1.8 attempts, respectively (P = .80). Based on the Columbia–Suicide Severity Rating Scale Pediatric Version (C-SSRS), participants in the DBT group had slightly more suicide attempts than the SOC group at study enrollment, with a mean of 1.4 and 0.6 attempts, respectively (P = .02).

Controlling for baseline attempts, participants in the DBT group had significantly fewer suicide attempts over the study period, compared with the SOC group as measured by both ALIFE (mean 0.2 vs. 1.1) and C-SSRS (mean 0.04 vs. 0.10, P = .03 for both measures). The incidence rate ratios for reduced suicide attempts were 0.32 for ALIFE and 0.13 for C-SSRS, both significant in favor of DBT, compared with SOC.

Overall, both groups showed similarly significant improvement on measures of mood symptoms and episodes over the study period. The standardized depression rating scale slope was –0.17 and the standardized mania rating scale slope was –0.24.

DBT was significantly more effective than SOC psychotherapy at decreasing suicide attempts over 1 year (ALIFE: incidence rate ratio, 0.32; 95% CI, 0.11-0.96; C-SSRS: IRR, 0.13; 95% CI, 0.02-0.78).

On further analysis, the decrease in suicide attempts in the DBT group was greater over time and among those with a lifetime history of suicide attempts (IRR, 0.23). “Decreased risk of suicide attempt in DBT was mediated by improvement in emotion dysregulation, particularly for those with high baseline emotion dysregulation,” the researchers wrote in their discussion.

The findings were limited by several factors including the mainly female, non-Hispanic White study population, and controlled clinical setting, the researchers noted. Data from a forthcoming community implementation field trial will address some generalizability issues, although more work is needed to address disparities in BP diagnosis and treatment, they added.

However, the results support the potential of DBT for mood management and for reducing suicide attempts in a high-risk adolescent population, especially those with high levels of emotional dysregulation, on par with other established psychosocial treatments, the researchers concluded.
 

More options needed to manage increased risk

“It was important to conduct this study at this time because, while still relatively rare, bipolar spectrum disorders in adolescents confer increased risk for suicide,” Peter L. Loper Jr., MD, of the University of South Carolina, Columbia, said in an interview. The complexity of BP and the increased risk of suicide in these patients challenge clinicians to identify robust evidence-based interventions beyond pharmacotherapy that mitigate this risk, said Dr. Loper, who is triple board certified in pediatrics, general psychiatry, and child & adolescent psychiatry, but was not involved in the study.

The current study findings were not surprising, because DBT has proven effective in decreasing suicidal ideation and suicide attempts in other high-risk adolescent patient populations, Dr. Loper said. “Given the therapeutic content of DBT, with emphasis on mindfulness, distress tolerance, social skills, and emotional regulation, I think it is reasonable to hypothesize that DBT might be a globally applicable intervention, independent of mental health diagnosis or etiology of suicidal ideation,” he said.

The take-home message for clinicians is that the results support the efficacy of DBT as an intervention for adolescents with BP and suicidal ideation, self-injurious behavior, or suicide attempts, said Dr. Loper. For these patients, given their increased suicide risk, “DBT should certainly be recommended as a component of their treatment plan,” he said.

However, barriers to the use of DBT in clinical practice exist, notably access and cost, Dr. Loper noted. “I think that the most prominent barrier in accessing DBT in clinical practice is the availability of certified, structured DBT treatment programs, and particularly those willing to provide services to adolescents,” he said. “Additionally, certified DBT programs, which are the gold standard, are often not covered by third-party payers, making cost yet another potential barrier.”

Looking ahead, Dr. Loper agreed with the study authors that additional research with a more diverse patient population representative of adolescents with bipolar spectrum disorder “is a crucial area of focus.”

The study was funded by the National Institutes of Mental Health through a grant to Dr. Goldstein, who also disclosed royalties from Guilford Press unrelated to the current study. Dr. Loper had no financial conflicts to disclose.
 

Use of dialectical behavior therapy significantly reduced suicide attempts in adolescents with bipolar disorder, compared with standard of care, based on data from 100 individuals aged 12-18 years.

University of Pittsburgh

Bipolar spectrum disorder (BP) is known to substantially increase the risk for suicide in youth, but no psychosocial intervention for this population has targeted suicidal behavior in particular, wrote Tina R. Goldstein, PhD, of the University of Pittsburgh, and colleagues.

Dialectical behavior therapy (DBT) had shown effectiveness for decreasing suicide attempts in adults with borderline personality disorder, and previous studies of DBT have shown reduced suicidal ideation, self-harm, and suicide attempts in suicidal adolescents, but these studies have mainly excluded BP teens, the researchers said.

In a study published in JAMA Psychiatry, the researchers recruited adolescents aged 12-18 years with a diagnosis of BP who were treated at an outpatient clinic between November 2014 and September 2019. Of these, 47 were randomized to 1 year of DBT (a total of 36 sessions) and 53 to standard of care (SOC) psychotherapy. All participants also received medication using a flexible algorithm.

The primary outcomes were suicide attempts over a 1-year period and measurements of mood symptoms and states, specifically depression and hypomania/mania. Secondary analyses included the effect of DBT on individuals with a history of suicide attempt and on improving emotion dysregulation. The mean age of the participants was 16.1 years; 85 were female, and 74% were White.

Participants in both DBT and SOC groups reported similar rates of suicide attempt rates at study enrollment based on the Adolescent Longitudinal Follow-Up Evaluation (ALIFE) with a mean of 2.0 and 1.8 attempts, respectively (P = .80). Based on the Columbia–Suicide Severity Rating Scale Pediatric Version (C-SSRS), participants in the DBT group had slightly more suicide attempts than the SOC group at study enrollment, with a mean of 1.4 and 0.6 attempts, respectively (P = .02).

Controlling for baseline attempts, participants in the DBT group had significantly fewer suicide attempts over the study period, compared with the SOC group as measured by both ALIFE (mean 0.2 vs. 1.1) and C-SSRS (mean 0.04 vs. 0.10, P = .03 for both measures). The incidence rate ratios for reduced suicide attempts were 0.32 for ALIFE and 0.13 for C-SSRS, both significant in favor of DBT, compared with SOC.

Overall, both groups showed similarly significant improvement on measures of mood symptoms and episodes over the study period. The standardized depression rating scale slope was –0.17 and the standardized mania rating scale slope was –0.24.

DBT was significantly more effective than SOC psychotherapy at decreasing suicide attempts over 1 year (ALIFE: incidence rate ratio, 0.32; 95% CI, 0.11-0.96; C-SSRS: IRR, 0.13; 95% CI, 0.02-0.78).

On further analysis, the decrease in suicide attempts in the DBT group was greater over time and among those with a lifetime history of suicide attempts (IRR, 0.23). “Decreased risk of suicide attempt in DBT was mediated by improvement in emotion dysregulation, particularly for those with high baseline emotion dysregulation,” the researchers wrote in their discussion.

The findings were limited by several factors including the mainly female, non-Hispanic White study population, and controlled clinical setting, the researchers noted. Data from a forthcoming community implementation field trial will address some generalizability issues, although more work is needed to address disparities in BP diagnosis and treatment, they added.

However, the results support the potential of DBT for mood management and for reducing suicide attempts in a high-risk adolescent population, especially those with high levels of emotional dysregulation, on par with other established psychosocial treatments, the researchers concluded.
 

More options needed to manage increased risk

“It was important to conduct this study at this time because, while still relatively rare, bipolar spectrum disorders in adolescents confer increased risk for suicide,” Peter L. Loper Jr., MD, of the University of South Carolina, Columbia, said in an interview. The complexity of BP and the increased risk of suicide in these patients challenge clinicians to identify robust evidence-based interventions beyond pharmacotherapy that mitigate this risk, said Dr. Loper, who is triple board certified in pediatrics, general psychiatry, and child & adolescent psychiatry, but was not involved in the study.

The current study findings were not surprising, because DBT has proven effective in decreasing suicidal ideation and suicide attempts in other high-risk adolescent patient populations, Dr. Loper said. “Given the therapeutic content of DBT, with emphasis on mindfulness, distress tolerance, social skills, and emotional regulation, I think it is reasonable to hypothesize that DBT might be a globally applicable intervention, independent of mental health diagnosis or etiology of suicidal ideation,” he said.

The take-home message for clinicians is that the results support the efficacy of DBT as an intervention for adolescents with BP and suicidal ideation, self-injurious behavior, or suicide attempts, said Dr. Loper. For these patients, given their increased suicide risk, “DBT should certainly be recommended as a component of their treatment plan,” he said.

However, barriers to the use of DBT in clinical practice exist, notably access and cost, Dr. Loper noted. “I think that the most prominent barrier in accessing DBT in clinical practice is the availability of certified, structured DBT treatment programs, and particularly those willing to provide services to adolescents,” he said. “Additionally, certified DBT programs, which are the gold standard, are often not covered by third-party payers, making cost yet another potential barrier.”

Looking ahead, Dr. Loper agreed with the study authors that additional research with a more diverse patient population representative of adolescents with bipolar spectrum disorder “is a crucial area of focus.”

The study was funded by the National Institutes of Mental Health through a grant to Dr. Goldstein, who also disclosed royalties from Guilford Press unrelated to the current study. Dr. Loper had no financial conflicts to disclose.
 

If you are a pediatrician, babies are your bread and butter. In fact, they are the whole enchilada. Without them you are going to starve. Even if you are an adolescent medicine specialist, the pipeline feeding your business begins with babies. The number of babies entering the conveyor belt that eventually ends up in your office is something that should interest you. It probably doesn’t surprise you to learn that the fertility rate in this country has fallen. In fact, it has now dipped below the “replacement” threshold of 2.1%.

Another number that might interest you is ideal family size. In others words, the number of children American adults consider when they are envisioning the ideal family. You may be surprised to learn that despite the downward dip on the fertility rate during the 2007-2009 recession and the pandemic, a significant number of Americans still believe that the ideal family includes three children. Looking at the broader population, the ideal family is around 2.5 children, which is a number that is up a little from the 1990s but has scarcely changed over the last 5 decades. Obviously, there is a gap between what the population as a whole believes and the reality of how many children the fertile population is producing. And, there is research that suggests that this gap between personal intention and ideal family size is growing. In other words, people may be saying they believe bigger families are a good thing ... if everything is going well in their life.

What is behind this gap and why is it growing? As people are delaying building their families, realities and expectations collide. Some examples? The impact of their student loans is greater than they anticipated. Climate change and news stories focused on political uncertainty can be unsettling. A person may end up marrying someone who doesn’t concur with their view of an ideal family. Fertility problems crop up with advancing age. The first child may have presented more of a challenge both physically, emotionally, and economically than new parents had expected.

If we agree that the fertility rate is an important number for our survival as a profession, can we agree that because of this vested interest we should become involved in helping families widen this growing gap between their view of the ideal family size and the realities of actually producing that family?

Maybe we don’t need to get involved. When the national climate – meteorologically, politically, and economically – improves families will start making more babies. Right now maybe the better option is to adjust our business model to the fluctuations in demand.

On the other hand, we could ask the American Academy of Pediatrics to join with the American Academy of Obstetricians and Gynecologists and hire a big name advertising agency to launch an ad campaign encouraging young and not so young adults to have more children. However, this might appear rather transparent and self-serving.

The best option is probably to continue to do what we are already doing, but try to do it better. If the challenges of having a first child are a major deterrent to having a second child, we should redouble our efforts toward making, if only in retrospect, that first parenting experience rewarding and enjoyable. That could come in the form of speaking out for parental leave, breastfeeding-friendly workplaces, and more affordable daycare. But it could also come in those scores of encounters we have every day in the office where we give solid, realistic, and compassionate advice on breastfeeding, sleep hygiene, and behavior management. If we can make those tough first 6 months of parenting go more smoothly and make the twos seem less terrible, we may see the average family size in our practice grow before our eyes.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

If you are a pediatrician, babies are your bread and butter. In fact, they are the whole enchilada. Without them you are going to starve. Even if you are an adolescent medicine specialist, the pipeline feeding your business begins with babies. The number of babies entering the conveyor belt that eventually ends up in your office is something that should interest you. It probably doesn’t surprise you to learn that the fertility rate in this country has fallen. In fact, it has now dipped below the “replacement” threshold of 2.1%.

Another number that might interest you is ideal family size. In others words, the number of children American adults consider when they are envisioning the ideal family. You may be surprised to learn that despite the downward dip on the fertility rate during the 2007-2009 recession and the pandemic, a significant number of Americans still believe that the ideal family includes three children. Looking at the broader population, the ideal family is around 2.5 children, which is a number that is up a little from the 1990s but has scarcely changed over the last 5 decades. Obviously, there is a gap between what the population as a whole believes and the reality of how many children the fertile population is producing. And, there is research that suggests that this gap between personal intention and ideal family size is growing. In other words, people may be saying they believe bigger families are a good thing ... if everything is going well in their life.

What is behind this gap and why is it growing? As people are delaying building their families, realities and expectations collide. Some examples? The impact of their student loans is greater than they anticipated. Climate change and news stories focused on political uncertainty can be unsettling. A person may end up marrying someone who doesn’t concur with their view of an ideal family. Fertility problems crop up with advancing age. The first child may have presented more of a challenge both physically, emotionally, and economically than new parents had expected.

If we agree that the fertility rate is an important number for our survival as a profession, can we agree that because of this vested interest we should become involved in helping families widen this growing gap between their view of the ideal family size and the realities of actually producing that family?

Maybe we don’t need to get involved. When the national climate – meteorologically, politically, and economically – improves families will start making more babies. Right now maybe the better option is to adjust our business model to the fluctuations in demand.

On the other hand, we could ask the American Academy of Pediatrics to join with the American Academy of Obstetricians and Gynecologists and hire a big name advertising agency to launch an ad campaign encouraging young and not so young adults to have more children. However, this might appear rather transparent and self-serving.

The best option is probably to continue to do what we are already doing, but try to do it better. If the challenges of having a first child are a major deterrent to having a second child, we should redouble our efforts toward making, if only in retrospect, that first parenting experience rewarding and enjoyable. That could come in the form of speaking out for parental leave, breastfeeding-friendly workplaces, and more affordable daycare. But it could also come in those scores of encounters we have every day in the office where we give solid, realistic, and compassionate advice on breastfeeding, sleep hygiene, and behavior management. If we can make those tough first 6 months of parenting go more smoothly and make the twos seem less terrible, we may see the average family size in our practice grow before our eyes.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

If you are a pediatrician, babies are your bread and butter. In fact, they are the whole enchilada. Without them you are going to starve. Even if you are an adolescent medicine specialist, the pipeline feeding your business begins with babies. The number of babies entering the conveyor belt that eventually ends up in your office is something that should interest you. It probably doesn’t surprise you to learn that the fertility rate in this country has fallen. In fact, it has now dipped below the “replacement” threshold of 2.1%.

Another number that might interest you is ideal family size. In others words, the number of children American adults consider when they are envisioning the ideal family. You may be surprised to learn that despite the downward dip on the fertility rate during the 2007-2009 recession and the pandemic, a significant number of Americans still believe that the ideal family includes three children. Looking at the broader population, the ideal family is around 2.5 children, which is a number that is up a little from the 1990s but has scarcely changed over the last 5 decades. Obviously, there is a gap between what the population as a whole believes and the reality of how many children the fertile population is producing. And, there is research that suggests that this gap between personal intention and ideal family size is growing. In other words, people may be saying they believe bigger families are a good thing ... if everything is going well in their life.

What is behind this gap and why is it growing? As people are delaying building their families, realities and expectations collide. Some examples? The impact of their student loans is greater than they anticipated. Climate change and news stories focused on political uncertainty can be unsettling. A person may end up marrying someone who doesn’t concur with their view of an ideal family. Fertility problems crop up with advancing age. The first child may have presented more of a challenge both physically, emotionally, and economically than new parents had expected.

If we agree that the fertility rate is an important number for our survival as a profession, can we agree that because of this vested interest we should become involved in helping families widen this growing gap between their view of the ideal family size and the realities of actually producing that family?

Maybe we don’t need to get involved. When the national climate – meteorologically, politically, and economically – improves families will start making more babies. Right now maybe the better option is to adjust our business model to the fluctuations in demand.

On the other hand, we could ask the American Academy of Pediatrics to join with the American Academy of Obstetricians and Gynecologists and hire a big name advertising agency to launch an ad campaign encouraging young and not so young adults to have more children. However, this might appear rather transparent and self-serving.

The best option is probably to continue to do what we are already doing, but try to do it better. If the challenges of having a first child are a major deterrent to having a second child, we should redouble our efforts toward making, if only in retrospect, that first parenting experience rewarding and enjoyable. That could come in the form of speaking out for parental leave, breastfeeding-friendly workplaces, and more affordable daycare. But it could also come in those scores of encounters we have every day in the office where we give solid, realistic, and compassionate advice on breastfeeding, sleep hygiene, and behavior management. If we can make those tough first 6 months of parenting go more smoothly and make the twos seem less terrible, we may see the average family size in our practice grow before our eyes.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

A precision treatment model for internet-delivered cognitive behavioral therapy provides a low-cost, accessible, and effective alternative for treating anxiety and depression, according to a study published in JAMA Psychiatry . The intervention was developed by researchers from the United States, Mexico, and Colombia and studied in undergraduate university students.

The research included 1,319 students with anxiety and depression. The students were randomly assigned to three groups that received either remote (internet-based) cognitive behavioral therapy guided by a therapist, self-guided cognitive behavioral therapy (without support from a therapist), or standard treatment provided by the health care services within their community (the control condition).

Students who received guided cognitive behavioral therapy had higher combined rates of remission of these disorders (51.8%) than students who received self-guided therapy (37.8%) or conventional therapy (40%). These differences were not significant for remission of anxiety, however.

Guided cognitive behavioral therapy was associated with the highest probability of remission of anxiety and depression in 91.7% of students, the highest probability of remission of anxiety in all students, and the highest probability of remission of depression in 71.5% of participants.

The results of this analysis could be used to improve psychological care by optimizing how different treatment methods are assigned, especially in mental health institutions where available technical and human resources are limited, according to the investigators.

“We started designing this study before COVID-19 with the idea of optimizing care for these mental health problems,” said study author Corina Benjet Miner, PhD, an epidemiological and psychosocial researcher at the Ramón de la Fuente National Institute of Psychiatry, Mexico City. “We wanted to find additional strategies to achieve better care. The pandemic helped us because, even though this has been undergoing research for many years, internet-delivered interventions were not as well accepted. But during the pandemic, there weren’t any other options.”

Given the high prevalence of mental disorders before and after the pandemic, no health care system in the world would be able to provide in-person care to each patient with depression or anxiety, said Dr. Benjet Miner. “So, the idea is to look for other cost-effective strategies that can ramp up our interventions and reach a greater number of people without negatively impacting the quality of care,” she explained.

“I believe that [the precision model] is an excellent proposal that can save financial resources and avoid transfers,” said Juana Olvera Méndez, PhD, research professor working with the cognitive behavioral approach at the Iztacala Faculty of Higher Studies (FESI) of the National Autonomous University of Mexico, Mexico City. “It also makes it possible to provide patients with immediate care, in contrast to when someone has to go in for [in-person] therapy, which will depend a lot on how the therapist approaches the situation.”

Students from seven universities in Colombia and Mexico were included in the study. They were aged 18 years or older and had a score of 10 or greater on the self-administered Generalized Anxiety Disorder scale-7 test, or had depression with scores of 10 or greater on the nine-item Patient Health Questionnaire, which is also self-administered.

The study’s exclusion criteria included a history of bipolar disorder, nonaffective psychosis, or suicidal ideation with suicide attempts. The investigators used 284 prescription predictors to anticipate the differential response to antianxiety and antidepression therapy.

By grouping these predictors into 11 conceptual categories (such as demographic characteristics, COVID-19–linked stressors, or mental disorder comorbidities) and using machine learning algorithms, the investigators were able to predict in an individualized manner the probability of remission for participants in each of the groups.

“For depression, we found that 28.5% of patients could experience better or equivalent effects from the self-guided program (in comparison to the guided program). Once you have this program, it doesn’t cost anything, so there could be a massive number of people who could benefit from a cost-free therapy,” said Dr. Benjet Miner.

While numerous studies in precision medicine have tried to determine the most appropriate treatment for each patient, “they don’t have the high number of predictors that we used in this research, and I feel like this gives us a significant edge,” she added.

She also explained that they found no differences in user satisfaction between the guided and unguided version of the therapy, so now they must discover why the guided version works better. One notable point is that patients accessed (online) the guided program twice as many times as those who used the self-guided version, but the number of times used is not enough to explain the better outcomes.

“We believe that patients develop some sort of connection with the guides, who are not providing therapy but only making recommendations in brief interactions with patients once a week. It has something to do with that connection, in addition to the longer time spent interacting with the platform, which provides better results with the guided version,” stated Dr. Benjet Miner.

One of the main limitations of this study is that, though it compares three treatment methods, the third one (standard care) is not homogeneous, because each of the seven universities from which the students were selected has different resources for this purpose. “Some universities, like the National Autonomous University of Mexico, have very formal services, with teams of psychologists and psychiatrists, while others don’t have this type of service, or they cover additional aspects, like vocational counseling. So, it’s very difficult to determine exactly what kind of care patients are receiving, because it’s not homogeneous,” she said.

As many as nine assessments using psychometric tests are sometimes required before the intervention can be evaluated, said Dr. Méndez. “This study doesn’t go into too much detail in that area, focusing rather on treatment. So, it would be important to know the diagnoses of the users, who may be experiencing different degrees of depression or anxiety. It would be worth asking what happens if a user requires psychiatric treatment or support.”

Dr. Méndez, who provides psychological therapy in person and online at the Student Support and Counselling Center at FESI, pointed out that it would be important to provide close follow-up on these results to see whether they are sustained in the short and long terms. In her opinion, this model could be presented to other users requiring treatment for anxiety or depression, provided that they can use information and communication technologies.

This precision model, which can also be supported on mobile phones or tablets, could be transferred to primary care facilities or vulnerable populations in rural areas, said Dr. Benjet Miner. “The idea is to reach a point where these algorithms become accurate enough and have a really strong predictive power so that clinicians can use them. The goal is always to find the best treatment at the lowest cost, so that it’s sustainable,” she concluded.

This study was funded by grant number R01MH120648 from the National Institute of Mental Health and the Fogarty International Center. Dr. Benjet Miner reports no relevant financial relationships; the declarations of the remaining authors can be found at the publication’s website.

This article was translated from Medscape’s Spanish Edition and a version first appeared on Medscape.com.

A precision treatment model for internet-delivered cognitive behavioral therapy provides a low-cost, accessible, and effective alternative for treating anxiety and depression, according to a study published in JAMA Psychiatry . The intervention was developed by researchers from the United States, Mexico, and Colombia and studied in undergraduate university students.

The research included 1,319 students with anxiety and depression. The students were randomly assigned to three groups that received either remote (internet-based) cognitive behavioral therapy guided by a therapist, self-guided cognitive behavioral therapy (without support from a therapist), or standard treatment provided by the health care services within their community (the control condition).

Students who received guided cognitive behavioral therapy had higher combined rates of remission of these disorders (51.8%) than students who received self-guided therapy (37.8%) or conventional therapy (40%). These differences were not significant for remission of anxiety, however.

Guided cognitive behavioral therapy was associated with the highest probability of remission of anxiety and depression in 91.7% of students, the highest probability of remission of anxiety in all students, and the highest probability of remission of depression in 71.5% of participants.

The results of this analysis could be used to improve psychological care by optimizing how different treatment methods are assigned, especially in mental health institutions where available technical and human resources are limited, according to the investigators.

“We started designing this study before COVID-19 with the idea of optimizing care for these mental health problems,” said study author Corina Benjet Miner, PhD, an epidemiological and psychosocial researcher at the Ramón de la Fuente National Institute of Psychiatry, Mexico City. “We wanted to find additional strategies to achieve better care. The pandemic helped us because, even though this has been undergoing research for many years, internet-delivered interventions were not as well accepted. But during the pandemic, there weren’t any other options.”

Given the high prevalence of mental disorders before and after the pandemic, no health care system in the world would be able to provide in-person care to each patient with depression or anxiety, said Dr. Benjet Miner. “So, the idea is to look for other cost-effective strategies that can ramp up our interventions and reach a greater number of people without negatively impacting the quality of care,” she explained.

“I believe that [the precision model] is an excellent proposal that can save financial resources and avoid transfers,” said Juana Olvera Méndez, PhD, research professor working with the cognitive behavioral approach at the Iztacala Faculty of Higher Studies (FESI) of the National Autonomous University of Mexico, Mexico City. “It also makes it possible to provide patients with immediate care, in contrast to when someone has to go in for [in-person] therapy, which will depend a lot on how the therapist approaches the situation.”

Students from seven universities in Colombia and Mexico were included in the study. They were aged 18 years or older and had a score of 10 or greater on the self-administered Generalized Anxiety Disorder scale-7 test, or had depression with scores of 10 or greater on the nine-item Patient Health Questionnaire, which is also self-administered.

The study’s exclusion criteria included a history of bipolar disorder, nonaffective psychosis, or suicidal ideation with suicide attempts. The investigators used 284 prescription predictors to anticipate the differential response to antianxiety and antidepression therapy.

By grouping these predictors into 11 conceptual categories (such as demographic characteristics, COVID-19–linked stressors, or mental disorder comorbidities) and using machine learning algorithms, the investigators were able to predict in an individualized manner the probability of remission for participants in each of the groups.

“For depression, we found that 28.5% of patients could experience better or equivalent effects from the self-guided program (in comparison to the guided program). Once you have this program, it doesn’t cost anything, so there could be a massive number of people who could benefit from a cost-free therapy,” said Dr. Benjet Miner.

While numerous studies in precision medicine have tried to determine the most appropriate treatment for each patient, “they don’t have the high number of predictors that we used in this research, and I feel like this gives us a significant edge,” she added.

She also explained that they found no differences in user satisfaction between the guided and unguided version of the therapy, so now they must discover why the guided version works better. One notable point is that patients accessed (online) the guided program twice as many times as those who used the self-guided version, but the number of times used is not enough to explain the better outcomes.

“We believe that patients develop some sort of connection with the guides, who are not providing therapy but only making recommendations in brief interactions with patients once a week. It has something to do with that connection, in addition to the longer time spent interacting with the platform, which provides better results with the guided version,” stated Dr. Benjet Miner.

One of the main limitations of this study is that, though it compares three treatment methods, the third one (standard care) is not homogeneous, because each of the seven universities from which the students were selected has different resources for this purpose. “Some universities, like the National Autonomous University of Mexico, have very formal services, with teams of psychologists and psychiatrists, while others don’t have this type of service, or they cover additional aspects, like vocational counseling. So, it’s very difficult to determine exactly what kind of care patients are receiving, because it’s not homogeneous,” she said.

As many as nine assessments using psychometric tests are sometimes required before the intervention can be evaluated, said Dr. Méndez. “This study doesn’t go into too much detail in that area, focusing rather on treatment. So, it would be important to know the diagnoses of the users, who may be experiencing different degrees of depression or anxiety. It would be worth asking what happens if a user requires psychiatric treatment or support.”

Dr. Méndez, who provides psychological therapy in person and online at the Student Support and Counselling Center at FESI, pointed out that it would be important to provide close follow-up on these results to see whether they are sustained in the short and long terms. In her opinion, this model could be presented to other users requiring treatment for anxiety or depression, provided that they can use information and communication technologies.

This precision model, which can also be supported on mobile phones or tablets, could be transferred to primary care facilities or vulnerable populations in rural areas, said Dr. Benjet Miner. “The idea is to reach a point where these algorithms become accurate enough and have a really strong predictive power so that clinicians can use them. The goal is always to find the best treatment at the lowest cost, so that it’s sustainable,” she concluded.

This study was funded by grant number R01MH120648 from the National Institute of Mental Health and the Fogarty International Center. Dr. Benjet Miner reports no relevant financial relationships; the declarations of the remaining authors can be found at the publication’s website.

This article was translated from Medscape’s Spanish Edition and a version first appeared on Medscape.com.

A precision treatment model for internet-delivered cognitive behavioral therapy provides a low-cost, accessible, and effective alternative for treating anxiety and depression, according to a study published in JAMA Psychiatry . The intervention was developed by researchers from the United States, Mexico, and Colombia and studied in undergraduate university students.

The research included 1,319 students with anxiety and depression. The students were randomly assigned to three groups that received either remote (internet-based) cognitive behavioral therapy guided by a therapist, self-guided cognitive behavioral therapy (without support from a therapist), or standard treatment provided by the health care services within their community (the control condition).

Students who received guided cognitive behavioral therapy had higher combined rates of remission of these disorders (51.8%) than students who received self-guided therapy (37.8%) or conventional therapy (40%). These differences were not significant for remission of anxiety, however.

Guided cognitive behavioral therapy was associated with the highest probability of remission of anxiety and depression in 91.7% of students, the highest probability of remission of anxiety in all students, and the highest probability of remission of depression in 71.5% of participants.

The results of this analysis could be used to improve psychological care by optimizing how different treatment methods are assigned, especially in mental health institutions where available technical and human resources are limited, according to the investigators.

“We started designing this study before COVID-19 with the idea of optimizing care for these mental health problems,” said study author Corina Benjet Miner, PhD, an epidemiological and psychosocial researcher at the Ramón de la Fuente National Institute of Psychiatry, Mexico City. “We wanted to find additional strategies to achieve better care. The pandemic helped us because, even though this has been undergoing research for many years, internet-delivered interventions were not as well accepted. But during the pandemic, there weren’t any other options.”

Given the high prevalence of mental disorders before and after the pandemic, no health care system in the world would be able to provide in-person care to each patient with depression or anxiety, said Dr. Benjet Miner. “So, the idea is to look for other cost-effective strategies that can ramp up our interventions and reach a greater number of people without negatively impacting the quality of care,” she explained.

“I believe that [the precision model] is an excellent proposal that can save financial resources and avoid transfers,” said Juana Olvera Méndez, PhD, research professor working with the cognitive behavioral approach at the Iztacala Faculty of Higher Studies (FESI) of the National Autonomous University of Mexico, Mexico City. “It also makes it possible to provide patients with immediate care, in contrast to when someone has to go in for [in-person] therapy, which will depend a lot on how the therapist approaches the situation.”

Students from seven universities in Colombia and Mexico were included in the study. They were aged 18 years or older and had a score of 10 or greater on the self-administered Generalized Anxiety Disorder scale-7 test, or had depression with scores of 10 or greater on the nine-item Patient Health Questionnaire, which is also self-administered.

The study’s exclusion criteria included a history of bipolar disorder, nonaffective psychosis, or suicidal ideation with suicide attempts. The investigators used 284 prescription predictors to anticipate the differential response to antianxiety and antidepression therapy.

By grouping these predictors into 11 conceptual categories (such as demographic characteristics, COVID-19–linked stressors, or mental disorder comorbidities) and using machine learning algorithms, the investigators were able to predict in an individualized manner the probability of remission for participants in each of the groups.

“For depression, we found that 28.5% of patients could experience better or equivalent effects from the self-guided program (in comparison to the guided program). Once you have this program, it doesn’t cost anything, so there could be a massive number of people who could benefit from a cost-free therapy,” said Dr. Benjet Miner.

While numerous studies in precision medicine have tried to determine the most appropriate treatment for each patient, “they don’t have the high number of predictors that we used in this research, and I feel like this gives us a significant edge,” she added.

She also explained that they found no differences in user satisfaction between the guided and unguided version of the therapy, so now they must discover why the guided version works better. One notable point is that patients accessed (online) the guided program twice as many times as those who used the self-guided version, but the number of times used is not enough to explain the better outcomes.

“We believe that patients develop some sort of connection with the guides, who are not providing therapy but only making recommendations in brief interactions with patients once a week. It has something to do with that connection, in addition to the longer time spent interacting with the platform, which provides better results with the guided version,” stated Dr. Benjet Miner.

One of the main limitations of this study is that, though it compares three treatment methods, the third one (standard care) is not homogeneous, because each of the seven universities from which the students were selected has different resources for this purpose. “Some universities, like the National Autonomous University of Mexico, have very formal services, with teams of psychologists and psychiatrists, while others don’t have this type of service, or they cover additional aspects, like vocational counseling. So, it’s very difficult to determine exactly what kind of care patients are receiving, because it’s not homogeneous,” she said.

As many as nine assessments using psychometric tests are sometimes required before the intervention can be evaluated, said Dr. Méndez. “This study doesn’t go into too much detail in that area, focusing rather on treatment. So, it would be important to know the diagnoses of the users, who may be experiencing different degrees of depression or anxiety. It would be worth asking what happens if a user requires psychiatric treatment or support.”

Dr. Méndez, who provides psychological therapy in person and online at the Student Support and Counselling Center at FESI, pointed out that it would be important to provide close follow-up on these results to see whether they are sustained in the short and long terms. In her opinion, this model could be presented to other users requiring treatment for anxiety or depression, provided that they can use information and communication technologies.

This precision model, which can also be supported on mobile phones or tablets, could be transferred to primary care facilities or vulnerable populations in rural areas, said Dr. Benjet Miner. “The idea is to reach a point where these algorithms become accurate enough and have a really strong predictive power so that clinicians can use them. The goal is always to find the best treatment at the lowest cost, so that it’s sustainable,” she concluded.

This study was funded by grant number R01MH120648 from the National Institute of Mental Health and the Fogarty International Center. Dr. Benjet Miner reports no relevant financial relationships; the declarations of the remaining authors can be found at the publication’s website.

This article was translated from Medscape’s Spanish Edition and a version first appeared on Medscape.com.

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
 

Phase 1 trial of muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.

Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.

“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m² or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
 

OCEAN (a)-DOSE extended study of olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

courtesy Brigham and Women's Hospital

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.

Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).

In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.

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

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
 

Phase 1 trial of muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.

Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.

“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m² or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
 

OCEAN (a)-DOSE extended study of olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

courtesy Brigham and Women's Hospital

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.

Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).

In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.

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

Investigational muvalaplin (Eli Lilly), the first oral therapy being developed to lower lipoprotein (a) levels, was shown to reduce levels in a phase 1 trial, with no safety concerns, researchers report.

In a separate phase 2 study, olpasiran (Amgen), which is given by injection, lowered Lp(a) levels for nearly 1 year after the last dose, also without safety concerns, in a phase 2 trial extension.

Researchers presented these findings in two late breaking science sessions at the recent annual congress of the European Society of Cardiology. The muvalaplin trial was also simultaneously published online as a preliminary communication in JAMA.
 

Phase 1 trial of muvalaplin

Epidemiologic and genetic evidence suggests that Lp(a) has a causal role in cardiovascular disease (CVD) events, Stephen J. Nicholls, MBBS, PhD, and colleagues wrote.

In initial studies, Lp(a) was reduced by approximately 80% with an antisense oligonucleotide (pelacarsen, Ionis) and by up to 98% with RNA interference (olpasiran) – both injectable therapies.

Muvalaplin is a small molecule that disrupts the binding of apolipoprotein(a) to apo B100 that forms Lp(a), said Dr. Nicholls, from Monash University and Victoria Heart Institute, both in Melbourne.

In this first-in-human, phase 1 trial in 114 healthy individuals, Lp(a) levels were reduced up to 65% following daily administration of 100-800 mg of muvalaplin for 14 days, without safety or tolerability concerns or significant effects on plasminogen, a homologous protein, he said in an interview.

Approximately 20% of the population have high LP(a) levels, Dr. Nicholls noted.

“We saw in the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor trials that Lp(a) lowering is associated with benefit, but those agents substantially lower LDL cholesterol,” he said. “Now, here for the first time we have an oral agent” that lowers Lp(a) levels. However, “we will still need to determine if this leads to a reduction in cardiovascular risk,” in longer and larger trials.

The researchers randomly assigned healthy adults aged 18-69 with a BMI of 30 kg/m² or less, into two groups.

The 55 participants in the single ascending dose group were randomly assigned to receive muvalaplin (1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or matching placebo daily for 14 days. They had a mean age of 29 years; 64% were female and 91% were White. Their median Lp(a) level was 10.3 mg/dL.

The 59 participants in the multiple ascending dose group, who were required to have Lp(a) of at least 30 mg/dL, were randomly assigned to receive muvalaplin (30 mg, 100 mg, 300 mg, 500 mg, or 800 mg) or placebo daily for 14 days. They had a mean age of 32; 58% were female and 80% were White. Their median Lp(a) level was 58.4 mg/dL.

The maximum placebo-adjusted Lp(a) reduction was 63% to 65%, which occurred on days 14 and 15, in participants who received doses of at least 100 mg.

The levels returned to baseline by day 29 for the 30-mg dose, day 43 for the 100-mg dose, and day 64 for the 300- to 800-mg doses. 

There were no deaths or serious adverse events. Treatment-associated adverse events were reported by 62% in the single ascending dose group and by 80% in the multiple ascending dose group; these were mild and transient and included headache, fatigue, and vomiting.  

Muvalaplin had no significant effects on LDL cholesterol, HDL cholesterol, or total cholesterol or apo B100, and did not significantly affect plasminogen levels or activity.

The team is currently conducting the phase 2 KRAKEN trial. They plan to enroll 233 patients aged 40 and older with elevated Lp(a) levels (≥ 175 nmol/L) and high risk for cardiovascular events. The primary outcome is change in Lp(a) levels at 12 weeks, and the estimated primary trial completion is this coming January.
 

OCEAN (a)-DOSE extended study of olpasiran

In a separate presentation, Michelle L. O’Donoghue, MD, MPH, reported findings from an extension of the phase 2 trial of olpasiran in patients with atherosclerotic CVD and elevated Lp(a).

courtesy Brigham and Women's Hospital

Olpasiran is a small interfering RNA (siRNA) molecule directed to the liver that prevents the assembly of Lp(a).

Dr. O’Donoghue, from Brigham and Women’s Hospital and Harvard Medical School in Boston, presented the main results from the OCEAN(a) DOSE (TIMI 67) study of olpasiran, at the 2022 annual scientific sessions of the American Heart Association, and the trial was simultaneously published online in the New England Journal of Medicine.

The trial included 281 patients with established atherosclerotic CVD and Lp(a) greater than 150 nmol/L (60 mg/dL). Participants were randomly assigned to one of four doses of olpasiran (10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.

At 36 weeks, doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a).

The extension study aimed to examine the effects of olpasiran on levels of the oxidized phospholipids on apolipoprotein B100 (OxPL-apoB) and on levels of Lp(a), as well as safety, after the last administered dose.

The minimum extended off-treatment period was 72 weeks from randomization (in 276 patients). Complete follow-up was a median of 86 weeks (50 weeks after the last administered dose).

The study showed that “olpasiran is an siRNA that robustly lowers Lp(a) levels” and “leads to a marked and durable reduction” in proatherogenic OxPL-apoB, Dr. O’Donoghue reported.

Patients on doses of at least 75 mg every 12 weeks “sustained around a 40%-50% placebo-adjusted reduction in Lp(a) levels close to 1 year after the last dose.”

The long-term clinical efficacy and safety of olpasiran are being further evaluated in the ongoing phase 3 OCEAN(a)-Outcomes trial which has as an estimated enrollment of 6000 and projected completion in December 2026.

These are “exciting” results, and “we’re all waiting with bated breath for more news,” said session cochairperson Louise Bowman, MD, University of Oxford (England).

In reply to questions from the audience, Dr. O’Donoghue said that the only adverse events that were imbalanced during the on-treatment phase were injection-site reactions and localized hypersensitivity reactions, which were not reported during the off-treatment period. There was also no evidence of a proinflammatory increase in phospholipids, or of a rebound effect on Lp(a) levels after stopping olpasiran.

The muvalaplin study was funded by Eli Lilly. Dr. Nicholls reported numerous conflicts of interest with various pharmaceutical companies. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Merck, and Novartis; consulting with Amgen and Novartis; and serving as a data and safety monitor for AstraZeneca and Janssen.

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

A newly published scientific statement from the American Heart Association focuses on the impact of aggressive low-density lipoprotein cholesterol (LDL-C) lowering on the risk for dementia and hemorrhagic stroke.

“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.

The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.

The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.

They reached four main conclusions:

• First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
• Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
• Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
• Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.

The research had no commercial funding. A list of disclosures for the writing group is available with the original article.

A version of this article appeared on Medscape.com.

A newly published scientific statement from the American Heart Association focuses on the impact of aggressive low-density lipoprotein cholesterol (LDL-C) lowering on the risk for dementia and hemorrhagic stroke.

“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.

The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.

The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.

They reached four main conclusions:

• First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
• Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
• Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
• Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.

The research had no commercial funding. A list of disclosures for the writing group is available with the original article.

A version of this article appeared on Medscape.com.

A newly published scientific statement from the American Heart Association focuses on the impact of aggressive low-density lipoprotein cholesterol (LDL-C) lowering on the risk for dementia and hemorrhagic stroke.

“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.

The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.

The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.

They reached four main conclusions:

• First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
• Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
• Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
• Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.

The research had no commercial funding. A list of disclosures for the writing group is available with the original article.

A version of this article appeared on Medscape.com.