When Denise M. Adams, MD, began her career as a pediatric oncologist 25 years ago, there were many interventions for vascular anomalies, but most were surgery based and medical options were limited.

“The medicines we had were believed to be antiangiogenic and they were used not only for tumors but for all sorts of malformations,” Dr. Adams, a pediatric hematologist-oncologist at Children’s Hospital of Philadelphia, recalled during the annual meeting of the Society for Pediatric Dermatology. “I didn’t understand how so many different phenotypes could respond to the same medicine. Not all of them did, but some did have some response.”

She also grew frustrated by the lack of clinical trials and collaborative research groups involving patients with vascular anomalies. “I called this the chicken soup of medical management,” she said. “As we got more involved in vascular anomalies, the power of one patient or that power of a few patients led us in a direction for improved medical management. Or knowledge was gained by one patient who failed all noted medical management and led us into a direction repurposing a drug that actually wound up working.”

Propranolol, for example, became a key medicine for the treatment of vascular anomalies when it was found to improve hemangiomas in children who were given the drug for other reasons. “From this observation a key prospective study was performed and this beta-blocker became FDA approved for the treatment of complicated hemangiomas,” said Dr. Adams, who directs the hospital’s Comprehensive Vascular Anomalies Program. “That was how a bedside observation let to bench intervention, and how presently we are investigating bench interventions related to the mechanism of propranolol therapy.”

Then there is the story of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. In her previous role as medical director of the Hemangioma and Vascular Malformation Center at Cincinnati Children’s Hospital, Dr. Adams and colleagues cared for an infant who presented with a Kaposiform hemangioendothelioma (KHE). “At that time, she was given our standard of practice for the treatment, but our standard of practice was not good enough,” she said.

While other options were being discussed for this patient, “we had been doing some collaborative work with pathology and nephrology on the PIKC3A pathway, because we knew that germline mutations of TEK were involved in this pathway, and we knew that 50% of patients with PTEN mutations had vascular anomalies. So, we hypothesized that this pathway was involved in vascular anomalies.”

They also had earlier success using mTOR inhibition for tuberous sclerosis patients with angiomyolipomas and patients with neurofibromatosis. “We needed a medicine that could be given orally because we did not think this patient was going to do well, so we started her on sirolimus,” Dr. Adams said. “She had a great response. This was followed by a phase 2 study, which proved efficacy and led to discovery of biomarkers.” This is where the angiopoietin-2 story started, she said, noting that this biomarker is now used “to differentiate KLA [Kaposiform lymphangiomatosis] from KHE and KLAs and KHE from other disorders.”

This bedside work helped researchers to better understand the mechanism of action in other disorders, such as observing somatic mutations in PIK3CA in patients with CLOVES syndrome. “This meant that we could now correlate the phenotype to the genotype, and it opened up targeted therapy with developmental therapeutics that were already in use for oncology,” Dr. Adams said. “We know we had mTOR inhibition with sirolimus and everolimus. We now have an AKT inhibitor, a PIK3CA inhibitor, and we now have another side of the pathway which deals with RASopathies, and some other medicines that we can use.”

Miransertib, a potent PAN-AKT inhibitor initially used for breast cancer, is currently being evaluated in open-label, phase 1 and 2 trials in patients with PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome. The dose used in a pilot study is about one-sixth of the dose used for oncology patients, Dr. Adams said.

She and her colleagues used miransertib to treat a 3-year-old with CLOVES syndrome who had lipomatous infiltration of the abdomen and retroperitoneum with failure to thrive. “He was not eating and was G-tube dependent,” she recalled. “After a month of therapy, he started eating and had improvement in his quality of life,” although despite this improvement volumetric MRI remained unchanged.

Advances in bench to bedside approaches are also under way. Hakon Hakonarson, MD, PhD, the founding director of the Center for Applied Genomics at CHOP, has discovered several genes with in vitro testing and zebra fish modeling, which has been followed by testing medicines on patients.

One such patient, according to Dr. Adams, had a severe central conducting lymphatic anomaly, with a pericardial effusion and significant dysfunction of the central conducting system. The patient was found to have an ARAF mutation, which induces ERK activation. “ERK is downstream of MEK, so the question was whether a MEK inhibitor, trametinib, could be used to treat this patient,” she said. “Trametinib was first used in tissue culture, then used in a zebra fish model and it showed some positive results. Then it was taken to the patient, who had improvement of pulmonary function, remodeling of the lymphatic system, and decrease in the size of his legs.”

Other antiangiogenic agents being used for the treatment of vascular anomalies include bevacizumab, which is being used in hereditary hemorrhagic telangiectasia, and thalidomide for HHT and arteriovenous malformations. For more information, Dr. Adams recommended a comprehensive review of vascular anomalies, related genes, and treatments that was published in Circulation Research.

The goal of future drug therapies is to support normal growth, “so we don’t need a maximum tolerated dose,” Dr. Adams said. “We need to be very careful of short-term and long-term side effects.”

Going forward, she said that she would like to see more natural history studies of vascular anomalies, improved outcome measures for clinical trials, adaptive study design, preclinical testing, animal model studies, universal availability of genomic testing, improvement of NIH funding, research collaboration nationally and internationally, and industry support.

Dr. Adams disclosed that she is a consultant to Venthera and Novartis.

[email protected]

When Denise M. Adams, MD, began her career as a pediatric oncologist 25 years ago, there were many interventions for vascular anomalies, but most were surgery based and medical options were limited.

“The medicines we had were believed to be antiangiogenic and they were used not only for tumors but for all sorts of malformations,” Dr. Adams, a pediatric hematologist-oncologist at Children’s Hospital of Philadelphia, recalled during the annual meeting of the Society for Pediatric Dermatology. “I didn’t understand how so many different phenotypes could respond to the same medicine. Not all of them did, but some did have some response.”

She also grew frustrated by the lack of clinical trials and collaborative research groups involving patients with vascular anomalies. “I called this the chicken soup of medical management,” she said. “As we got more involved in vascular anomalies, the power of one patient or that power of a few patients led us in a direction for improved medical management. Or knowledge was gained by one patient who failed all noted medical management and led us into a direction repurposing a drug that actually wound up working.”

Propranolol, for example, became a key medicine for the treatment of vascular anomalies when it was found to improve hemangiomas in children who were given the drug for other reasons. “From this observation a key prospective study was performed and this beta-blocker became FDA approved for the treatment of complicated hemangiomas,” said Dr. Adams, who directs the hospital’s Comprehensive Vascular Anomalies Program. “That was how a bedside observation let to bench intervention, and how presently we are investigating bench interventions related to the mechanism of propranolol therapy.”

Then there is the story of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. In her previous role as medical director of the Hemangioma and Vascular Malformation Center at Cincinnati Children’s Hospital, Dr. Adams and colleagues cared for an infant who presented with a Kaposiform hemangioendothelioma (KHE). “At that time, she was given our standard of practice for the treatment, but our standard of practice was not good enough,” she said.

While other options were being discussed for this patient, “we had been doing some collaborative work with pathology and nephrology on the PIKC3A pathway, because we knew that germline mutations of TEK were involved in this pathway, and we knew that 50% of patients with PTEN mutations had vascular anomalies. So, we hypothesized that this pathway was involved in vascular anomalies.”

They also had earlier success using mTOR inhibition for tuberous sclerosis patients with angiomyolipomas and patients with neurofibromatosis. “We needed a medicine that could be given orally because we did not think this patient was going to do well, so we started her on sirolimus,” Dr. Adams said. “She had a great response. This was followed by a phase 2 study, which proved efficacy and led to discovery of biomarkers.” This is where the angiopoietin-2 story started, she said, noting that this biomarker is now used “to differentiate KLA [Kaposiform lymphangiomatosis] from KHE and KLAs and KHE from other disorders.”

This bedside work helped researchers to better understand the mechanism of action in other disorders, such as observing somatic mutations in PIK3CA in patients with CLOVES syndrome. “This meant that we could now correlate the phenotype to the genotype, and it opened up targeted therapy with developmental therapeutics that were already in use for oncology,” Dr. Adams said. “We know we had mTOR inhibition with sirolimus and everolimus. We now have an AKT inhibitor, a PIK3CA inhibitor, and we now have another side of the pathway which deals with RASopathies, and some other medicines that we can use.”

Miransertib, a potent PAN-AKT inhibitor initially used for breast cancer, is currently being evaluated in open-label, phase 1 and 2 trials in patients with PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome. The dose used in a pilot study is about one-sixth of the dose used for oncology patients, Dr. Adams said.

She and her colleagues used miransertib to treat a 3-year-old with CLOVES syndrome who had lipomatous infiltration of the abdomen and retroperitoneum with failure to thrive. “He was not eating and was G-tube dependent,” she recalled. “After a month of therapy, he started eating and had improvement in his quality of life,” although despite this improvement volumetric MRI remained unchanged.

Advances in bench to bedside approaches are also under way. Hakon Hakonarson, MD, PhD, the founding director of the Center for Applied Genomics at CHOP, has discovered several genes with in vitro testing and zebra fish modeling, which has been followed by testing medicines on patients.

One such patient, according to Dr. Adams, had a severe central conducting lymphatic anomaly, with a pericardial effusion and significant dysfunction of the central conducting system. The patient was found to have an ARAF mutation, which induces ERK activation. “ERK is downstream of MEK, so the question was whether a MEK inhibitor, trametinib, could be used to treat this patient,” she said. “Trametinib was first used in tissue culture, then used in a zebra fish model and it showed some positive results. Then it was taken to the patient, who had improvement of pulmonary function, remodeling of the lymphatic system, and decrease in the size of his legs.”

Other antiangiogenic agents being used for the treatment of vascular anomalies include bevacizumab, which is being used in hereditary hemorrhagic telangiectasia, and thalidomide for HHT and arteriovenous malformations. For more information, Dr. Adams recommended a comprehensive review of vascular anomalies, related genes, and treatments that was published in Circulation Research.

The goal of future drug therapies is to support normal growth, “so we don’t need a maximum tolerated dose,” Dr. Adams said. “We need to be very careful of short-term and long-term side effects.”

Going forward, she said that she would like to see more natural history studies of vascular anomalies, improved outcome measures for clinical trials, adaptive study design, preclinical testing, animal model studies, universal availability of genomic testing, improvement of NIH funding, research collaboration nationally and internationally, and industry support.

Dr. Adams disclosed that she is a consultant to Venthera and Novartis.

[email protected]

When Denise M. Adams, MD, began her career as a pediatric oncologist 25 years ago, there were many interventions for vascular anomalies, but most were surgery based and medical options were limited.

“The medicines we had were believed to be antiangiogenic and they were used not only for tumors but for all sorts of malformations,” Dr. Adams, a pediatric hematologist-oncologist at Children’s Hospital of Philadelphia, recalled during the annual meeting of the Society for Pediatric Dermatology. “I didn’t understand how so many different phenotypes could respond to the same medicine. Not all of them did, but some did have some response.”

She also grew frustrated by the lack of clinical trials and collaborative research groups involving patients with vascular anomalies. “I called this the chicken soup of medical management,” she said. “As we got more involved in vascular anomalies, the power of one patient or that power of a few patients led us in a direction for improved medical management. Or knowledge was gained by one patient who failed all noted medical management and led us into a direction repurposing a drug that actually wound up working.”

Propranolol, for example, became a key medicine for the treatment of vascular anomalies when it was found to improve hemangiomas in children who were given the drug for other reasons. “From this observation a key prospective study was performed and this beta-blocker became FDA approved for the treatment of complicated hemangiomas,” said Dr. Adams, who directs the hospital’s Comprehensive Vascular Anomalies Program. “That was how a bedside observation let to bench intervention, and how presently we are investigating bench interventions related to the mechanism of propranolol therapy.”

Then there is the story of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. In her previous role as medical director of the Hemangioma and Vascular Malformation Center at Cincinnati Children’s Hospital, Dr. Adams and colleagues cared for an infant who presented with a Kaposiform hemangioendothelioma (KHE). “At that time, she was given our standard of practice for the treatment, but our standard of practice was not good enough,” she said.

While other options were being discussed for this patient, “we had been doing some collaborative work with pathology and nephrology on the PIKC3A pathway, because we knew that germline mutations of TEK were involved in this pathway, and we knew that 50% of patients with PTEN mutations had vascular anomalies. So, we hypothesized that this pathway was involved in vascular anomalies.”

They also had earlier success using mTOR inhibition for tuberous sclerosis patients with angiomyolipomas and patients with neurofibromatosis. “We needed a medicine that could be given orally because we did not think this patient was going to do well, so we started her on sirolimus,” Dr. Adams said. “She had a great response. This was followed by a phase 2 study, which proved efficacy and led to discovery of biomarkers.” This is where the angiopoietin-2 story started, she said, noting that this biomarker is now used “to differentiate KLA [Kaposiform lymphangiomatosis] from KHE and KLAs and KHE from other disorders.”

This bedside work helped researchers to better understand the mechanism of action in other disorders, such as observing somatic mutations in PIK3CA in patients with CLOVES syndrome. “This meant that we could now correlate the phenotype to the genotype, and it opened up targeted therapy with developmental therapeutics that were already in use for oncology,” Dr. Adams said. “We know we had mTOR inhibition with sirolimus and everolimus. We now have an AKT inhibitor, a PIK3CA inhibitor, and we now have another side of the pathway which deals with RASopathies, and some other medicines that we can use.”

Miransertib, a potent PAN-AKT inhibitor initially used for breast cancer, is currently being evaluated in open-label, phase 1 and 2 trials in patients with PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome. The dose used in a pilot study is about one-sixth of the dose used for oncology patients, Dr. Adams said.

She and her colleagues used miransertib to treat a 3-year-old with CLOVES syndrome who had lipomatous infiltration of the abdomen and retroperitoneum with failure to thrive. “He was not eating and was G-tube dependent,” she recalled. “After a month of therapy, he started eating and had improvement in his quality of life,” although despite this improvement volumetric MRI remained unchanged.

Advances in bench to bedside approaches are also under way. Hakon Hakonarson, MD, PhD, the founding director of the Center for Applied Genomics at CHOP, has discovered several genes with in vitro testing and zebra fish modeling, which has been followed by testing medicines on patients.

One such patient, according to Dr. Adams, had a severe central conducting lymphatic anomaly, with a pericardial effusion and significant dysfunction of the central conducting system. The patient was found to have an ARAF mutation, which induces ERK activation. “ERK is downstream of MEK, so the question was whether a MEK inhibitor, trametinib, could be used to treat this patient,” she said. “Trametinib was first used in tissue culture, then used in a zebra fish model and it showed some positive results. Then it was taken to the patient, who had improvement of pulmonary function, remodeling of the lymphatic system, and decrease in the size of his legs.”

Other antiangiogenic agents being used for the treatment of vascular anomalies include bevacizumab, which is being used in hereditary hemorrhagic telangiectasia, and thalidomide for HHT and arteriovenous malformations. For more information, Dr. Adams recommended a comprehensive review of vascular anomalies, related genes, and treatments that was published in Circulation Research.

The goal of future drug therapies is to support normal growth, “so we don’t need a maximum tolerated dose,” Dr. Adams said. “We need to be very careful of short-term and long-term side effects.”

Going forward, she said that she would like to see more natural history studies of vascular anomalies, improved outcome measures for clinical trials, adaptive study design, preclinical testing, animal model studies, universal availability of genomic testing, improvement of NIH funding, research collaboration nationally and internationally, and industry support.

Dr. Adams disclosed that she is a consultant to Venthera and Novartis.

[email protected]

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

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

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

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

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

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

Not so long ago, Heather Simpson of Dallas was known as the anti-vaccine mom who dressed as “the measles” for Halloween. She painted red spots on her face and posted her photo on Facebook, joking: “Was trying to think of the least scary thing I could be for Halloween … so I became the measles.” It went viral with the anti-vaccine crowd.

But between that Halloween and today, a series of “aha” moments transformed Ms. Simpson’s attitudes toward vaccines.

In January 2021, one of those moments involved her daughter, now 4, who was scratched by a feral cat, raising concerns about tetanus. Her daughter had been bitten by a dog when she was just 1, and Ms. Simpson turned down advice then to get a tetanus shot. “I was convinced the tetanus shot would kill her faster than the tetanus.”

After the cat incident, the anxiety was so exhausting, she listened to the nurse practitioner at the clinic, whom she trusted. The nurse gently reassured Ms. Simpson that the shot was less risky than the possibility of tetanus – but did not bombard her with statistics – and that won over Ms. Simpson and triggered an overall rethinking of her vaccine stance.

Fast-forward to February, and that “aha” turned into action when Ms. Simpson launched a “Back to the Vax” effort with a fellow former vaccine opponent. Through their website, Facebook page, and podcasts, they now encourage people to get the COVID-19 vaccine, as well as other immunizations.
 

Challenge: Reaching the rest

With just over 52% of those eligible in the United States fully vaccinated as of Sept. 1, health care providers and others have a continuing challenge ahead: Trying to convince those who are eligible but still holding out to get vaccinated.

Recent data and a poll show some movement in the right direction, as immunizations are increasing and hesitancy is declining among certain groups. According to federal officials, about 14 million people in the United States got their first dose in August, an increase of 4 million, compared to the numbers who got it in July.

And a new poll from the Axios-IPSOS Coronavirus Index found only one in five Americans, or 20%, say they are not likely to get the vaccine, while “hard opposition,” those not at all likely, has dropped to 14% of those adults.

But there is still a lot of work to do. So, how do medical professionals or concerned citizens reach those who haven’t gotten vaccinated yet, whatever their reason?

Many experts in communication and persuasion that this news organization talked to agree that throwing statistics at people hesitant to get the COVID-19 vaccine is generally useless and often backfires.

So what does work, according to these experts?

• Emphasizing the trends of more people getting vaccinated.
• Focusing on everyone’s freedom of choice.
• Listening to concerns without judgment.
• Offering credible information.
• Correcting myths when necessary.
• Helping them fit vaccination into their “world view.”

Stories over statistics

Talking about the trends of vaccinations can definitely change minds about getting vaccinated, said Robert Cialdini, PhD, regents professor emeritus of psychology and marketing at Arizona State University, Tempe, and author of the recently updated book, “Influence: The Psychology of Persuasion,” which has sold over 5 million copies since it was first published in 1984.

Face-to-face with a hesitant patient, a doctor can say: “More and more people are being vaccinated every day,” Dr. Cialdini says. “The reason you say more and more is [that] it conveys a trend. When people see a trend, they project it into the future that it is going to get even larger.”

A focus on choice can also help people change their minds and accept the vaccine, he says. “A lot of conspiracy theorists claim they don’t want to do it because they are being pushed or forced by the government, and they are resisting that.”

If that’s the case, presenting people with new information, such as the increased infectiousness of the Delta variant, and suggesting that a decision be made based on the new information, can work, Dr. Cialdini says, but be sure to end with: “It’s completely up to you.”

“This removes all their sense of being pushed. It says, ‘Here is all the evidence.’ ” At this point, a doctor’s personal recommendation with a patient who trusts him or her may sway them, Dr. Cialdini said. “I think you have to personalize the communication in both directions. That is, to say, ‘For someone in your situation, I would personally recommend that you get the vaccine.’ ” A health care professional’s authority and expertise can carry the day, he says, although “not always.”

This approach worked, Dr. Cialdini says, with a friend of the family hesitant about the COVID-19 vaccine. “I told him: ‘We have gotten it. You trust us, right?’ ” He waited for the person to say yes.

Then: “For someone in your position, my personal recommendation is to get vaccinated. There is new information about the vaccine, and more and more people are getting vaccinated. And of course, it is completely up to you.”

The person decided to get the vaccine.
 

‘Live in that space’

“People develop negative attitudes [about vaccines] by accessing alternative sources of information, anecdotes, and personal stories,” said Matthew Seeger, PhD, dean of the College of Fine, Performing, and Communication Arts and codirector of the Center for Emerging Infectious Diseases at Wayne State University in Detroit.

“If we are going to change their opinion, we need to live in that space.” That means listening first, he says. Ask: “Where did you get that information? How credible do you think the sources are? What do you mean about the vaccine changing DNA?”

Then, you might respond, he said, by addressing that specific information, such as, “We have no cases of DNA being changed.”

Dr. Seeger recalls that his mother would simply talk louder when she couldn’t understand someone who wasn’t a native English speaker. “That’s what we are trying to do with the vaccine-hesitant,” he says. “In some cases, we are yelling at them.” Instead, he says, probe their sources of information.

For some who are vaccine-hesitant, Dr. Seeger said, it is not just about the vaccine. The attitude about vaccines is tied in, often, with a distrust of government and feelings about personal freedom. “That’s one reason it’s so hard to change the attitude.” For some, getting the vaccine in a family against the vaccine might also disrupt their social structure or even get them ostracized.

For these people, a health care provider might give opportunities to get the vaccine without affecting either what they see as their political stance or upsetting family harmony. “There are places you can go, make an appointment, get a vaccine, and nobody knows,” Dr. Seeger said.

One Missouri doctor told CNN that some people calling for a vaccine appointment do request privacy, such as going through a drive-thru or having the shot as they sit in their cars. She said the hospital tries to accommodate them, reasoning that every additional vaccine shot is a win.

Dr. Seeger agrees. “Of course there are still public records,” he says, “but you can still claim you are a vaccine denier. It’s very difficult to persuade people to give up their whole world. Vaccine denial is part of that world. At this point, we need to do whatever we can to get people vaccinated.”
 

From peer to peer

A theme that runs through many of these persuasion techniques is peer pressure.

One example, while a bit more profane and confrontational than some groups, is COVIDAteMyFace, a subgroup, or “subreddit,” of the popular online site Reddit, which hosts numerous forums inviting users to share news and comments on a variety of topics. The subreddit has over 20,000 members. Its purpose, says the sub’s creator, “was to document the folks who denied COVID, then got bitten in the ass by it.” Reports are of actual cases.

“It’s interesting and powerful that Reddit users are taking this on,” Dr. Seeger said. And this kind of peer pressure, or peer-to-peer information, can be persuasive, he says. “We often seek consensual validation from peers about risk messages and risk behaviors.”

For instance, hurricane evacuation notices are more effective, he said, when people learn their neighbors are leaving.

Peer information – “the number of others who are doing or believing or responding to something – definitely persuades people,” agreed Dr. Cialdini. “When a lot of others are responding in a particular way – for example, getting vaccinated – people follow for three reasons: The action seems more appropriate or correct, it appears more feasible to perform, and it avoids social disapproval from those others.”
 

Let them talk, give them time

Gladys Jimenez is a contact tracer and “vaccine ambassador” for Tracing Health, a partnership between the Oregon Public Health Institute and the Public Health Institute that has nearly 300 bilingual contract tracers who serve the ethnic communities they’re from. During a typical week, she talks to 50 people or more, and promoting the vaccine is top of mind.

The conversations, Ms. Jimenez said, are like a dance. She presents information, then steps back and lets them talk. “I want to hear the person talk, where they are coming from, where they are at.” Depending on what they say, she gives them more information or corrects their misinformation. “They often will say, ‘Oh, I didn’t know that.’ ”

It’s rarely one conversation that convinces hesitant people, she said. “I’m planting this seed in their brain. ... people want someone to listen to them ... they want to vent.”

Once you let them do that, Ms. Jimenez said, “I can tell the person is in a different state of mind.” She also knows that people “will make the decision in their own time.”

With time, people can change their minds, as a Southern California woman who resisted at first (and asked to remain anonymous) can attest. “When the vaccine first came out, I remember thinking [that] it was a quick fix to a very big problem,” she said. The lack of full FDA approval, which has since been granted, was also an issue. She doesn’t oppose vaccines, she said, but was leery just of the COVID-19 vaccine.

When her longtime partner got his vaccine, he urged her to go right away for hers. She stalled. He got his second dose and grew impatient with her hesitancy. It began to wear on the relationship. Finally, the woman talked to two health care professionals she knew socially. They both follow the science, and “they both could explain vaccination to me in a way that resonated. The information was coming from sources I already trusted.”

Those conversations are what convinced her to get vaccinated this summer.
 

Simpson’s transformation

Ms. Simpson of Back to the Vax got her first COVID-19 immunization April 16. She had an allergic reaction, including severe itchiness and a bad headache, and needed emergency care, she said. Even so, she scheduled her second shot appointment.

Like many who turned against vaccines as adults, Ms. Simpson had all her childhood vaccines, but she developed a distrust after watching a lengthy documentary series that warned of vaccine dangers as an adult.

Looking back at that documentary, she thought about how it seems to blame everything – childhood cancer, ADHD, autism, allergies – on vaccinations. That suddenly seemed like sketchy science to her.

So did the claim from a family friend who said she knew someone who got the flu shot and began walking backward. She researched on her own, and with time, she decided to be pro-vaccines.

These days, she continues to find that stories, not statistics, are changing the minds of many who decide to get vaccinated. If the nurse practitioner urging the tetanus shot for her daughter had told her that the tetanus shot is linked with problems in one of a specific number of people who get it, no matter how large that second number was, Ms. Simpson said she would have thought: “What if she is that one?”

So she relies on stories that point out how universally vulnerable people are to COVID-19 first, facts next.

“Facts help once you are already moved,” Ms. Simpson said.

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

Not so long ago, Heather Simpson of Dallas was known as the anti-vaccine mom who dressed as “the measles” for Halloween. She painted red spots on her face and posted her photo on Facebook, joking: “Was trying to think of the least scary thing I could be for Halloween … so I became the measles.” It went viral with the anti-vaccine crowd.

But between that Halloween and today, a series of “aha” moments transformed Ms. Simpson’s attitudes toward vaccines.

In January 2021, one of those moments involved her daughter, now 4, who was scratched by a feral cat, raising concerns about tetanus. Her daughter had been bitten by a dog when she was just 1, and Ms. Simpson turned down advice then to get a tetanus shot. “I was convinced the tetanus shot would kill her faster than the tetanus.”

After the cat incident, the anxiety was so exhausting, she listened to the nurse practitioner at the clinic, whom she trusted. The nurse gently reassured Ms. Simpson that the shot was less risky than the possibility of tetanus – but did not bombard her with statistics – and that won over Ms. Simpson and triggered an overall rethinking of her vaccine stance.

Fast-forward to February, and that “aha” turned into action when Ms. Simpson launched a “Back to the Vax” effort with a fellow former vaccine opponent. Through their website, Facebook page, and podcasts, they now encourage people to get the COVID-19 vaccine, as well as other immunizations.
 

Challenge: Reaching the rest

With just over 52% of those eligible in the United States fully vaccinated as of Sept. 1, health care providers and others have a continuing challenge ahead: Trying to convince those who are eligible but still holding out to get vaccinated.

Recent data and a poll show some movement in the right direction, as immunizations are increasing and hesitancy is declining among certain groups. According to federal officials, about 14 million people in the United States got their first dose in August, an increase of 4 million, compared to the numbers who got it in July.

And a new poll from the Axios-IPSOS Coronavirus Index found only one in five Americans, or 20%, say they are not likely to get the vaccine, while “hard opposition,” those not at all likely, has dropped to 14% of those adults.

But there is still a lot of work to do. So, how do medical professionals or concerned citizens reach those who haven’t gotten vaccinated yet, whatever their reason?

Many experts in communication and persuasion that this news organization talked to agree that throwing statistics at people hesitant to get the COVID-19 vaccine is generally useless and often backfires.

So what does work, according to these experts?

• Emphasizing the trends of more people getting vaccinated.
• Focusing on everyone’s freedom of choice.
• Listening to concerns without judgment.
• Offering credible information.
• Correcting myths when necessary.
• Helping them fit vaccination into their “world view.”

Stories over statistics

Talking about the trends of vaccinations can definitely change minds about getting vaccinated, said Robert Cialdini, PhD, regents professor emeritus of psychology and marketing at Arizona State University, Tempe, and author of the recently updated book, “Influence: The Psychology of Persuasion,” which has sold over 5 million copies since it was first published in 1984.

Face-to-face with a hesitant patient, a doctor can say: “More and more people are being vaccinated every day,” Dr. Cialdini says. “The reason you say more and more is [that] it conveys a trend. When people see a trend, they project it into the future that it is going to get even larger.”

A focus on choice can also help people change their minds and accept the vaccine, he says. “A lot of conspiracy theorists claim they don’t want to do it because they are being pushed or forced by the government, and they are resisting that.”

If that’s the case, presenting people with new information, such as the increased infectiousness of the Delta variant, and suggesting that a decision be made based on the new information, can work, Dr. Cialdini says, but be sure to end with: “It’s completely up to you.”

“This removes all their sense of being pushed. It says, ‘Here is all the evidence.’ ” At this point, a doctor’s personal recommendation with a patient who trusts him or her may sway them, Dr. Cialdini said. “I think you have to personalize the communication in both directions. That is, to say, ‘For someone in your situation, I would personally recommend that you get the vaccine.’ ” A health care professional’s authority and expertise can carry the day, he says, although “not always.”

This approach worked, Dr. Cialdini says, with a friend of the family hesitant about the COVID-19 vaccine. “I told him: ‘We have gotten it. You trust us, right?’ ” He waited for the person to say yes.

Then: “For someone in your position, my personal recommendation is to get vaccinated. There is new information about the vaccine, and more and more people are getting vaccinated. And of course, it is completely up to you.”

The person decided to get the vaccine.
 

‘Live in that space’

“People develop negative attitudes [about vaccines] by accessing alternative sources of information, anecdotes, and personal stories,” said Matthew Seeger, PhD, dean of the College of Fine, Performing, and Communication Arts and codirector of the Center for Emerging Infectious Diseases at Wayne State University in Detroit.

“If we are going to change their opinion, we need to live in that space.” That means listening first, he says. Ask: “Where did you get that information? How credible do you think the sources are? What do you mean about the vaccine changing DNA?”

Then, you might respond, he said, by addressing that specific information, such as, “We have no cases of DNA being changed.”

Dr. Seeger recalls that his mother would simply talk louder when she couldn’t understand someone who wasn’t a native English speaker. “That’s what we are trying to do with the vaccine-hesitant,” he says. “In some cases, we are yelling at them.” Instead, he says, probe their sources of information.

For some who are vaccine-hesitant, Dr. Seeger said, it is not just about the vaccine. The attitude about vaccines is tied in, often, with a distrust of government and feelings about personal freedom. “That’s one reason it’s so hard to change the attitude.” For some, getting the vaccine in a family against the vaccine might also disrupt their social structure or even get them ostracized.

For these people, a health care provider might give opportunities to get the vaccine without affecting either what they see as their political stance or upsetting family harmony. “There are places you can go, make an appointment, get a vaccine, and nobody knows,” Dr. Seeger said.

One Missouri doctor told CNN that some people calling for a vaccine appointment do request privacy, such as going through a drive-thru or having the shot as they sit in their cars. She said the hospital tries to accommodate them, reasoning that every additional vaccine shot is a win.

Dr. Seeger agrees. “Of course there are still public records,” he says, “but you can still claim you are a vaccine denier. It’s very difficult to persuade people to give up their whole world. Vaccine denial is part of that world. At this point, we need to do whatever we can to get people vaccinated.”
 

From peer to peer

A theme that runs through many of these persuasion techniques is peer pressure.

One example, while a bit more profane and confrontational than some groups, is COVIDAteMyFace, a subgroup, or “subreddit,” of the popular online site Reddit, which hosts numerous forums inviting users to share news and comments on a variety of topics. The subreddit has over 20,000 members. Its purpose, says the sub’s creator, “was to document the folks who denied COVID, then got bitten in the ass by it.” Reports are of actual cases.

“It’s interesting and powerful that Reddit users are taking this on,” Dr. Seeger said. And this kind of peer pressure, or peer-to-peer information, can be persuasive, he says. “We often seek consensual validation from peers about risk messages and risk behaviors.”

For instance, hurricane evacuation notices are more effective, he said, when people learn their neighbors are leaving.

Peer information – “the number of others who are doing or believing or responding to something – definitely persuades people,” agreed Dr. Cialdini. “When a lot of others are responding in a particular way – for example, getting vaccinated – people follow for three reasons: The action seems more appropriate or correct, it appears more feasible to perform, and it avoids social disapproval from those others.”
 

Let them talk, give them time

Gladys Jimenez is a contact tracer and “vaccine ambassador” for Tracing Health, a partnership between the Oregon Public Health Institute and the Public Health Institute that has nearly 300 bilingual contract tracers who serve the ethnic communities they’re from. During a typical week, she talks to 50 people or more, and promoting the vaccine is top of mind.

The conversations, Ms. Jimenez said, are like a dance. She presents information, then steps back and lets them talk. “I want to hear the person talk, where they are coming from, where they are at.” Depending on what they say, she gives them more information or corrects their misinformation. “They often will say, ‘Oh, I didn’t know that.’ ”

It’s rarely one conversation that convinces hesitant people, she said. “I’m planting this seed in their brain. ... people want someone to listen to them ... they want to vent.”

Once you let them do that, Ms. Jimenez said, “I can tell the person is in a different state of mind.” She also knows that people “will make the decision in their own time.”

With time, people can change their minds, as a Southern California woman who resisted at first (and asked to remain anonymous) can attest. “When the vaccine first came out, I remember thinking [that] it was a quick fix to a very big problem,” she said. The lack of full FDA approval, which has since been granted, was also an issue. She doesn’t oppose vaccines, she said, but was leery just of the COVID-19 vaccine.

When her longtime partner got his vaccine, he urged her to go right away for hers. She stalled. He got his second dose and grew impatient with her hesitancy. It began to wear on the relationship. Finally, the woman talked to two health care professionals she knew socially. They both follow the science, and “they both could explain vaccination to me in a way that resonated. The information was coming from sources I already trusted.”

Those conversations are what convinced her to get vaccinated this summer.
 

Simpson’s transformation

Ms. Simpson of Back to the Vax got her first COVID-19 immunization April 16. She had an allergic reaction, including severe itchiness and a bad headache, and needed emergency care, she said. Even so, she scheduled her second shot appointment.

Like many who turned against vaccines as adults, Ms. Simpson had all her childhood vaccines, but she developed a distrust after watching a lengthy documentary series that warned of vaccine dangers as an adult.

Looking back at that documentary, she thought about how it seems to blame everything – childhood cancer, ADHD, autism, allergies – on vaccinations. That suddenly seemed like sketchy science to her.

So did the claim from a family friend who said she knew someone who got the flu shot and began walking backward. She researched on her own, and with time, she decided to be pro-vaccines.

These days, she continues to find that stories, not statistics, are changing the minds of many who decide to get vaccinated. If the nurse practitioner urging the tetanus shot for her daughter had told her that the tetanus shot is linked with problems in one of a specific number of people who get it, no matter how large that second number was, Ms. Simpson said she would have thought: “What if she is that one?”

So she relies on stories that point out how universally vulnerable people are to COVID-19 first, facts next.

“Facts help once you are already moved,” Ms. Simpson said.

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

Not so long ago, Heather Simpson of Dallas was known as the anti-vaccine mom who dressed as “the measles” for Halloween. She painted red spots on her face and posted her photo on Facebook, joking: “Was trying to think of the least scary thing I could be for Halloween … so I became the measles.” It went viral with the anti-vaccine crowd.

But between that Halloween and today, a series of “aha” moments transformed Ms. Simpson’s attitudes toward vaccines.

In January 2021, one of those moments involved her daughter, now 4, who was scratched by a feral cat, raising concerns about tetanus. Her daughter had been bitten by a dog when she was just 1, and Ms. Simpson turned down advice then to get a tetanus shot. “I was convinced the tetanus shot would kill her faster than the tetanus.”

After the cat incident, the anxiety was so exhausting, she listened to the nurse practitioner at the clinic, whom she trusted. The nurse gently reassured Ms. Simpson that the shot was less risky than the possibility of tetanus – but did not bombard her with statistics – and that won over Ms. Simpson and triggered an overall rethinking of her vaccine stance.

Fast-forward to February, and that “aha” turned into action when Ms. Simpson launched a “Back to the Vax” effort with a fellow former vaccine opponent. Through their website, Facebook page, and podcasts, they now encourage people to get the COVID-19 vaccine, as well as other immunizations.
 

Challenge: Reaching the rest

With just over 52% of those eligible in the United States fully vaccinated as of Sept. 1, health care providers and others have a continuing challenge ahead: Trying to convince those who are eligible but still holding out to get vaccinated.

Recent data and a poll show some movement in the right direction, as immunizations are increasing and hesitancy is declining among certain groups. According to federal officials, about 14 million people in the United States got their first dose in August, an increase of 4 million, compared to the numbers who got it in July.

And a new poll from the Axios-IPSOS Coronavirus Index found only one in five Americans, or 20%, say they are not likely to get the vaccine, while “hard opposition,” those not at all likely, has dropped to 14% of those adults.

But there is still a lot of work to do. So, how do medical professionals or concerned citizens reach those who haven’t gotten vaccinated yet, whatever their reason?

Many experts in communication and persuasion that this news organization talked to agree that throwing statistics at people hesitant to get the COVID-19 vaccine is generally useless and often backfires.

So what does work, according to these experts?

• Emphasizing the trends of more people getting vaccinated.
• Focusing on everyone’s freedom of choice.
• Listening to concerns without judgment.
• Offering credible information.
• Correcting myths when necessary.
• Helping them fit vaccination into their “world view.”

Stories over statistics

Talking about the trends of vaccinations can definitely change minds about getting vaccinated, said Robert Cialdini, PhD, regents professor emeritus of psychology and marketing at Arizona State University, Tempe, and author of the recently updated book, “Influence: The Psychology of Persuasion,” which has sold over 5 million copies since it was first published in 1984.

Face-to-face with a hesitant patient, a doctor can say: “More and more people are being vaccinated every day,” Dr. Cialdini says. “The reason you say more and more is [that] it conveys a trend. When people see a trend, they project it into the future that it is going to get even larger.”

A focus on choice can also help people change their minds and accept the vaccine, he says. “A lot of conspiracy theorists claim they don’t want to do it because they are being pushed or forced by the government, and they are resisting that.”

If that’s the case, presenting people with new information, such as the increased infectiousness of the Delta variant, and suggesting that a decision be made based on the new information, can work, Dr. Cialdini says, but be sure to end with: “It’s completely up to you.”

“This removes all their sense of being pushed. It says, ‘Here is all the evidence.’ ” At this point, a doctor’s personal recommendation with a patient who trusts him or her may sway them, Dr. Cialdini said. “I think you have to personalize the communication in both directions. That is, to say, ‘For someone in your situation, I would personally recommend that you get the vaccine.’ ” A health care professional’s authority and expertise can carry the day, he says, although “not always.”

This approach worked, Dr. Cialdini says, with a friend of the family hesitant about the COVID-19 vaccine. “I told him: ‘We have gotten it. You trust us, right?’ ” He waited for the person to say yes.

Then: “For someone in your position, my personal recommendation is to get vaccinated. There is new information about the vaccine, and more and more people are getting vaccinated. And of course, it is completely up to you.”

The person decided to get the vaccine.
 

‘Live in that space’

“People develop negative attitudes [about vaccines] by accessing alternative sources of information, anecdotes, and personal stories,” said Matthew Seeger, PhD, dean of the College of Fine, Performing, and Communication Arts and codirector of the Center for Emerging Infectious Diseases at Wayne State University in Detroit.

“If we are going to change their opinion, we need to live in that space.” That means listening first, he says. Ask: “Where did you get that information? How credible do you think the sources are? What do you mean about the vaccine changing DNA?”

Then, you might respond, he said, by addressing that specific information, such as, “We have no cases of DNA being changed.”

Dr. Seeger recalls that his mother would simply talk louder when she couldn’t understand someone who wasn’t a native English speaker. “That’s what we are trying to do with the vaccine-hesitant,” he says. “In some cases, we are yelling at them.” Instead, he says, probe their sources of information.

For some who are vaccine-hesitant, Dr. Seeger said, it is not just about the vaccine. The attitude about vaccines is tied in, often, with a distrust of government and feelings about personal freedom. “That’s one reason it’s so hard to change the attitude.” For some, getting the vaccine in a family against the vaccine might also disrupt their social structure or even get them ostracized.

For these people, a health care provider might give opportunities to get the vaccine without affecting either what they see as their political stance or upsetting family harmony. “There are places you can go, make an appointment, get a vaccine, and nobody knows,” Dr. Seeger said.

One Missouri doctor told CNN that some people calling for a vaccine appointment do request privacy, such as going through a drive-thru or having the shot as they sit in their cars. She said the hospital tries to accommodate them, reasoning that every additional vaccine shot is a win.

Dr. Seeger agrees. “Of course there are still public records,” he says, “but you can still claim you are a vaccine denier. It’s very difficult to persuade people to give up their whole world. Vaccine denial is part of that world. At this point, we need to do whatever we can to get people vaccinated.”
 

From peer to peer

A theme that runs through many of these persuasion techniques is peer pressure.

One example, while a bit more profane and confrontational than some groups, is COVIDAteMyFace, a subgroup, or “subreddit,” of the popular online site Reddit, which hosts numerous forums inviting users to share news and comments on a variety of topics. The subreddit has over 20,000 members. Its purpose, says the sub’s creator, “was to document the folks who denied COVID, then got bitten in the ass by it.” Reports are of actual cases.

“It’s interesting and powerful that Reddit users are taking this on,” Dr. Seeger said. And this kind of peer pressure, or peer-to-peer information, can be persuasive, he says. “We often seek consensual validation from peers about risk messages and risk behaviors.”

For instance, hurricane evacuation notices are more effective, he said, when people learn their neighbors are leaving.

Peer information – “the number of others who are doing or believing or responding to something – definitely persuades people,” agreed Dr. Cialdini. “When a lot of others are responding in a particular way – for example, getting vaccinated – people follow for three reasons: The action seems more appropriate or correct, it appears more feasible to perform, and it avoids social disapproval from those others.”
 

Let them talk, give them time

Gladys Jimenez is a contact tracer and “vaccine ambassador” for Tracing Health, a partnership between the Oregon Public Health Institute and the Public Health Institute that has nearly 300 bilingual contract tracers who serve the ethnic communities they’re from. During a typical week, she talks to 50 people or more, and promoting the vaccine is top of mind.

The conversations, Ms. Jimenez said, are like a dance. She presents information, then steps back and lets them talk. “I want to hear the person talk, where they are coming from, where they are at.” Depending on what they say, she gives them more information or corrects their misinformation. “They often will say, ‘Oh, I didn’t know that.’ ”

It’s rarely one conversation that convinces hesitant people, she said. “I’m planting this seed in their brain. ... people want someone to listen to them ... they want to vent.”

Once you let them do that, Ms. Jimenez said, “I can tell the person is in a different state of mind.” She also knows that people “will make the decision in their own time.”

With time, people can change their minds, as a Southern California woman who resisted at first (and asked to remain anonymous) can attest. “When the vaccine first came out, I remember thinking [that] it was a quick fix to a very big problem,” she said. The lack of full FDA approval, which has since been granted, was also an issue. She doesn’t oppose vaccines, she said, but was leery just of the COVID-19 vaccine.

When her longtime partner got his vaccine, he urged her to go right away for hers. She stalled. He got his second dose and grew impatient with her hesitancy. It began to wear on the relationship. Finally, the woman talked to two health care professionals she knew socially. They both follow the science, and “they both could explain vaccination to me in a way that resonated. The information was coming from sources I already trusted.”

Those conversations are what convinced her to get vaccinated this summer.
 

Simpson’s transformation

Ms. Simpson of Back to the Vax got her first COVID-19 immunization April 16. She had an allergic reaction, including severe itchiness and a bad headache, and needed emergency care, she said. Even so, she scheduled her second shot appointment.

Like many who turned against vaccines as adults, Ms. Simpson had all her childhood vaccines, but she developed a distrust after watching a lengthy documentary series that warned of vaccine dangers as an adult.

Looking back at that documentary, she thought about how it seems to blame everything – childhood cancer, ADHD, autism, allergies – on vaccinations. That suddenly seemed like sketchy science to her.

So did the claim from a family friend who said she knew someone who got the flu shot and began walking backward. She researched on her own, and with time, she decided to be pro-vaccines.

These days, she continues to find that stories, not statistics, are changing the minds of many who decide to get vaccinated. If the nurse practitioner urging the tetanus shot for her daughter had told her that the tetanus shot is linked with problems in one of a specific number of people who get it, no matter how large that second number was, Ms. Simpson said she would have thought: “What if she is that one?”

So she relies on stories that point out how universally vulnerable people are to COVID-19 first, facts next.

“Facts help once you are already moved,” Ms. Simpson said.

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

Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
 

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
 

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
 

Future research directions

Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?

Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.

In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.

They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.

Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
 

Better-than-expected outcomes

Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.

In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”

The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.

On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.

They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.

However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.

“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.

Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”

He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”

Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”

NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.

Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
 

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
 

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
 

Future research directions

Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?

Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.

In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.

They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.

Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
 

Better-than-expected outcomes

Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.

In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”

The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.

On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.

They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.

However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.

“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.

Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”

He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”

Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”

NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.

Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
 

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
 

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
 

Future research directions

Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?

Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.

In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.

They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.

Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
 

Better-than-expected outcomes

Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.

In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”

The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.

On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.

They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.

However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.

“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.

Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”

He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”

Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”

NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.

Equine therapy, which involves interactions with horses in a controlled environment, reduces fear and other symptoms of posttraumatic stress disorder, new research suggests.

Man O'War Project

Results from a study of about 60 military veterans who underwent weekly sessions of horse-assisted therapy showed “marked reductions” in clinician-rated and self-reported symptoms of PTSD and depression up to 3 months post treatment.

“What we’re doing here with horses is helping people overcome something very specific to PTSD,” coinvestigator Yuval Neria, PhD, professor of clinical medical psychology and director of the PTSD treatment and research program, Columbia University Medical Center, New York, said in an interview.

“It offers the opportunity to overcome fear, to facilitate self-efficacy, to facilitate trust in yourself, to understand your feelings, and perhaps to change them over time, he said.

In addition, veterans loved the experience, Dr. Neria reported. He noted that many patients with PTSD have trouble with traditional treatments and are eager to try something “creative and new.”

The findings were published online Aug. 31, 2021, in the Journal of Clinical Psychiatry.
 

Building bonds

PTSD affects an estimated 10%-30% of U.S. military personnel. These rates are higher than in the general population because veterans may experience increased trauma through combat, injury, and sexual assault, the investigators noted.

Previous research has suggested that horse-human interactions can build bonds that foster behavioral changes. These powerful animals provide instantaneous feedback, allowing patients to develop emotional awareness.

“Horses are very sensitive to whatever we communicate with them, whether it’s fear or anger or stress,” said Dr. Neria.

Equine-assisted therapy is increasingly being used for various mental and physical conditions. Launching an open-label study to examine this type of treatment for PTSD “was an opportunity to look at something very, very different,” Dr. Neria said.

“This is not psychotherapy, it’s not medication, and it’s not neural stimulation,” he added.

The study included 63 veterans with PTSD (mean age, 50 years; 37% women). Of these, 47 were receiving psychotherapy alone, pharmacotherapy alone, or both. In addition, 48 had at least one comorbid disorder. All were divided into 16 groups of three to five participants each.

The program consisted of eight 90-minute weekly sessions conducted at a large equestrian center. Sessions were coled by a mental health professional and an equine specialist who guided participants in horse communication and behavior.

Early sessions focused on acquainting patients with the horses, grooming exercises, and learning “leading,” which involved directing a horse with a rope or wand. During subsequent sessions, patients became more comfortable with managing the horses in individual and teamwork exercises.

The horses were specifically chosen for their temperament and had no history of aggression. A horse wrangler attended sessions to further ensure safety.
 

Few dropouts

The study included four assessment points: pretreatment, midpoint, post treatment, and 3-month follow-up.

All 63 participants completed baseline assessments. Only five patients (7.9%) discontinued the program.

“We didn’t see dropouts at the rate we usually see in evidence-based therapies for PTSD, which is remarkable and suggests that people really loved it,” said Dr. Neria.

Man O'War Project

The primary outcome was the Clinician-Administered PTSD Scale–5 (CAPS-5), a structured interview that evaluates intrusive memories, social avoidance, and other symptoms based on DSM-5 criteria.

In the intent-to-treat analysis, mean CAPS-5 scores decreased from 38.6 at baseline to 26.9 post treatment. In addition, 29 (46.0%) and 23 (36.5%) participants scored below the PTSD diagnostic threshold of 25 at posttreatment and follow-up, respectively.

Notably, 50.8% of the study population had a clinically significant change, defined as 30% or greater decrease in CAPS-5 score, at post treatment; 54.0% had a significant change at follow-up.

Mean scores on the self-reported 20-item PTSD Checklist for DSM-5 questionnaire decreased from 50.7 at baseline to 34.6 at study termination.

Depression symptoms, measured by the clinician-rated Hamilton Depression Rating Scale and the self-reported Beck Depression Inventory–II, also improved.
 

Structural, functional change

The results did not differ by age, gender, or type of trauma. Dr. Neria noted that many women in the study had suffered sexual abuse or assault, suggesting that the intervention might be appropriate for PTSD outside the military.

“I’m very keen on moving this along into a civilian population,” he said.

The study did not examine potential mechanisms of action. The benefits may come from something inherent in the equine interactions, the human group process, or just being in the beautiful setting where the treatment took place, the investigators noted.

However, Dr. Neria thinks there is another potential explanation – real changes in the brain.

Neuroimaging of a subsample of 20 participants before and after the intervention showed a significant increase in caudate functional connectivity and a reduction in gray matter density of the thalamus and the caudate.

“We see a big change both structurally and functionally,” with the results pointing to an impact on the reward network of the brain, said Dr. Neria.

“This suggests that pleasure was perhaps the main mechanism of action,” which corresponds with patient reports of really enjoying the experience, he added.

Dr. Neria noted that equine therapy is different from bonding with a loyal dog. Interacting with a large and powerful animal may give veterans a sense of accomplishment and self-worth, which can be tremendously therapeutic.
 

Next step in therapy?

Commenting on the research, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, called equine therapy “innovative” in PTSD.

“I see this as the next step in finding acceptable therapies that people like to do,” she said.

Some patients have an aversion to talk therapy because it makes them relive their trauma; and many dislike the side effects of medications, which can include erectile dysfunction, said Dr. Ritchie, who was not involved with the research.

“So something like this that they can enjoy, have a sense of mastery, can bond with an animal, I think is wonderful,” she said.

Dr. Ritchie noted that working with animals offers “a kind of biofeedback” that may calm anxieties, help maintain control, and “is very nonjudgmental.”

However, she pointed out that equine therapy is not new. For example, horses have been used previously to treat patients with a variety of disabilities, including autism.

Dr. Ritchie thought it was “very wise” that study participants just learned to control the horses and didn’t actually ride them, because that could be a frightening experience.

Nonetheless, she noted equine therapy “is not going to be accessible for everybody.”

In addition, Dr. Ritchie was surprised that the investigators didn’t mention more of the quite extensive research that has been conducted on dog therapy in patients with PTSD.

Dr. Neria and Ritchie disclosed no relevant financial relationships.

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

Equine therapy, which involves interactions with horses in a controlled environment, reduces fear and other symptoms of posttraumatic stress disorder, new research suggests.

Man O'War Project

Results from a study of about 60 military veterans who underwent weekly sessions of horse-assisted therapy showed “marked reductions” in clinician-rated and self-reported symptoms of PTSD and depression up to 3 months post treatment.

“What we’re doing here with horses is helping people overcome something very specific to PTSD,” coinvestigator Yuval Neria, PhD, professor of clinical medical psychology and director of the PTSD treatment and research program, Columbia University Medical Center, New York, said in an interview.

“It offers the opportunity to overcome fear, to facilitate self-efficacy, to facilitate trust in yourself, to understand your feelings, and perhaps to change them over time, he said.

In addition, veterans loved the experience, Dr. Neria reported. He noted that many patients with PTSD have trouble with traditional treatments and are eager to try something “creative and new.”

The findings were published online Aug. 31, 2021, in the Journal of Clinical Psychiatry.
 

Building bonds

PTSD affects an estimated 10%-30% of U.S. military personnel. These rates are higher than in the general population because veterans may experience increased trauma through combat, injury, and sexual assault, the investigators noted.

Previous research has suggested that horse-human interactions can build bonds that foster behavioral changes. These powerful animals provide instantaneous feedback, allowing patients to develop emotional awareness.

“Horses are very sensitive to whatever we communicate with them, whether it’s fear or anger or stress,” said Dr. Neria.

Equine-assisted therapy is increasingly being used for various mental and physical conditions. Launching an open-label study to examine this type of treatment for PTSD “was an opportunity to look at something very, very different,” Dr. Neria said.

“This is not psychotherapy, it’s not medication, and it’s not neural stimulation,” he added.

The study included 63 veterans with PTSD (mean age, 50 years; 37% women). Of these, 47 were receiving psychotherapy alone, pharmacotherapy alone, or both. In addition, 48 had at least one comorbid disorder. All were divided into 16 groups of three to five participants each.

The program consisted of eight 90-minute weekly sessions conducted at a large equestrian center. Sessions were coled by a mental health professional and an equine specialist who guided participants in horse communication and behavior.

Early sessions focused on acquainting patients with the horses, grooming exercises, and learning “leading,” which involved directing a horse with a rope or wand. During subsequent sessions, patients became more comfortable with managing the horses in individual and teamwork exercises.

The horses were specifically chosen for their temperament and had no history of aggression. A horse wrangler attended sessions to further ensure safety.
 

Few dropouts

The study included four assessment points: pretreatment, midpoint, post treatment, and 3-month follow-up.

All 63 participants completed baseline assessments. Only five patients (7.9%) discontinued the program.

“We didn’t see dropouts at the rate we usually see in evidence-based therapies for PTSD, which is remarkable and suggests that people really loved it,” said Dr. Neria.

Man O'War Project

The primary outcome was the Clinician-Administered PTSD Scale–5 (CAPS-5), a structured interview that evaluates intrusive memories, social avoidance, and other symptoms based on DSM-5 criteria.

In the intent-to-treat analysis, mean CAPS-5 scores decreased from 38.6 at baseline to 26.9 post treatment. In addition, 29 (46.0%) and 23 (36.5%) participants scored below the PTSD diagnostic threshold of 25 at posttreatment and follow-up, respectively.

Notably, 50.8% of the study population had a clinically significant change, defined as 30% or greater decrease in CAPS-5 score, at post treatment; 54.0% had a significant change at follow-up.

Mean scores on the self-reported 20-item PTSD Checklist for DSM-5 questionnaire decreased from 50.7 at baseline to 34.6 at study termination.

Depression symptoms, measured by the clinician-rated Hamilton Depression Rating Scale and the self-reported Beck Depression Inventory–II, also improved.
 

Structural, functional change

The results did not differ by age, gender, or type of trauma. Dr. Neria noted that many women in the study had suffered sexual abuse or assault, suggesting that the intervention might be appropriate for PTSD outside the military.

“I’m very keen on moving this along into a civilian population,” he said.

The study did not examine potential mechanisms of action. The benefits may come from something inherent in the equine interactions, the human group process, or just being in the beautiful setting where the treatment took place, the investigators noted.

However, Dr. Neria thinks there is another potential explanation – real changes in the brain.

Neuroimaging of a subsample of 20 participants before and after the intervention showed a significant increase in caudate functional connectivity and a reduction in gray matter density of the thalamus and the caudate.

“We see a big change both structurally and functionally,” with the results pointing to an impact on the reward network of the brain, said Dr. Neria.

“This suggests that pleasure was perhaps the main mechanism of action,” which corresponds with patient reports of really enjoying the experience, he added.

Dr. Neria noted that equine therapy is different from bonding with a loyal dog. Interacting with a large and powerful animal may give veterans a sense of accomplishment and self-worth, which can be tremendously therapeutic.
 

Next step in therapy?

Commenting on the research, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, called equine therapy “innovative” in PTSD.

“I see this as the next step in finding acceptable therapies that people like to do,” she said.

Some patients have an aversion to talk therapy because it makes them relive their trauma; and many dislike the side effects of medications, which can include erectile dysfunction, said Dr. Ritchie, who was not involved with the research.

“So something like this that they can enjoy, have a sense of mastery, can bond with an animal, I think is wonderful,” she said.

Dr. Ritchie noted that working with animals offers “a kind of biofeedback” that may calm anxieties, help maintain control, and “is very nonjudgmental.”

However, she pointed out that equine therapy is not new. For example, horses have been used previously to treat patients with a variety of disabilities, including autism.

Dr. Ritchie thought it was “very wise” that study participants just learned to control the horses and didn’t actually ride them, because that could be a frightening experience.

Nonetheless, she noted equine therapy “is not going to be accessible for everybody.”

In addition, Dr. Ritchie was surprised that the investigators didn’t mention more of the quite extensive research that has been conducted on dog therapy in patients with PTSD.

Dr. Neria and Ritchie disclosed no relevant financial relationships.

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

Equine therapy, which involves interactions with horses in a controlled environment, reduces fear and other symptoms of posttraumatic stress disorder, new research suggests.

Man O'War Project

Results from a study of about 60 military veterans who underwent weekly sessions of horse-assisted therapy showed “marked reductions” in clinician-rated and self-reported symptoms of PTSD and depression up to 3 months post treatment.

“What we’re doing here with horses is helping people overcome something very specific to PTSD,” coinvestigator Yuval Neria, PhD, professor of clinical medical psychology and director of the PTSD treatment and research program, Columbia University Medical Center, New York, said in an interview.

“It offers the opportunity to overcome fear, to facilitate self-efficacy, to facilitate trust in yourself, to understand your feelings, and perhaps to change them over time, he said.

In addition, veterans loved the experience, Dr. Neria reported. He noted that many patients with PTSD have trouble with traditional treatments and are eager to try something “creative and new.”

The findings were published online Aug. 31, 2021, in the Journal of Clinical Psychiatry.
 

Building bonds

PTSD affects an estimated 10%-30% of U.S. military personnel. These rates are higher than in the general population because veterans may experience increased trauma through combat, injury, and sexual assault, the investigators noted.

Previous research has suggested that horse-human interactions can build bonds that foster behavioral changes. These powerful animals provide instantaneous feedback, allowing patients to develop emotional awareness.

“Horses are very sensitive to whatever we communicate with them, whether it’s fear or anger or stress,” said Dr. Neria.

Equine-assisted therapy is increasingly being used for various mental and physical conditions. Launching an open-label study to examine this type of treatment for PTSD “was an opportunity to look at something very, very different,” Dr. Neria said.

“This is not psychotherapy, it’s not medication, and it’s not neural stimulation,” he added.

The study included 63 veterans with PTSD (mean age, 50 years; 37% women). Of these, 47 were receiving psychotherapy alone, pharmacotherapy alone, or both. In addition, 48 had at least one comorbid disorder. All were divided into 16 groups of three to five participants each.

The program consisted of eight 90-minute weekly sessions conducted at a large equestrian center. Sessions were coled by a mental health professional and an equine specialist who guided participants in horse communication and behavior.

Early sessions focused on acquainting patients with the horses, grooming exercises, and learning “leading,” which involved directing a horse with a rope or wand. During subsequent sessions, patients became more comfortable with managing the horses in individual and teamwork exercises.

The horses were specifically chosen for their temperament and had no history of aggression. A horse wrangler attended sessions to further ensure safety.
 

Few dropouts

The study included four assessment points: pretreatment, midpoint, post treatment, and 3-month follow-up.

All 63 participants completed baseline assessments. Only five patients (7.9%) discontinued the program.

“We didn’t see dropouts at the rate we usually see in evidence-based therapies for PTSD, which is remarkable and suggests that people really loved it,” said Dr. Neria.

Man O'War Project

The primary outcome was the Clinician-Administered PTSD Scale–5 (CAPS-5), a structured interview that evaluates intrusive memories, social avoidance, and other symptoms based on DSM-5 criteria.

In the intent-to-treat analysis, mean CAPS-5 scores decreased from 38.6 at baseline to 26.9 post treatment. In addition, 29 (46.0%) and 23 (36.5%) participants scored below the PTSD diagnostic threshold of 25 at posttreatment and follow-up, respectively.

Notably, 50.8% of the study population had a clinically significant change, defined as 30% or greater decrease in CAPS-5 score, at post treatment; 54.0% had a significant change at follow-up.

Mean scores on the self-reported 20-item PTSD Checklist for DSM-5 questionnaire decreased from 50.7 at baseline to 34.6 at study termination.

Depression symptoms, measured by the clinician-rated Hamilton Depression Rating Scale and the self-reported Beck Depression Inventory–II, also improved.
 

Structural, functional change

The results did not differ by age, gender, or type of trauma. Dr. Neria noted that many women in the study had suffered sexual abuse or assault, suggesting that the intervention might be appropriate for PTSD outside the military.

“I’m very keen on moving this along into a civilian population,” he said.

The study did not examine potential mechanisms of action. The benefits may come from something inherent in the equine interactions, the human group process, or just being in the beautiful setting where the treatment took place, the investigators noted.

However, Dr. Neria thinks there is another potential explanation – real changes in the brain.

Neuroimaging of a subsample of 20 participants before and after the intervention showed a significant increase in caudate functional connectivity and a reduction in gray matter density of the thalamus and the caudate.

“We see a big change both structurally and functionally,” with the results pointing to an impact on the reward network of the brain, said Dr. Neria.

“This suggests that pleasure was perhaps the main mechanism of action,” which corresponds with patient reports of really enjoying the experience, he added.

Dr. Neria noted that equine therapy is different from bonding with a loyal dog. Interacting with a large and powerful animal may give veterans a sense of accomplishment and self-worth, which can be tremendously therapeutic.
 

Next step in therapy?

Commenting on the research, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, called equine therapy “innovative” in PTSD.

“I see this as the next step in finding acceptable therapies that people like to do,” she said.

Some patients have an aversion to talk therapy because it makes them relive their trauma; and many dislike the side effects of medications, which can include erectile dysfunction, said Dr. Ritchie, who was not involved with the research.

“So something like this that they can enjoy, have a sense of mastery, can bond with an animal, I think is wonderful,” she said.

Dr. Ritchie noted that working with animals offers “a kind of biofeedback” that may calm anxieties, help maintain control, and “is very nonjudgmental.”

However, she pointed out that equine therapy is not new. For example, horses have been used previously to treat patients with a variety of disabilities, including autism.

Dr. Ritchie thought it was “very wise” that study participants just learned to control the horses and didn’t actually ride them, because that could be a frightening experience.

Nonetheless, she noted equine therapy “is not going to be accessible for everybody.”

In addition, Dr. Ritchie was surprised that the investigators didn’t mention more of the quite extensive research that has been conducted on dog therapy in patients with PTSD.

Dr. Neria and Ritchie disclosed no relevant financial relationships.

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

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a major driver of disease-related morbidity. Their prevention and treatment are a focus of COPD management. Antibiotics, corticosteroids, and nebulized bronchodilators are all given to patients with AECOPD, and while the supporting data aren’t perfect, there’s little debate surrounding their use. These medications are well known to most physicians; we’re comfortable with their efficacy and aware of their side effects. They are nothing if not familiar.

What about magnesium (Mg), though? Apparently, in the emergency room (ER) it is part of the standard AECOPD cocktail. I would argue that Mg is familiar to most too; every internal medicine trainee in the United States is taught to infuse 2 g of Mg intravenously for any inpatient (ICU or otherwise) with a serum level <2.0 mg/dL. In fact, “electrolyte protocols” are part of the order sets at most hospitals where I’ve worked. Mg is infused reflexively when it drops below certain levels.

I’m less familiar with using Mg in the setting of an AECOPD, though. A recent online post by an academic ER physician (Richard Pescatore, DO) urged caution in this setting. He argues that too many in the ER are embracing the “Dutch Hypothesis” and treating asthma and COPD as the same disease. Dr. Pescatore believes that Mg works for asthma exacerbations because asthma is a disease of smooth muscle and large airways, while COPD is not. COPD, he says, is a disease of the small airways, largely resulting from parenchymal distortions due to emphysema. Therefore, Mg, which is thought to act on the smooth muscle surrounding the large airways, won’t be beneficial for AECOPD and may even cause harm.

Data are lacking

What data exist for using Mg for AECOPD? The best randomized controlled trial (RCT) I could find was published in 1995 and is cited in the reader’s rebuttal. The trial found a significant improvement in peak expiratory flow rate (PEFR) with Mg and a nonsignificant reduction in hospitalizations.

A poorly done systematic review of RCTs using Mg for AECOPD was published in 2014, and in 2020 the Agency for Healthcare Research and Quality (AHRQ) included Mg in its well-executed meta-analysis of pharmacologic treatments for AECOPD. Data across the four to five Mg RCTs included in each of the reviews (study inclusion criteria were slightly different) could not be combined. All RCTs were small, and only soft outcomes like PEFR and forced expiratory volume in 1 second (FEV1) seemed to improve with Mg. No adverse events were noted, but this should be interpreted with caution given that many studies did not report on adverse events at all.

A small RCT published this year (after both systematic reviews were completed) showed that using intravenous magnesium sulfate had no significant effect on FEV1, vital signs, or symptoms.

In summary, the data aren’t great. Mg doesn’t show up at all as a treatment option in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report on COPD, and the authors of the AHRQ review concluded that large, high-quality RCTs are needed to assess the impact of Mg in AECOPD. Although I didn’t do an extensive review of Mg for asthma exacerbations, it’s not clear that the data here are much better. Mg gets an honorable mention (add for severe exacerbations when there’s inadequate response to standard treatments) in both the 2007 National Heart, Lung, and Blood Institute (NHLBI) guideline and the 2019 Global Initiative for Asthma (GINA) guide. The 2020 update to the 2007 NHLBI guideline is more targeted in its review and does not cover Mg as a treatment option. On the basis of my anecdotal clinical experience and on networking with airway experts, I do think Mg is used more often for asthma than for AECOPD.

Final thoughts on using Mg for AECOPD

All that being said, is it reasonable to use Mg for AECOPD? I think so. I’d stick to using it for severe cases where conventional treatments have failed, just like the NHLBI and GINA advise for asthma. I’d also limit it to 2-3 g, which is the dosing range employed by several of the existing AECOPD RCTs. The assertion that Mg may be harmful in AECOPD because COPD affects the small airways, and asthma does not, is misguided. Both affect the small airways. Furthermore, none of our inhaled therapies reach the small airways, so one can’t argue against using Mg because it only targets larger airways without abandoning albuterol and ipratropium as well. I don’t think anyone would advise that. Given what we now know about asthma and COPD phenotypes and asthma-COPD overlap, I’d caution against pedantic theories about response to therapies.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center. He has received research grants from Fisher-Paykel and has received payments from the American College of Chest Physicians.

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

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a major driver of disease-related morbidity. Their prevention and treatment are a focus of COPD management. Antibiotics, corticosteroids, and nebulized bronchodilators are all given to patients with AECOPD, and while the supporting data aren’t perfect, there’s little debate surrounding their use. These medications are well known to most physicians; we’re comfortable with their efficacy and aware of their side effects. They are nothing if not familiar.

What about magnesium (Mg), though? Apparently, in the emergency room (ER) it is part of the standard AECOPD cocktail. I would argue that Mg is familiar to most too; every internal medicine trainee in the United States is taught to infuse 2 g of Mg intravenously for any inpatient (ICU or otherwise) with a serum level <2.0 mg/dL. In fact, “electrolyte protocols” are part of the order sets at most hospitals where I’ve worked. Mg is infused reflexively when it drops below certain levels.

I’m less familiar with using Mg in the setting of an AECOPD, though. A recent online post by an academic ER physician (Richard Pescatore, DO) urged caution in this setting. He argues that too many in the ER are embracing the “Dutch Hypothesis” and treating asthma and COPD as the same disease. Dr. Pescatore believes that Mg works for asthma exacerbations because asthma is a disease of smooth muscle and large airways, while COPD is not. COPD, he says, is a disease of the small airways, largely resulting from parenchymal distortions due to emphysema. Therefore, Mg, which is thought to act on the smooth muscle surrounding the large airways, won’t be beneficial for AECOPD and may even cause harm.

Data are lacking

What data exist for using Mg for AECOPD? The best randomized controlled trial (RCT) I could find was published in 1995 and is cited in the reader’s rebuttal. The trial found a significant improvement in peak expiratory flow rate (PEFR) with Mg and a nonsignificant reduction in hospitalizations.

A poorly done systematic review of RCTs using Mg for AECOPD was published in 2014, and in 2020 the Agency for Healthcare Research and Quality (AHRQ) included Mg in its well-executed meta-analysis of pharmacologic treatments for AECOPD. Data across the four to five Mg RCTs included in each of the reviews (study inclusion criteria were slightly different) could not be combined. All RCTs were small, and only soft outcomes like PEFR and forced expiratory volume in 1 second (FEV1) seemed to improve with Mg. No adverse events were noted, but this should be interpreted with caution given that many studies did not report on adverse events at all.

A small RCT published this year (after both systematic reviews were completed) showed that using intravenous magnesium sulfate had no significant effect on FEV1, vital signs, or symptoms.

In summary, the data aren’t great. Mg doesn’t show up at all as a treatment option in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report on COPD, and the authors of the AHRQ review concluded that large, high-quality RCTs are needed to assess the impact of Mg in AECOPD. Although I didn’t do an extensive review of Mg for asthma exacerbations, it’s not clear that the data here are much better. Mg gets an honorable mention (add for severe exacerbations when there’s inadequate response to standard treatments) in both the 2007 National Heart, Lung, and Blood Institute (NHLBI) guideline and the 2019 Global Initiative for Asthma (GINA) guide. The 2020 update to the 2007 NHLBI guideline is more targeted in its review and does not cover Mg as a treatment option. On the basis of my anecdotal clinical experience and on networking with airway experts, I do think Mg is used more often for asthma than for AECOPD.

Final thoughts on using Mg for AECOPD

All that being said, is it reasonable to use Mg for AECOPD? I think so. I’d stick to using it for severe cases where conventional treatments have failed, just like the NHLBI and GINA advise for asthma. I’d also limit it to 2-3 g, which is the dosing range employed by several of the existing AECOPD RCTs. The assertion that Mg may be harmful in AECOPD because COPD affects the small airways, and asthma does not, is misguided. Both affect the small airways. Furthermore, none of our inhaled therapies reach the small airways, so one can’t argue against using Mg because it only targets larger airways without abandoning albuterol and ipratropium as well. I don’t think anyone would advise that. Given what we now know about asthma and COPD phenotypes and asthma-COPD overlap, I’d caution against pedantic theories about response to therapies.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center. He has received research grants from Fisher-Paykel and has received payments from the American College of Chest Physicians.

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

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a major driver of disease-related morbidity. Their prevention and treatment are a focus of COPD management. Antibiotics, corticosteroids, and nebulized bronchodilators are all given to patients with AECOPD, and while the supporting data aren’t perfect, there’s little debate surrounding their use. These medications are well known to most physicians; we’re comfortable with their efficacy and aware of their side effects. They are nothing if not familiar.

What about magnesium (Mg), though? Apparently, in the emergency room (ER) it is part of the standard AECOPD cocktail. I would argue that Mg is familiar to most too; every internal medicine trainee in the United States is taught to infuse 2 g of Mg intravenously for any inpatient (ICU or otherwise) with a serum level <2.0 mg/dL. In fact, “electrolyte protocols” are part of the order sets at most hospitals where I’ve worked. Mg is infused reflexively when it drops below certain levels.

I’m less familiar with using Mg in the setting of an AECOPD, though. A recent online post by an academic ER physician (Richard Pescatore, DO) urged caution in this setting. He argues that too many in the ER are embracing the “Dutch Hypothesis” and treating asthma and COPD as the same disease. Dr. Pescatore believes that Mg works for asthma exacerbations because asthma is a disease of smooth muscle and large airways, while COPD is not. COPD, he says, is a disease of the small airways, largely resulting from parenchymal distortions due to emphysema. Therefore, Mg, which is thought to act on the smooth muscle surrounding the large airways, won’t be beneficial for AECOPD and may even cause harm.

Data are lacking

What data exist for using Mg for AECOPD? The best randomized controlled trial (RCT) I could find was published in 1995 and is cited in the reader’s rebuttal. The trial found a significant improvement in peak expiratory flow rate (PEFR) with Mg and a nonsignificant reduction in hospitalizations.

A poorly done systematic review of RCTs using Mg for AECOPD was published in 2014, and in 2020 the Agency for Healthcare Research and Quality (AHRQ) included Mg in its well-executed meta-analysis of pharmacologic treatments for AECOPD. Data across the four to five Mg RCTs included in each of the reviews (study inclusion criteria were slightly different) could not be combined. All RCTs were small, and only soft outcomes like PEFR and forced expiratory volume in 1 second (FEV1) seemed to improve with Mg. No adverse events were noted, but this should be interpreted with caution given that many studies did not report on adverse events at all.

A small RCT published this year (after both systematic reviews were completed) showed that using intravenous magnesium sulfate had no significant effect on FEV1, vital signs, or symptoms.

In summary, the data aren’t great. Mg doesn’t show up at all as a treatment option in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report on COPD, and the authors of the AHRQ review concluded that large, high-quality RCTs are needed to assess the impact of Mg in AECOPD. Although I didn’t do an extensive review of Mg for asthma exacerbations, it’s not clear that the data here are much better. Mg gets an honorable mention (add for severe exacerbations when there’s inadequate response to standard treatments) in both the 2007 National Heart, Lung, and Blood Institute (NHLBI) guideline and the 2019 Global Initiative for Asthma (GINA) guide. The 2020 update to the 2007 NHLBI guideline is more targeted in its review and does not cover Mg as a treatment option. On the basis of my anecdotal clinical experience and on networking with airway experts, I do think Mg is used more often for asthma than for AECOPD.

Final thoughts on using Mg for AECOPD

All that being said, is it reasonable to use Mg for AECOPD? I think so. I’d stick to using it for severe cases where conventional treatments have failed, just like the NHLBI and GINA advise for asthma. I’d also limit it to 2-3 g, which is the dosing range employed by several of the existing AECOPD RCTs. The assertion that Mg may be harmful in AECOPD because COPD affects the small airways, and asthma does not, is misguided. Both affect the small airways. Furthermore, none of our inhaled therapies reach the small airways, so one can’t argue against using Mg because it only targets larger airways without abandoning albuterol and ipratropium as well. I don’t think anyone would advise that. Given what we now know about asthma and COPD phenotypes and asthma-COPD overlap, I’d caution against pedantic theories about response to therapies.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center. He has received research grants from Fisher-Paykel and has received payments from the American College of Chest Physicians.

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

Compared with placebo, tranexamic acid did not reduce hematoma growth in patients with intracerebral hemorrhage (ICH), a new study shows.

In the randomized controlled trial, the rate of hematoma expansion was 40.4% among patients who received tranexamic acid and 41.5% among those who received placebo. The degree of disability at 90 days also did not differ between treatment arms.

“Our work has once again shown that tranexamic acid is safe in spontaneous ICH,” said Jingyi Liu, MD, a physician in the neurocritical care unit at Beijing Tiantan Hospital, Capital Medical University, Beijing. “Larger studies with more specified population are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.”

The findings of the TRAIGE study were presented at the virtual European Stroke Organization Conference (ESOC) 2021. They were also published online June 28 in Stroke and Vascular Neurology.
 

Imaging-based patient selection

ICH is often fatal and entails a high risk for disability, the researchers wrote. Approximately 40% of patients with ICH die within a month of onset, and about two-thirds of patients do not achieve long-term functional independence.

Intracerebral hematoma expansion is predictive of poor clinical outcome in ICH. Data indicate that tranexamic acid, an antifibrinolytic agent, reduces hematoma expansion. But evidence of a clinical benefit of tranexamic acid has been elusive, they noted.

This lack of observed benefit may result from the inappropriate selection of research participants. The emergence of imaging biomarkers may help address this potential problem. In recent years, the blend sign and the black hole sign on noncontrast CT, as well as the spot sign on CT angiography, have been associated with higher risk for hematoma expansion and worse clinical outcome, the researchers wrote.

Between January 2015 and March 2020, the investigators enrolled consecutive patients with acute primary spontaneous ICH into their prospective study. Eligible patients presented at any of 10 stroke centers in China. They had the spot sign, blend sign, or black hole sign at admission and were able to receive treatment within 8 hours of onset.

The investigators randomly assigned patients in equal groups to receive placebo (0.9% NaCl) or tranexamic acid. Patients and study investigators were blinded to treatment assignment. Treatment was administered as an intravenous infusion over 8 hours.

The study’s primary endpoint was intracerebral hematoma expansion by 24 hours after start of treatment. Expansion was defined as an increase of > 6 mL or a growth of > 33% from baseline. Secondary endpoints included poor clinical outcome, defined as a Modified Rankin Scale (mRS) score of 4-6, and all-cause mortality, both at 90 days.
 

No differences in disability

The investigators enrolled 171 patients in their study; 24-hour CT images were available for 169 of them. Follow-up data at 90 days were available for 164 patients. The mean age of the patients was 55.9 years, and 72.5% of participants were men. At baseline, the mean ICH volume was 23.7 mL, and the median hematoma volume was 19.8 mL.

All patients received treatment within 8 hours. Hematoma expansion occurred in 40.9% of patients overall; 34.9% had a poor clinical outcome.

The investigators found no significant difference between treatment arms in the rate of hematoma expansion. This outcome occurred in 40.4% of the tranexamic acid group and 41.5% of the placebo group (odds ratio, 0.96; P = .89).

In addition, the researchers found no significant difference in the distribution of mRS scores at day 90 (P = .70). The rate of all-cause mortality at 90 days was lower in the tranexamic acid group (8.1%) than in the control group (10.0%), but this difference was not statistically significant (P = .71).
 

Potential clotting risk

One reason for the lack of observed benefit with tranexamic acid may be an inappropriate sample size, said Dr. Liu. Patient recruitment was difficult, especially in centers that used the spot sign as an inclusion criterion.

“We think a positive result could be seen in a substantially larger sample size,” said Dr. Liu. “Furthermore, we infer from our subgroup analysis that a more specified patient selection and shorter treatment window may be required for better effect.”

In some of their subgroup analyses, the researchers found a trend toward an increased effect in patients with moderate-size hematoma who received treatment in an earlier window. “That could be the targeted population for future studies,” said Dr. Liu. “We are working on further analysis of the population and possibly international collaboration.”

But tranexamic acid also entails risks, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, who provided independent commentary on the findings. “Tranexamic acid works on the thrombolytic system, so it increases clotting, and it does have a risk in people who are older and have risk factors for coronary disease and pulmonary embolism.”

As in ischemic stroke, time to treatment is a crucial consideration. Patients with ICH may receive treatment within 5 or 6 hours of onset, but most hemorrhages have reached their maximum size at that point. “The number of people that you can actually help by reducing the size is small,” said Dr. Caplan. “And then reducing the size in most hemorrhages doesn’t make any clinical difference.”

Stereotactic drainage, in which fluid is physically removed, is more likely to lead to long-term improvement for some patients with hemorrhage than limiting expansion, said Dr. Caplan. “That seems to be a more promising therapy,” he added.

The study was supported by the National Key R&D program of China, the National Natural Science Foundation of China, and the Beijing Science and Technology Commission. Dr. Liu and Dr. Caplan have disclosed no relevant financial relationshps.

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

Compared with placebo, tranexamic acid did not reduce hematoma growth in patients with intracerebral hemorrhage (ICH), a new study shows.

In the randomized controlled trial, the rate of hematoma expansion was 40.4% among patients who received tranexamic acid and 41.5% among those who received placebo. The degree of disability at 90 days also did not differ between treatment arms.

“Our work has once again shown that tranexamic acid is safe in spontaneous ICH,” said Jingyi Liu, MD, a physician in the neurocritical care unit at Beijing Tiantan Hospital, Capital Medical University, Beijing. “Larger studies with more specified population are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.”

The findings of the TRAIGE study were presented at the virtual European Stroke Organization Conference (ESOC) 2021. They were also published online June 28 in Stroke and Vascular Neurology.
 

Imaging-based patient selection

ICH is often fatal and entails a high risk for disability, the researchers wrote. Approximately 40% of patients with ICH die within a month of onset, and about two-thirds of patients do not achieve long-term functional independence.

Intracerebral hematoma expansion is predictive of poor clinical outcome in ICH. Data indicate that tranexamic acid, an antifibrinolytic agent, reduces hematoma expansion. But evidence of a clinical benefit of tranexamic acid has been elusive, they noted.

This lack of observed benefit may result from the inappropriate selection of research participants. The emergence of imaging biomarkers may help address this potential problem. In recent years, the blend sign and the black hole sign on noncontrast CT, as well as the spot sign on CT angiography, have been associated with higher risk for hematoma expansion and worse clinical outcome, the researchers wrote.

Between January 2015 and March 2020, the investigators enrolled consecutive patients with acute primary spontaneous ICH into their prospective study. Eligible patients presented at any of 10 stroke centers in China. They had the spot sign, blend sign, or black hole sign at admission and were able to receive treatment within 8 hours of onset.

The investigators randomly assigned patients in equal groups to receive placebo (0.9% NaCl) or tranexamic acid. Patients and study investigators were blinded to treatment assignment. Treatment was administered as an intravenous infusion over 8 hours.

The study’s primary endpoint was intracerebral hematoma expansion by 24 hours after start of treatment. Expansion was defined as an increase of > 6 mL or a growth of > 33% from baseline. Secondary endpoints included poor clinical outcome, defined as a Modified Rankin Scale (mRS) score of 4-6, and all-cause mortality, both at 90 days.
 

No differences in disability

The investigators enrolled 171 patients in their study; 24-hour CT images were available for 169 of them. Follow-up data at 90 days were available for 164 patients. The mean age of the patients was 55.9 years, and 72.5% of participants were men. At baseline, the mean ICH volume was 23.7 mL, and the median hematoma volume was 19.8 mL.

All patients received treatment within 8 hours. Hematoma expansion occurred in 40.9% of patients overall; 34.9% had a poor clinical outcome.

The investigators found no significant difference between treatment arms in the rate of hematoma expansion. This outcome occurred in 40.4% of the tranexamic acid group and 41.5% of the placebo group (odds ratio, 0.96; P = .89).

In addition, the researchers found no significant difference in the distribution of mRS scores at day 90 (P = .70). The rate of all-cause mortality at 90 days was lower in the tranexamic acid group (8.1%) than in the control group (10.0%), but this difference was not statistically significant (P = .71).
 

Potential clotting risk

One reason for the lack of observed benefit with tranexamic acid may be an inappropriate sample size, said Dr. Liu. Patient recruitment was difficult, especially in centers that used the spot sign as an inclusion criterion.

“We think a positive result could be seen in a substantially larger sample size,” said Dr. Liu. “Furthermore, we infer from our subgroup analysis that a more specified patient selection and shorter treatment window may be required for better effect.”

In some of their subgroup analyses, the researchers found a trend toward an increased effect in patients with moderate-size hematoma who received treatment in an earlier window. “That could be the targeted population for future studies,” said Dr. Liu. “We are working on further analysis of the population and possibly international collaboration.”

But tranexamic acid also entails risks, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, who provided independent commentary on the findings. “Tranexamic acid works on the thrombolytic system, so it increases clotting, and it does have a risk in people who are older and have risk factors for coronary disease and pulmonary embolism.”

As in ischemic stroke, time to treatment is a crucial consideration. Patients with ICH may receive treatment within 5 or 6 hours of onset, but most hemorrhages have reached their maximum size at that point. “The number of people that you can actually help by reducing the size is small,” said Dr. Caplan. “And then reducing the size in most hemorrhages doesn’t make any clinical difference.”

Stereotactic drainage, in which fluid is physically removed, is more likely to lead to long-term improvement for some patients with hemorrhage than limiting expansion, said Dr. Caplan. “That seems to be a more promising therapy,” he added.

The study was supported by the National Key R&D program of China, the National Natural Science Foundation of China, and the Beijing Science and Technology Commission. Dr. Liu and Dr. Caplan have disclosed no relevant financial relationshps.

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

Compared with placebo, tranexamic acid did not reduce hematoma growth in patients with intracerebral hemorrhage (ICH), a new study shows.

In the randomized controlled trial, the rate of hematoma expansion was 40.4% among patients who received tranexamic acid and 41.5% among those who received placebo. The degree of disability at 90 days also did not differ between treatment arms.

“Our work has once again shown that tranexamic acid is safe in spontaneous ICH,” said Jingyi Liu, MD, a physician in the neurocritical care unit at Beijing Tiantan Hospital, Capital Medical University, Beijing. “Larger studies with more specified population are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.”

The findings of the TRAIGE study were presented at the virtual European Stroke Organization Conference (ESOC) 2021. They were also published online June 28 in Stroke and Vascular Neurology.
 

Imaging-based patient selection

ICH is often fatal and entails a high risk for disability, the researchers wrote. Approximately 40% of patients with ICH die within a month of onset, and about two-thirds of patients do not achieve long-term functional independence.

Intracerebral hematoma expansion is predictive of poor clinical outcome in ICH. Data indicate that tranexamic acid, an antifibrinolytic agent, reduces hematoma expansion. But evidence of a clinical benefit of tranexamic acid has been elusive, they noted.

This lack of observed benefit may result from the inappropriate selection of research participants. The emergence of imaging biomarkers may help address this potential problem. In recent years, the blend sign and the black hole sign on noncontrast CT, as well as the spot sign on CT angiography, have been associated with higher risk for hematoma expansion and worse clinical outcome, the researchers wrote.

Between January 2015 and March 2020, the investigators enrolled consecutive patients with acute primary spontaneous ICH into their prospective study. Eligible patients presented at any of 10 stroke centers in China. They had the spot sign, blend sign, or black hole sign at admission and were able to receive treatment within 8 hours of onset.

The investigators randomly assigned patients in equal groups to receive placebo (0.9% NaCl) or tranexamic acid. Patients and study investigators were blinded to treatment assignment. Treatment was administered as an intravenous infusion over 8 hours.

The study’s primary endpoint was intracerebral hematoma expansion by 24 hours after start of treatment. Expansion was defined as an increase of > 6 mL or a growth of > 33% from baseline. Secondary endpoints included poor clinical outcome, defined as a Modified Rankin Scale (mRS) score of 4-6, and all-cause mortality, both at 90 days.
 

No differences in disability

The investigators enrolled 171 patients in their study; 24-hour CT images were available for 169 of them. Follow-up data at 90 days were available for 164 patients. The mean age of the patients was 55.9 years, and 72.5% of participants were men. At baseline, the mean ICH volume was 23.7 mL, and the median hematoma volume was 19.8 mL.

All patients received treatment within 8 hours. Hematoma expansion occurred in 40.9% of patients overall; 34.9% had a poor clinical outcome.

The investigators found no significant difference between treatment arms in the rate of hematoma expansion. This outcome occurred in 40.4% of the tranexamic acid group and 41.5% of the placebo group (odds ratio, 0.96; P = .89).

In addition, the researchers found no significant difference in the distribution of mRS scores at day 90 (P = .70). The rate of all-cause mortality at 90 days was lower in the tranexamic acid group (8.1%) than in the control group (10.0%), but this difference was not statistically significant (P = .71).
 

Potential clotting risk

One reason for the lack of observed benefit with tranexamic acid may be an inappropriate sample size, said Dr. Liu. Patient recruitment was difficult, especially in centers that used the spot sign as an inclusion criterion.

“We think a positive result could be seen in a substantially larger sample size,” said Dr. Liu. “Furthermore, we infer from our subgroup analysis that a more specified patient selection and shorter treatment window may be required for better effect.”

In some of their subgroup analyses, the researchers found a trend toward an increased effect in patients with moderate-size hematoma who received treatment in an earlier window. “That could be the targeted population for future studies,” said Dr. Liu. “We are working on further analysis of the population and possibly international collaboration.”

But tranexamic acid also entails risks, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, who provided independent commentary on the findings. “Tranexamic acid works on the thrombolytic system, so it increases clotting, and it does have a risk in people who are older and have risk factors for coronary disease and pulmonary embolism.”

As in ischemic stroke, time to treatment is a crucial consideration. Patients with ICH may receive treatment within 5 or 6 hours of onset, but most hemorrhages have reached their maximum size at that point. “The number of people that you can actually help by reducing the size is small,” said Dr. Caplan. “And then reducing the size in most hemorrhages doesn’t make any clinical difference.”

Stereotactic drainage, in which fluid is physically removed, is more likely to lead to long-term improvement for some patients with hemorrhage than limiting expansion, said Dr. Caplan. “That seems to be a more promising therapy,” he added.

The study was supported by the National Key R&D program of China, the National Natural Science Foundation of China, and the Beijing Science and Technology Commission. Dr. Liu and Dr. Caplan have disclosed no relevant financial relationshps.

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

Basing referral of patients with chronic kidney disease (CKD) to nephrologists on 2-year kidney failure risk exceeding 1% would catch those at higher risk without increasing referral volumes generated from current laboratory-based guidelines, new research indicates.

And combining the two methods – predicted kidney failure risk with lab values – will lead to better patient outcomes by pinpointing CKD patients who most need specialty care, said study author Vishal Duggal, MD, who was a postdoctoral fellow in medical informatics at the Veterans Affairs Palo Alto (Calif.) Health Care System while conducting the research.

“We hope this can provide guidance to primary care physicians and nephrologists to give context for their decision-making,” Dr. Duggal told this news organization.

The VA is the largest provider of CKD care in the United States, developing clinical practice guidelines for CKD management that include suggested indications for nephrology referral based on laboratory values. Laboratory values that are typically used to guide referral include estimated glomerular filtration rate (eGFR) and its rate of decline per year, as well as heavy proteinuria in patients with and without diabetes. 

Dr. Duggal and colleagues – who published their findings in the American Journal of Kidney Diseases – conducted a retrospective analysis of nearly 400,000 veterans with CKD over a yearlong period to determine if referral volume would change if it was based on the estimated risk for kidney failure, rather than solely using laboratory values.

They also estimated the potential volume of nephrology referrals based on a combination of both estimated risk for kidney failure and laboratory data.

Kidney failure risk was calculated using an electronic clinical decision support tool, called Kidney Failure Risk Equation incorporating age, eGFR, gender, and urine albumin-to-creatinine ratio.
 

Targeting fewer patients to specialty care

Among all participants with CKD not already receiving nephrology care, more than 150,000 (41.5%) had a urine albumin or protein measurement leading to computable risk for end-stage kidney disease.

More than 66,200 patients met actual laboratory indications for referral but had not previously seen a nephrologist. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year, and all had a median 2-year predicted risk for kidney failure of 1.5%.

Referred patients were more likely to meet several potential referral criteria, especially eGFR less than 30 mL/min per 1.73 m² and heavy proteinuria. Those with heavy proteinuria with diabetes, or the eGFR indication, had the highest predicted risk for kidney failure at 2 years, at 10% and 7.1% respectively.

Boosting referral volume can be problematic if patients aren’t prioritized by need, Dr. Duggal said, noting that many reasons explain why fewer than one in five CKD patients meeting lab indications for referral aren’t actually referred.

This can include patient preference, he noted: “Kidney disease is a disease of aging, and some patients don’t want to see a specialist or escalate their care.”

“Also, not everyone who has CKD is recommended to see a nephrologist, since primary care physicians do manage a lot of CKD as well.”

Basing referral on predicted kidney failure risk alone, a 2-year risk threshold of at least 1%, would identify a comparable number of patients (n = 72,948) as laboratory-based criteria, the team found, although they note that the patients identified using the KFRE tool would be at higher risk than those identified by lab values alone.

But when they combined the two – a minimum kidney failure risk of at least 1% over 2 years being applied to all new patients meeting lab-based referral indications, those pinpointed for nephrology referral dropped by 42.3%, from 66,276 to an estimated 38,229 patients.

“The current guidelines that just incorporate lab values identify a significant number of patients who are at low risk of developing end-stage kidney disease (ESKD), so incorporating kidney failure risk into current guidelines would target fewer patients to get to specialty care,” Dr. Duggal explained.
 

KFRE tool can be found online

Dr. Duggal emphasized that his findings do not change nephrology referral guidelines, but said physicians can find the KFRE tool online and use it to supplement their decision-making about a patient’s care.

“Further incorporating this [kidney failure] risk into referral practices might highlight a patient at extremely high risk who would benefit more from an interdisciplinary care team,” he said.

This could include, for example, a nutritionist to help the patient modify his or her diet. “Getting that kind of teaching process in place for a patient might be highly valuable,” he added.

Dr. Duggal disclosed no relevant financial relationships.

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

Basing referral of patients with chronic kidney disease (CKD) to nephrologists on 2-year kidney failure risk exceeding 1% would catch those at higher risk without increasing referral volumes generated from current laboratory-based guidelines, new research indicates.

And combining the two methods – predicted kidney failure risk with lab values – will lead to better patient outcomes by pinpointing CKD patients who most need specialty care, said study author Vishal Duggal, MD, who was a postdoctoral fellow in medical informatics at the Veterans Affairs Palo Alto (Calif.) Health Care System while conducting the research.

“We hope this can provide guidance to primary care physicians and nephrologists to give context for their decision-making,” Dr. Duggal told this news organization.

The VA is the largest provider of CKD care in the United States, developing clinical practice guidelines for CKD management that include suggested indications for nephrology referral based on laboratory values. Laboratory values that are typically used to guide referral include estimated glomerular filtration rate (eGFR) and its rate of decline per year, as well as heavy proteinuria in patients with and without diabetes. 

Dr. Duggal and colleagues – who published their findings in the American Journal of Kidney Diseases – conducted a retrospective analysis of nearly 400,000 veterans with CKD over a yearlong period to determine if referral volume would change if it was based on the estimated risk for kidney failure, rather than solely using laboratory values.

They also estimated the potential volume of nephrology referrals based on a combination of both estimated risk for kidney failure and laboratory data.

Kidney failure risk was calculated using an electronic clinical decision support tool, called Kidney Failure Risk Equation incorporating age, eGFR, gender, and urine albumin-to-creatinine ratio.
 

Targeting fewer patients to specialty care

Among all participants with CKD not already receiving nephrology care, more than 150,000 (41.5%) had a urine albumin or protein measurement leading to computable risk for end-stage kidney disease.

More than 66,200 patients met actual laboratory indications for referral but had not previously seen a nephrologist. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year, and all had a median 2-year predicted risk for kidney failure of 1.5%.

Referred patients were more likely to meet several potential referral criteria, especially eGFR less than 30 mL/min per 1.73 m² and heavy proteinuria. Those with heavy proteinuria with diabetes, or the eGFR indication, had the highest predicted risk for kidney failure at 2 years, at 10% and 7.1% respectively.

Boosting referral volume can be problematic if patients aren’t prioritized by need, Dr. Duggal said, noting that many reasons explain why fewer than one in five CKD patients meeting lab indications for referral aren’t actually referred.

This can include patient preference, he noted: “Kidney disease is a disease of aging, and some patients don’t want to see a specialist or escalate their care.”

“Also, not everyone who has CKD is recommended to see a nephrologist, since primary care physicians do manage a lot of CKD as well.”

Basing referral on predicted kidney failure risk alone, a 2-year risk threshold of at least 1%, would identify a comparable number of patients (n = 72,948) as laboratory-based criteria, the team found, although they note that the patients identified using the KFRE tool would be at higher risk than those identified by lab values alone.

But when they combined the two – a minimum kidney failure risk of at least 1% over 2 years being applied to all new patients meeting lab-based referral indications, those pinpointed for nephrology referral dropped by 42.3%, from 66,276 to an estimated 38,229 patients.

“The current guidelines that just incorporate lab values identify a significant number of patients who are at low risk of developing end-stage kidney disease (ESKD), so incorporating kidney failure risk into current guidelines would target fewer patients to get to specialty care,” Dr. Duggal explained.
 

KFRE tool can be found online

Dr. Duggal emphasized that his findings do not change nephrology referral guidelines, but said physicians can find the KFRE tool online and use it to supplement their decision-making about a patient’s care.

“Further incorporating this [kidney failure] risk into referral practices might highlight a patient at extremely high risk who would benefit more from an interdisciplinary care team,” he said.

This could include, for example, a nutritionist to help the patient modify his or her diet. “Getting that kind of teaching process in place for a patient might be highly valuable,” he added.

Dr. Duggal disclosed no relevant financial relationships.

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

Basing referral of patients with chronic kidney disease (CKD) to nephrologists on 2-year kidney failure risk exceeding 1% would catch those at higher risk without increasing referral volumes generated from current laboratory-based guidelines, new research indicates.

And combining the two methods – predicted kidney failure risk with lab values – will lead to better patient outcomes by pinpointing CKD patients who most need specialty care, said study author Vishal Duggal, MD, who was a postdoctoral fellow in medical informatics at the Veterans Affairs Palo Alto (Calif.) Health Care System while conducting the research.

“We hope this can provide guidance to primary care physicians and nephrologists to give context for their decision-making,” Dr. Duggal told this news organization.

The VA is the largest provider of CKD care in the United States, developing clinical practice guidelines for CKD management that include suggested indications for nephrology referral based on laboratory values. Laboratory values that are typically used to guide referral include estimated glomerular filtration rate (eGFR) and its rate of decline per year, as well as heavy proteinuria in patients with and without diabetes. 

Dr. Duggal and colleagues – who published their findings in the American Journal of Kidney Diseases – conducted a retrospective analysis of nearly 400,000 veterans with CKD over a yearlong period to determine if referral volume would change if it was based on the estimated risk for kidney failure, rather than solely using laboratory values.

They also estimated the potential volume of nephrology referrals based on a combination of both estimated risk for kidney failure and laboratory data.

Kidney failure risk was calculated using an electronic clinical decision support tool, called Kidney Failure Risk Equation incorporating age, eGFR, gender, and urine albumin-to-creatinine ratio.
 

Targeting fewer patients to specialty care

Among all participants with CKD not already receiving nephrology care, more than 150,000 (41.5%) had a urine albumin or protein measurement leading to computable risk for end-stage kidney disease.

More than 66,200 patients met actual laboratory indications for referral but had not previously seen a nephrologist. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year, and all had a median 2-year predicted risk for kidney failure of 1.5%.

Referred patients were more likely to meet several potential referral criteria, especially eGFR less than 30 mL/min per 1.73 m² and heavy proteinuria. Those with heavy proteinuria with diabetes, or the eGFR indication, had the highest predicted risk for kidney failure at 2 years, at 10% and 7.1% respectively.

Boosting referral volume can be problematic if patients aren’t prioritized by need, Dr. Duggal said, noting that many reasons explain why fewer than one in five CKD patients meeting lab indications for referral aren’t actually referred.

This can include patient preference, he noted: “Kidney disease is a disease of aging, and some patients don’t want to see a specialist or escalate their care.”

“Also, not everyone who has CKD is recommended to see a nephrologist, since primary care physicians do manage a lot of CKD as well.”

Basing referral on predicted kidney failure risk alone, a 2-year risk threshold of at least 1%, would identify a comparable number of patients (n = 72,948) as laboratory-based criteria, the team found, although they note that the patients identified using the KFRE tool would be at higher risk than those identified by lab values alone.

But when they combined the two – a minimum kidney failure risk of at least 1% over 2 years being applied to all new patients meeting lab-based referral indications, those pinpointed for nephrology referral dropped by 42.3%, from 66,276 to an estimated 38,229 patients.

“The current guidelines that just incorporate lab values identify a significant number of patients who are at low risk of developing end-stage kidney disease (ESKD), so incorporating kidney failure risk into current guidelines would target fewer patients to get to specialty care,” Dr. Duggal explained.
 

KFRE tool can be found online

Dr. Duggal emphasized that his findings do not change nephrology referral guidelines, but said physicians can find the KFRE tool online and use it to supplement their decision-making about a patient’s care.

“Further incorporating this [kidney failure] risk into referral practices might highlight a patient at extremely high risk who would benefit more from an interdisciplinary care team,” he said.

This could include, for example, a nutritionist to help the patient modify his or her diet. “Getting that kind of teaching process in place for a patient might be highly valuable,” he added.

Dr. Duggal disclosed no relevant financial relationships.

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

Estimating an individual’s risk of cardiovascular disease (CVD) remains the cornerstone of the 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice. The new guidelines were published online Aug. 30 in the European Heart Journal to coincide with presentation at the European Stroke Congress (ESOC) 2021.   

They were developed by an ESOC task force in collaboration with 12 medical societies and with special contribution of the European Association of Preventive Cardiology.

“A chief goal of the task force was to create a single CVD prevention guideline for everyone – for primary care, for hospital care, for guiding clinical practice – so one guideline for all,” said cochair of the guideline committee Frank Visseren, MD, PhD, University Medical Center Utrecht, Netherlands. “We also wanted to make a more personalized CVD prevention guideline, instead of a one-size-fits-all. In clinical practice, people are very, very different, and we really want to have a more individualized prevention guideline,” said Dr. Visseren, as well as provide “more room for shared decision-making.”
 

Prevention at the individual and population levels

The new guidelines also give more attention to CVD prevention in older persons. “Many of our patients are over 70 years old and we really want to have more detail, more guidance on older persons,” said Dr. Visseren.

The guideline is divided into two sections. One section covers CVD prevention at the individual level in apparently healthy people, in patients with established CVD, and in those with diabetes, familial hypercholesterolemia, or chronic kidney disease.

The other section covers CVD prevention at the population level, including public health policy, interventions, and the environment, including putting in place measures to reduce air pollution, use of fossil fuels, and limiting carbon dioxide emissions.

Targets for blood lipids, blood pressure, and glycemic control in diabetes remain in line with recent ESC guidelines on dyslipidemias, hypertension, or diabetes.

However, the guidelines introduce a new stepwise treatment-intensification approach to achieve these targets, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences.

The 2021 CVD prevention guidelines also embrace the recently published Systemic Coronary Risk Estimation 2 (SCORE2) and Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) algorithms. “The algorithms we are using are a bit old and we want to have more updated risk prediction, because that’s the starting point of CVD prevention,” Dr. Visseren said.

The guidelines also introduce age-specific risk thresholds for risk factor treatments in apparently healthy people and provide estimation of lifetime CVD risk and treatment benefit. This will allow clinicians to have “an informed discussion with patients on lifetime risk and potential treatment benefits,” Dr. Visseren said.

For the first time, the guidelines recommend smoking cessation regardless of whether it leads to weight gain, as weight gain does not lessen the benefits of cessation.

Regarding exercise, adults of all ages should aim for at least 150-300 minutes a week of moderate, or 75-150 minutes a week of vigorous, aerobic physical activity. The guidelines recommend reducing sedentary time and engaging in at least light activity throughout the day.

Regarding nutrition, the guidelines advise adopting a Mediterranean or similar diet; restricting alcohol intake to a maximum of 100 g per week (a standard drink is 8-14 g); eating fish, preferably fatty fish, at least once a week; and restricting consumption of meat, particularly processed meat.

Also for the first time, the guidelines state that bariatric surgery should be considered for obese individuals at elevated risk of CVD when a healthy diet and exercise fail to lead to weight loss that is maintained.

They note that individuals with mental disorders need additional attention and support to improve adherence to lifestyle changes and drug treatment.

They advise consideration of referring patients with heart disease and significant stress and anxiety to psychotherapeutic stress management to reduce stress symptoms and improve CV outcomes.

Potential cost issues that could be considered when implementing the guidelines are also reviewed.

Dr. Visseren acknowledged and thanked the task force members for continuing their work on the guidelines over the 2 “challenging” years.
 

Setting the bar lower?

Discussant for the guideline presentation, Diederick Grobbee, MD, University Medical Center Utrecht, who was not involved in drafting the guidelines, said he does have one conflict of interest, which is a “passion for prevention.” From that perspective, he said the guideline panel “should be applauded; the once-every-5-year issuing of the prevention guidelines is a major event.”

Dr. Grobbee noted that the working group “really tried to follow their ambitions and goals, in a way making the guidelines simpler, or perhaps setting the bar not initially as high as we used to do, which may, in fact, sometimes scare off physicians and patients alike.”

“We’ve had prevention guidelines for quite some time now, yet looking at what is accomplished in practice is sobering,” said Dr. Grobbee. Introducing a stepwise approach is “really appealing,” he added.

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

Estimating an individual’s risk of cardiovascular disease (CVD) remains the cornerstone of the 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice. The new guidelines were published online Aug. 30 in the European Heart Journal to coincide with presentation at the European Stroke Congress (ESOC) 2021.   

They were developed by an ESOC task force in collaboration with 12 medical societies and with special contribution of the European Association of Preventive Cardiology.

“A chief goal of the task force was to create a single CVD prevention guideline for everyone – for primary care, for hospital care, for guiding clinical practice – so one guideline for all,” said cochair of the guideline committee Frank Visseren, MD, PhD, University Medical Center Utrecht, Netherlands. “We also wanted to make a more personalized CVD prevention guideline, instead of a one-size-fits-all. In clinical practice, people are very, very different, and we really want to have a more individualized prevention guideline,” said Dr. Visseren, as well as provide “more room for shared decision-making.”
 

Prevention at the individual and population levels

The new guidelines also give more attention to CVD prevention in older persons. “Many of our patients are over 70 years old and we really want to have more detail, more guidance on older persons,” said Dr. Visseren.

The guideline is divided into two sections. One section covers CVD prevention at the individual level in apparently healthy people, in patients with established CVD, and in those with diabetes, familial hypercholesterolemia, or chronic kidney disease.

The other section covers CVD prevention at the population level, including public health policy, interventions, and the environment, including putting in place measures to reduce air pollution, use of fossil fuels, and limiting carbon dioxide emissions.

Targets for blood lipids, blood pressure, and glycemic control in diabetes remain in line with recent ESC guidelines on dyslipidemias, hypertension, or diabetes.

However, the guidelines introduce a new stepwise treatment-intensification approach to achieve these targets, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences.

The 2021 CVD prevention guidelines also embrace the recently published Systemic Coronary Risk Estimation 2 (SCORE2) and Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) algorithms. “The algorithms we are using are a bit old and we want to have more updated risk prediction, because that’s the starting point of CVD prevention,” Dr. Visseren said.

The guidelines also introduce age-specific risk thresholds for risk factor treatments in apparently healthy people and provide estimation of lifetime CVD risk and treatment benefit. This will allow clinicians to have “an informed discussion with patients on lifetime risk and potential treatment benefits,” Dr. Visseren said.

For the first time, the guidelines recommend smoking cessation regardless of whether it leads to weight gain, as weight gain does not lessen the benefits of cessation.

Regarding exercise, adults of all ages should aim for at least 150-300 minutes a week of moderate, or 75-150 minutes a week of vigorous, aerobic physical activity. The guidelines recommend reducing sedentary time and engaging in at least light activity throughout the day.

Regarding nutrition, the guidelines advise adopting a Mediterranean or similar diet; restricting alcohol intake to a maximum of 100 g per week (a standard drink is 8-14 g); eating fish, preferably fatty fish, at least once a week; and restricting consumption of meat, particularly processed meat.

Also for the first time, the guidelines state that bariatric surgery should be considered for obese individuals at elevated risk of CVD when a healthy diet and exercise fail to lead to weight loss that is maintained.

They note that individuals with mental disorders need additional attention and support to improve adherence to lifestyle changes and drug treatment.

They advise consideration of referring patients with heart disease and significant stress and anxiety to psychotherapeutic stress management to reduce stress symptoms and improve CV outcomes.

Potential cost issues that could be considered when implementing the guidelines are also reviewed.

Dr. Visseren acknowledged and thanked the task force members for continuing their work on the guidelines over the 2 “challenging” years.
 

Setting the bar lower?

Discussant for the guideline presentation, Diederick Grobbee, MD, University Medical Center Utrecht, who was not involved in drafting the guidelines, said he does have one conflict of interest, which is a “passion for prevention.” From that perspective, he said the guideline panel “should be applauded; the once-every-5-year issuing of the prevention guidelines is a major event.”

Dr. Grobbee noted that the working group “really tried to follow their ambitions and goals, in a way making the guidelines simpler, or perhaps setting the bar not initially as high as we used to do, which may, in fact, sometimes scare off physicians and patients alike.”

“We’ve had prevention guidelines for quite some time now, yet looking at what is accomplished in practice is sobering,” said Dr. Grobbee. Introducing a stepwise approach is “really appealing,” he added.

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

Estimating an individual’s risk of cardiovascular disease (CVD) remains the cornerstone of the 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice. The new guidelines were published online Aug. 30 in the European Heart Journal to coincide with presentation at the European Stroke Congress (ESOC) 2021.   

They were developed by an ESOC task force in collaboration with 12 medical societies and with special contribution of the European Association of Preventive Cardiology.

“A chief goal of the task force was to create a single CVD prevention guideline for everyone – for primary care, for hospital care, for guiding clinical practice – so one guideline for all,” said cochair of the guideline committee Frank Visseren, MD, PhD, University Medical Center Utrecht, Netherlands. “We also wanted to make a more personalized CVD prevention guideline, instead of a one-size-fits-all. In clinical practice, people are very, very different, and we really want to have a more individualized prevention guideline,” said Dr. Visseren, as well as provide “more room for shared decision-making.”
 

Prevention at the individual and population levels

The new guidelines also give more attention to CVD prevention in older persons. “Many of our patients are over 70 years old and we really want to have more detail, more guidance on older persons,” said Dr. Visseren.

The guideline is divided into two sections. One section covers CVD prevention at the individual level in apparently healthy people, in patients with established CVD, and in those with diabetes, familial hypercholesterolemia, or chronic kidney disease.

The other section covers CVD prevention at the population level, including public health policy, interventions, and the environment, including putting in place measures to reduce air pollution, use of fossil fuels, and limiting carbon dioxide emissions.

Targets for blood lipids, blood pressure, and glycemic control in diabetes remain in line with recent ESC guidelines on dyslipidemias, hypertension, or diabetes.

However, the guidelines introduce a new stepwise treatment-intensification approach to achieve these targets, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences.

The 2021 CVD prevention guidelines also embrace the recently published Systemic Coronary Risk Estimation 2 (SCORE2) and Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) algorithms. “The algorithms we are using are a bit old and we want to have more updated risk prediction, because that’s the starting point of CVD prevention,” Dr. Visseren said.

The guidelines also introduce age-specific risk thresholds for risk factor treatments in apparently healthy people and provide estimation of lifetime CVD risk and treatment benefit. This will allow clinicians to have “an informed discussion with patients on lifetime risk and potential treatment benefits,” Dr. Visseren said.

For the first time, the guidelines recommend smoking cessation regardless of whether it leads to weight gain, as weight gain does not lessen the benefits of cessation.

Regarding exercise, adults of all ages should aim for at least 150-300 minutes a week of moderate, or 75-150 minutes a week of vigorous, aerobic physical activity. The guidelines recommend reducing sedentary time and engaging in at least light activity throughout the day.

Regarding nutrition, the guidelines advise adopting a Mediterranean or similar diet; restricting alcohol intake to a maximum of 100 g per week (a standard drink is 8-14 g); eating fish, preferably fatty fish, at least once a week; and restricting consumption of meat, particularly processed meat.

Also for the first time, the guidelines state that bariatric surgery should be considered for obese individuals at elevated risk of CVD when a healthy diet and exercise fail to lead to weight loss that is maintained.

They note that individuals with mental disorders need additional attention and support to improve adherence to lifestyle changes and drug treatment.

They advise consideration of referring patients with heart disease and significant stress and anxiety to psychotherapeutic stress management to reduce stress symptoms and improve CV outcomes.

Potential cost issues that could be considered when implementing the guidelines are also reviewed.

Dr. Visseren acknowledged and thanked the task force members for continuing their work on the guidelines over the 2 “challenging” years.
 

Setting the bar lower?

Discussant for the guideline presentation, Diederick Grobbee, MD, University Medical Center Utrecht, who was not involved in drafting the guidelines, said he does have one conflict of interest, which is a “passion for prevention.” From that perspective, he said the guideline panel “should be applauded; the once-every-5-year issuing of the prevention guidelines is a major event.”

Dr. Grobbee noted that the working group “really tried to follow their ambitions and goals, in a way making the guidelines simpler, or perhaps setting the bar not initially as high as we used to do, which may, in fact, sometimes scare off physicians and patients alike.”

“We’ve had prevention guidelines for quite some time now, yet looking at what is accomplished in practice is sobering,” said Dr. Grobbee. Introducing a stepwise approach is “really appealing,” he added.

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