Mixed Topics

Q1. Correct answer: D. Lorcaserin (Belviq). 
 
Rationale 
Lorcaserin may cause valvulopathy, attention, or memory disturbance. This patient has normal ECHO and does not work with heavy machinery. Given his other history, this may be the best choice for him. Naltrexone/bupropion extended release is contraindicated in patients with seizure disorder, chronic opioid use, anorexia nervosa, bulimia, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs because bupropion lowers the seizure threshold. Liraglutide is contraindicated with personal or family history of medullary thyroid carcinoma or MENII. In addition, GLP1 receptor agonists can increase the risk of pancreatitis in patients with a history of pancreatitis. Phentermine/topiramate can increase the risk of nephrolithiasis. All of these medications are contraindicated in pregnancy and in patients with hypersensitivity to the drug and drug class. 
 
References 
Bays HE et al. Obesity algorithm, presented by the Obesity Medical Association. 2016-2017. https://cmcoem.info/pdf/curso/evaluacion_preoperatoria/oma_obesity-algorithm.pdf.  
Steelman M and Westman E. Obesity: Evaluation and Treatment Essentials. Boca Raton: CRC press, 2016. https://www.abom.org/wp-content/uploads/2016/06/Obesity-Evaluation-and-Treatment-Essentials.pdf.  
Liraglutide Prescribing Information (Saxenda). https://www.novo-pi.com/saxenda.pdf.  
Lorcaserin (Belviq) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf.  
Naltrexone HCl/Bupropion HCl Extended Release Prescribing Information (CONTRAVE). https://contrave.com/contrave-pi/.  
Phentermine HCl/Topiramate Extended Release Prescribing Information (Qsymia). https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf

Q1. Correct answer: D. Lorcaserin (Belviq). 
 
Rationale 
Lorcaserin may cause valvulopathy, attention, or memory disturbance. This patient has normal ECHO and does not work with heavy machinery. Given his other history, this may be the best choice for him. Naltrexone/bupropion extended release is contraindicated in patients with seizure disorder, chronic opioid use, anorexia nervosa, bulimia, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs because bupropion lowers the seizure threshold. Liraglutide is contraindicated with personal or family history of medullary thyroid carcinoma or MENII. In addition, GLP1 receptor agonists can increase the risk of pancreatitis in patients with a history of pancreatitis. Phentermine/topiramate can increase the risk of nephrolithiasis. All of these medications are contraindicated in pregnancy and in patients with hypersensitivity to the drug and drug class. 
 
References 
Bays HE et al. Obesity algorithm, presented by the Obesity Medical Association. 2016-2017. https://cmcoem.info/pdf/curso/evaluacion_preoperatoria/oma_obesity-algorithm.pdf.  
Steelman M and Westman E. Obesity: Evaluation and Treatment Essentials. Boca Raton: CRC press, 2016. https://www.abom.org/wp-content/uploads/2016/06/Obesity-Evaluation-and-Treatment-Essentials.pdf.  
Liraglutide Prescribing Information (Saxenda). https://www.novo-pi.com/saxenda.pdf.  
Lorcaserin (Belviq) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf.  
Naltrexone HCl/Bupropion HCl Extended Release Prescribing Information (CONTRAVE). https://contrave.com/contrave-pi/.  
Phentermine HCl/Topiramate Extended Release Prescribing Information (Qsymia). https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf

Q1. Correct answer: D. Lorcaserin (Belviq). 
 
Rationale 
Lorcaserin may cause valvulopathy, attention, or memory disturbance. This patient has normal ECHO and does not work with heavy machinery. Given his other history, this may be the best choice for him. Naltrexone/bupropion extended release is contraindicated in patients with seizure disorder, chronic opioid use, anorexia nervosa, bulimia, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs because bupropion lowers the seizure threshold. Liraglutide is contraindicated with personal or family history of medullary thyroid carcinoma or MENII. In addition, GLP1 receptor agonists can increase the risk of pancreatitis in patients with a history of pancreatitis. Phentermine/topiramate can increase the risk of nephrolithiasis. All of these medications are contraindicated in pregnancy and in patients with hypersensitivity to the drug and drug class. 
 
References 
Bays HE et al. Obesity algorithm, presented by the Obesity Medical Association. 2016-2017. https://cmcoem.info/pdf/curso/evaluacion_preoperatoria/oma_obesity-algorithm.pdf.  
Steelman M and Westman E. Obesity: Evaluation and Treatment Essentials. Boca Raton: CRC press, 2016. https://www.abom.org/wp-content/uploads/2016/06/Obesity-Evaluation-and-Treatment-Essentials.pdf.  
Liraglutide Prescribing Information (Saxenda). https://www.novo-pi.com/saxenda.pdf.  
Lorcaserin (Belviq) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf.  
Naltrexone HCl/Bupropion HCl Extended Release Prescribing Information (CONTRAVE). https://contrave.com/contrave-pi/.  
Phentermine HCl/Topiramate Extended Release Prescribing Information (Qsymia). https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf

Men have a significantly increased risk of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” said lead author Sarah S. Jackson, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggested.

In an interview, Dr. Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told this news organization. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”
 

Comprehensive analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” said the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University in St. Louis.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they said.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wondered if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggested.

Nevertheless, they pointed out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic variable should be enforced along the whole cancer continuum, from risk prediction and cancer primary prevention, cancer screening, and secondary prevention to cancer treatment and patient management,” Dr. Luo and Dr. Colditz concluded.
 

Details of the analysis 

In their paper, Dr. Jackson and colleagues pointed out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs. 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of health care, and cancer screening between men and women, to explain the sex disparity, the researchers noted, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health–AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six U.S. states. At the time, 617,119 returned the baseline questionnaire (a 17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow-up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8,742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio versus women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team said that, overall, the increased relative risk among men was retained after adjustment for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters-Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

There were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Dr. Jackson told this news organization that sex differences in cancer outcomes “represents a very promising area of research” and the researchers “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Dr. Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the division of cancer epidemiology and genetics, National Cancer Institute. Dr. Marks reports relationships with Merck outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Dr. Luo reports grants from the National Institutes of Health outside the submitted work. Dr. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships were declared.

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

Men have a significantly increased risk of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” said lead author Sarah S. Jackson, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggested.

In an interview, Dr. Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told this news organization. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”
 

Comprehensive analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” said the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University in St. Louis.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they said.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wondered if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggested.

Nevertheless, they pointed out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic variable should be enforced along the whole cancer continuum, from risk prediction and cancer primary prevention, cancer screening, and secondary prevention to cancer treatment and patient management,” Dr. Luo and Dr. Colditz concluded.
 

Details of the analysis 

In their paper, Dr. Jackson and colleagues pointed out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs. 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of health care, and cancer screening between men and women, to explain the sex disparity, the researchers noted, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health–AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six U.S. states. At the time, 617,119 returned the baseline questionnaire (a 17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow-up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8,742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio versus women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team said that, overall, the increased relative risk among men was retained after adjustment for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters-Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

There were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Dr. Jackson told this news organization that sex differences in cancer outcomes “represents a very promising area of research” and the researchers “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Dr. Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the division of cancer epidemiology and genetics, National Cancer Institute. Dr. Marks reports relationships with Merck outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Dr. Luo reports grants from the National Institutes of Health outside the submitted work. Dr. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships were declared.

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

Men have a significantly increased risk of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” said lead author Sarah S. Jackson, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggested.

In an interview, Dr. Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told this news organization. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”
 

Comprehensive analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” said the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University in St. Louis.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they said.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wondered if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggested.

Nevertheless, they pointed out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic variable should be enforced along the whole cancer continuum, from risk prediction and cancer primary prevention, cancer screening, and secondary prevention to cancer treatment and patient management,” Dr. Luo and Dr. Colditz concluded.
 

Details of the analysis 

In their paper, Dr. Jackson and colleagues pointed out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs. 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of health care, and cancer screening between men and women, to explain the sex disparity, the researchers noted, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health–AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six U.S. states. At the time, 617,119 returned the baseline questionnaire (a 17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow-up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8,742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio versus women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team said that, overall, the increased relative risk among men was retained after adjustment for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters-Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

There were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Dr. Jackson told this news organization that sex differences in cancer outcomes “represents a very promising area of research” and the researchers “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Dr. Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the division of cancer epidemiology and genetics, National Cancer Institute. Dr. Marks reports relationships with Merck outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Dr. Luo reports grants from the National Institutes of Health outside the submitted work. Dr. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships were declared.

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

Background

Ketogenic diet (KD) is a high-fat and low carbohydrate diet that has been reported as a treatment option for patients with cancer. KD creates a metabolic state in which blood glucose levels are reduced and ketone bodies are elevated. Cancer cells are unable to use ketone bodies for energy and metabolism due to mitochondrial dysfunction. We published the efficacy of KD in patients with cancer after failure of chemotherapy. 1 This case report is presented to evaluate the feasibility of KD concurrent with chemoimmunotherapy.

Case Report

Patient is a 69-year-old male who presented with iron deficiency anemia in 2018. Colonoscopy and biopsy showed colon adenocarcinoma. He underwent resection which confirmed stage IIIC disease. He received adjuvant treatment with FOLFOX but quickly developed pancreatic and omental metastasis. He was started on FOLFIRI + bevacizumab followed by pancreatic mass resection in 2019. Molecular testing revealed wild type KRAS, positive BRAF V600E, and high MSI. He received encorafenib + cetuximab until disease progression. Treatment was changed to pembrolizumab until PET scan showed progression. His CEA increased to 1031 in January 2021. He was subsequently started on KD concurrent with trifluridine + tipiracil + bevacizumab. He progressed after 10 months. Therapy was changed to ipilimumab + nivolumab with continuation of KD. He was strictly adherent to KD with low Glucose Ketone Index of 8.2 (confirming ketosis) but in 2022 his GKI level started to rise. His CEA, however, significantly decreased to 20 in March 2022 and PET scan showed stable disease. He presently is on maintenance nivolumab + KD while maintaining an excellent quality of life by EORTC QLQ scores.

Conclusions

The use of KD concurrently with chemotherapy and immunotherapy is still under investigation. Our case report shows that KD is tolerable with treatment and can possibly contribute to controlling progression of metastatic cancer. We are starting an investigator initiative KD trial that received a grant from R&D at VACCHCS. We will present the study protocol in poster presentation.

Background

Ketogenic diet (KD) is a high-fat and low carbohydrate diet that has been reported as a treatment option for patients with cancer. KD creates a metabolic state in which blood glucose levels are reduced and ketone bodies are elevated. Cancer cells are unable to use ketone bodies for energy and metabolism due to mitochondrial dysfunction. We published the efficacy of KD in patients with cancer after failure of chemotherapy. 1 This case report is presented to evaluate the feasibility of KD concurrent with chemoimmunotherapy.

Case Report

Patient is a 69-year-old male who presented with iron deficiency anemia in 2018. Colonoscopy and biopsy showed colon adenocarcinoma. He underwent resection which confirmed stage IIIC disease. He received adjuvant treatment with FOLFOX but quickly developed pancreatic and omental metastasis. He was started on FOLFIRI + bevacizumab followed by pancreatic mass resection in 2019. Molecular testing revealed wild type KRAS, positive BRAF V600E, and high MSI. He received encorafenib + cetuximab until disease progression. Treatment was changed to pembrolizumab until PET scan showed progression. His CEA increased to 1031 in January 2021. He was subsequently started on KD concurrent with trifluridine + tipiracil + bevacizumab. He progressed after 10 months. Therapy was changed to ipilimumab + nivolumab with continuation of KD. He was strictly adherent to KD with low Glucose Ketone Index of 8.2 (confirming ketosis) but in 2022 his GKI level started to rise. His CEA, however, significantly decreased to 20 in March 2022 and PET scan showed stable disease. He presently is on maintenance nivolumab + KD while maintaining an excellent quality of life by EORTC QLQ scores.

Conclusions

The use of KD concurrently with chemotherapy and immunotherapy is still under investigation. Our case report shows that KD is tolerable with treatment and can possibly contribute to controlling progression of metastatic cancer. We are starting an investigator initiative KD trial that received a grant from R&D at VACCHCS. We will present the study protocol in poster presentation.

Background

Ketogenic diet (KD) is a high-fat and low carbohydrate diet that has been reported as a treatment option for patients with cancer. KD creates a metabolic state in which blood glucose levels are reduced and ketone bodies are elevated. Cancer cells are unable to use ketone bodies for energy and metabolism due to mitochondrial dysfunction. We published the efficacy of KD in patients with cancer after failure of chemotherapy. 1 This case report is presented to evaluate the feasibility of KD concurrent with chemoimmunotherapy.

Case Report

Patient is a 69-year-old male who presented with iron deficiency anemia in 2018. Colonoscopy and biopsy showed colon adenocarcinoma. He underwent resection which confirmed stage IIIC disease. He received adjuvant treatment with FOLFOX but quickly developed pancreatic and omental metastasis. He was started on FOLFIRI + bevacizumab followed by pancreatic mass resection in 2019. Molecular testing revealed wild type KRAS, positive BRAF V600E, and high MSI. He received encorafenib + cetuximab until disease progression. Treatment was changed to pembrolizumab until PET scan showed progression. His CEA increased to 1031 in January 2021. He was subsequently started on KD concurrent with trifluridine + tipiracil + bevacizumab. He progressed after 10 months. Therapy was changed to ipilimumab + nivolumab with continuation of KD. He was strictly adherent to KD with low Glucose Ketone Index of 8.2 (confirming ketosis) but in 2022 his GKI level started to rise. His CEA, however, significantly decreased to 20 in March 2022 and PET scan showed stable disease. He presently is on maintenance nivolumab + KD while maintaining an excellent quality of life by EORTC QLQ scores.

Conclusions

The use of KD concurrently with chemotherapy and immunotherapy is still under investigation. Our case report shows that KD is tolerable with treatment and can possibly contribute to controlling progression of metastatic cancer. We are starting an investigator initiative KD trial that received a grant from R&D at VACCHCS. We will present the study protocol in poster presentation.

The passage of time felt altered for many people during the COVID-19 pandemic, ranging from difficulty keeping track of the days of the week to feeling that the hours either crawled by or sped up, new research suggests.

Results showed the sense of present focus, blurring weekdays and weekends together, and uncertainly about the future were reported by over 65% of the 5,661 survey respondents. And more than half reported the experience of feeling “time speeding up or slowing down,” report the investigators, led by E. Alison Holman, PhD, professor at the University of California, Irvine.

Significant predictors of these time distortions included being exposed to daily pandemic-related media and having a mental health diagnosis prior to the pandemic; secondary stress such as school closures and lockdown; financial stress; lifetime stress; and lifetime trauma exposure.

“Continuity between past experiences, present life, and future hopes is critical to one’s well-being, and disruption of that synergy presents mental health challenges,” Dr. Holman said in a news release.

“We were able to measure this in a nationally representative sample of Americans as they were experiencing a protracted collective trauma, which has never been done before, and this study is the first to document the prevalence and early predictors of these time distortions,” added Dr. Holman.

The findings were published online in Psychological Trauma: Theory, Research, Practice, and Policy.
 

Unique opportunity

During the pandemic, many people’s time perspective (TP), defined as “our view of time as it spans from our past into the future,” shifted as they “focused on the immediate, present danger of the COVID-19 pandemic and future plans became uncertain,” the investigators wrote.

Studies of convenience samples “suggested that many people experienced time slowing down, stopping, and/or speeding up as they coped with the challenges of the pandemic” – a phenomenon known as temporal disintegration (TD) in psychiatric literature.

Dr. Holman said in an interview that she researched TD after the Sept.11, 2001 World Trade Center attacks.

“We found that people who experienced that early sense of TD, the sense of ‘time falling apart,’ were more prone to getting stuck in the past and staying focused on the past event,” which led to feeling “more distress over time,” she said.

Research examining the prevalence of and psychosocial factors predicting TD are “quite rare” and studies examining TD “during an unfolding, protracted collective trauma are even rarer,” the researchers note. The COVID pandemic “presented a unique opportunity to conduct such a study,” the researchers wrote.

For their study, the investigators surveyed participants in the NORC AmeriSpeak online panel, a “probability-based panel” of 35,000 U.S. households selected at random from across the country.

The study was conducted in two waves: the first survey was administered March–April 2020, the second in September–October 2020.
 

Speeding up, slowing down

At wave 2, participants completed a 7-item index of TD symptoms experienced over the previous 6 months. To adjust for psychological processes that may have predisposed individuals to experience TD during the pandemic, the researchers included a Wave 1 measure of future uncertainty as a covariate.

Prepandemic health data had been collected prior to the current study.

Wave 1 participants completed a checklist reporting personal, work, and community-wide exposure to the COVID outbreak, including contracting the virus, sheltering in place, and experiencing secondary stressors. The extent and type of pandemic-related media exposure were also assessed.

At wave 2, they reported the extent of exposure to the coronavirus, financial exposures, and secondary stressors. They also completed a non–COVID-related stress/trauma exposure checklist and were asked to indicate whether the trauma, disaster, or bereavement took place prior to or during the pandemic.

The final sample consisted of 5,661 adults (52% female) who completed the wave 2 survey. Participants were divided into four age groups: 18-34, 35-49, 50-64, and 65 and older.

The most common experiences (reported by more than 65% of respondents) included being focused on the present moment, feeling that weekdays and weekends were the same, and feeling uncertain about the future.

Over half of respondents (50.4%) reported feeling as though time was speeding up, and 55.2% reported feeling as though time was slowing down. Some also reported feeling uncertain about the time of day (46.4%) and forgetting events they had just experienced (35.2%).

When the researchers controlled for feeling uncertain about the future, they found that women reported more TD than men (b = 0.11; 95% confidence interval, 0.07-0.14; P < .001).

At wave 1, associations were found between TD and COVID-related media exposure, prepandemic mental health diagnoses, and prepandemic non–COVID-related stress and trauma. At wave 2, associations were found between TD and COVID-related secondary and financial stressors (P < .001 for all).

In contrast, COVID-related work exposure at wave 1, being 45-59 years old, and living in the Midwest region were negatively associated with TD.

“The sense of the flow of the past into the present, and the present into the future is important for our mental health,” Dr. Holman said. “We need to remember who we have been, how that shaped who we are today, and where we want to go with our lives.”

Staying in the present moment is “good, when you’re doing it mindfully. But you still need to feel you can shape and work toward the future and have some sense of control,” she added.

Dr. Homan also recommended time-perspective therapy, which helps patients with PTSD to “build continuity across time – to understand and learn from the past, live in the present, and move toward the future.”
 

Widespread distortion

In an interview, Ruth Ogden, PhD, a lecturer at Liverpool (England) John Moores University, said the findings “confirm those reported in Europe, South America, and the Middle East, that widespread distortion to time was common during the pandemic and that distortions to time were greatest amongst those most negatively affected by the pandemic.”

The results also support her own recent research in the United Kingdom “suggesting that distortions to time during the pandemic extend to our memory for the length of the pandemic, with most people believing that lockdowns lasted far longer than they actually did,” said Dr. Ogden, who was not involved with Dr. Holman and colleagues’ current study.

“This type of subjective lengthening of the pandemic may reinforce trauma by making the traumatic period seem longer, further damaging health and well-being,” she noted. “As the negative fallouts of the pandemic continue, it is important to establish the long-term effects of time distortions during the pandemic on mental health and well-being.”

The study was funded by U.S. National Science Foundation and the National Institute on Minority Health and Health Disparities. The investigators reported no relevant financial relationships. Dr. Ogden receives funding from the Wellcome Trust.

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

The passage of time felt altered for many people during the COVID-19 pandemic, ranging from difficulty keeping track of the days of the week to feeling that the hours either crawled by or sped up, new research suggests.

Results showed the sense of present focus, blurring weekdays and weekends together, and uncertainly about the future were reported by over 65% of the 5,661 survey respondents. And more than half reported the experience of feeling “time speeding up or slowing down,” report the investigators, led by E. Alison Holman, PhD, professor at the University of California, Irvine.

Significant predictors of these time distortions included being exposed to daily pandemic-related media and having a mental health diagnosis prior to the pandemic; secondary stress such as school closures and lockdown; financial stress; lifetime stress; and lifetime trauma exposure.

“Continuity between past experiences, present life, and future hopes is critical to one’s well-being, and disruption of that synergy presents mental health challenges,” Dr. Holman said in a news release.

“We were able to measure this in a nationally representative sample of Americans as they were experiencing a protracted collective trauma, which has never been done before, and this study is the first to document the prevalence and early predictors of these time distortions,” added Dr. Holman.

The findings were published online in Psychological Trauma: Theory, Research, Practice, and Policy.
 

Unique opportunity

During the pandemic, many people’s time perspective (TP), defined as “our view of time as it spans from our past into the future,” shifted as they “focused on the immediate, present danger of the COVID-19 pandemic and future plans became uncertain,” the investigators wrote.

Studies of convenience samples “suggested that many people experienced time slowing down, stopping, and/or speeding up as they coped with the challenges of the pandemic” – a phenomenon known as temporal disintegration (TD) in psychiatric literature.

Dr. Holman said in an interview that she researched TD after the Sept.11, 2001 World Trade Center attacks.

“We found that people who experienced that early sense of TD, the sense of ‘time falling apart,’ were more prone to getting stuck in the past and staying focused on the past event,” which led to feeling “more distress over time,” she said.

Research examining the prevalence of and psychosocial factors predicting TD are “quite rare” and studies examining TD “during an unfolding, protracted collective trauma are even rarer,” the researchers note. The COVID pandemic “presented a unique opportunity to conduct such a study,” the researchers wrote.

For their study, the investigators surveyed participants in the NORC AmeriSpeak online panel, a “probability-based panel” of 35,000 U.S. households selected at random from across the country.

The study was conducted in two waves: the first survey was administered March–April 2020, the second in September–October 2020.
 

Speeding up, slowing down

At wave 2, participants completed a 7-item index of TD symptoms experienced over the previous 6 months. To adjust for psychological processes that may have predisposed individuals to experience TD during the pandemic, the researchers included a Wave 1 measure of future uncertainty as a covariate.

Prepandemic health data had been collected prior to the current study.

Wave 1 participants completed a checklist reporting personal, work, and community-wide exposure to the COVID outbreak, including contracting the virus, sheltering in place, and experiencing secondary stressors. The extent and type of pandemic-related media exposure were also assessed.

At wave 2, they reported the extent of exposure to the coronavirus, financial exposures, and secondary stressors. They also completed a non–COVID-related stress/trauma exposure checklist and were asked to indicate whether the trauma, disaster, or bereavement took place prior to or during the pandemic.

The final sample consisted of 5,661 adults (52% female) who completed the wave 2 survey. Participants were divided into four age groups: 18-34, 35-49, 50-64, and 65 and older.

The most common experiences (reported by more than 65% of respondents) included being focused on the present moment, feeling that weekdays and weekends were the same, and feeling uncertain about the future.

Over half of respondents (50.4%) reported feeling as though time was speeding up, and 55.2% reported feeling as though time was slowing down. Some also reported feeling uncertain about the time of day (46.4%) and forgetting events they had just experienced (35.2%).

When the researchers controlled for feeling uncertain about the future, they found that women reported more TD than men (b = 0.11; 95% confidence interval, 0.07-0.14; P < .001).

At wave 1, associations were found between TD and COVID-related media exposure, prepandemic mental health diagnoses, and prepandemic non–COVID-related stress and trauma. At wave 2, associations were found between TD and COVID-related secondary and financial stressors (P < .001 for all).

In contrast, COVID-related work exposure at wave 1, being 45-59 years old, and living in the Midwest region were negatively associated with TD.

“The sense of the flow of the past into the present, and the present into the future is important for our mental health,” Dr. Holman said. “We need to remember who we have been, how that shaped who we are today, and where we want to go with our lives.”

Staying in the present moment is “good, when you’re doing it mindfully. But you still need to feel you can shape and work toward the future and have some sense of control,” she added.

Dr. Homan also recommended time-perspective therapy, which helps patients with PTSD to “build continuity across time – to understand and learn from the past, live in the present, and move toward the future.”
 

Widespread distortion

In an interview, Ruth Ogden, PhD, a lecturer at Liverpool (England) John Moores University, said the findings “confirm those reported in Europe, South America, and the Middle East, that widespread distortion to time was common during the pandemic and that distortions to time were greatest amongst those most negatively affected by the pandemic.”

The results also support her own recent research in the United Kingdom “suggesting that distortions to time during the pandemic extend to our memory for the length of the pandemic, with most people believing that lockdowns lasted far longer than they actually did,” said Dr. Ogden, who was not involved with Dr. Holman and colleagues’ current study.

“This type of subjective lengthening of the pandemic may reinforce trauma by making the traumatic period seem longer, further damaging health and well-being,” she noted. “As the negative fallouts of the pandemic continue, it is important to establish the long-term effects of time distortions during the pandemic on mental health and well-being.”

The study was funded by U.S. National Science Foundation and the National Institute on Minority Health and Health Disparities. The investigators reported no relevant financial relationships. Dr. Ogden receives funding from the Wellcome Trust.

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

The passage of time felt altered for many people during the COVID-19 pandemic, ranging from difficulty keeping track of the days of the week to feeling that the hours either crawled by or sped up, new research suggests.

Results showed the sense of present focus, blurring weekdays and weekends together, and uncertainly about the future were reported by over 65% of the 5,661 survey respondents. And more than half reported the experience of feeling “time speeding up or slowing down,” report the investigators, led by E. Alison Holman, PhD, professor at the University of California, Irvine.

Significant predictors of these time distortions included being exposed to daily pandemic-related media and having a mental health diagnosis prior to the pandemic; secondary stress such as school closures and lockdown; financial stress; lifetime stress; and lifetime trauma exposure.

“Continuity between past experiences, present life, and future hopes is critical to one’s well-being, and disruption of that synergy presents mental health challenges,” Dr. Holman said in a news release.

“We were able to measure this in a nationally representative sample of Americans as they were experiencing a protracted collective trauma, which has never been done before, and this study is the first to document the prevalence and early predictors of these time distortions,” added Dr. Holman.

The findings were published online in Psychological Trauma: Theory, Research, Practice, and Policy.
 

Unique opportunity

During the pandemic, many people’s time perspective (TP), defined as “our view of time as it spans from our past into the future,” shifted as they “focused on the immediate, present danger of the COVID-19 pandemic and future plans became uncertain,” the investigators wrote.

Studies of convenience samples “suggested that many people experienced time slowing down, stopping, and/or speeding up as they coped with the challenges of the pandemic” – a phenomenon known as temporal disintegration (TD) in psychiatric literature.

Dr. Holman said in an interview that she researched TD after the Sept.11, 2001 World Trade Center attacks.

“We found that people who experienced that early sense of TD, the sense of ‘time falling apart,’ were more prone to getting stuck in the past and staying focused on the past event,” which led to feeling “more distress over time,” she said.

Research examining the prevalence of and psychosocial factors predicting TD are “quite rare” and studies examining TD “during an unfolding, protracted collective trauma are even rarer,” the researchers note. The COVID pandemic “presented a unique opportunity to conduct such a study,” the researchers wrote.

For their study, the investigators surveyed participants in the NORC AmeriSpeak online panel, a “probability-based panel” of 35,000 U.S. households selected at random from across the country.

The study was conducted in two waves: the first survey was administered March–April 2020, the second in September–October 2020.
 

Speeding up, slowing down

At wave 2, participants completed a 7-item index of TD symptoms experienced over the previous 6 months. To adjust for psychological processes that may have predisposed individuals to experience TD during the pandemic, the researchers included a Wave 1 measure of future uncertainty as a covariate.

Prepandemic health data had been collected prior to the current study.

Wave 1 participants completed a checklist reporting personal, work, and community-wide exposure to the COVID outbreak, including contracting the virus, sheltering in place, and experiencing secondary stressors. The extent and type of pandemic-related media exposure were also assessed.

At wave 2, they reported the extent of exposure to the coronavirus, financial exposures, and secondary stressors. They also completed a non–COVID-related stress/trauma exposure checklist and were asked to indicate whether the trauma, disaster, or bereavement took place prior to or during the pandemic.

The final sample consisted of 5,661 adults (52% female) who completed the wave 2 survey. Participants were divided into four age groups: 18-34, 35-49, 50-64, and 65 and older.

The most common experiences (reported by more than 65% of respondents) included being focused on the present moment, feeling that weekdays and weekends were the same, and feeling uncertain about the future.

Over half of respondents (50.4%) reported feeling as though time was speeding up, and 55.2% reported feeling as though time was slowing down. Some also reported feeling uncertain about the time of day (46.4%) and forgetting events they had just experienced (35.2%).

When the researchers controlled for feeling uncertain about the future, they found that women reported more TD than men (b = 0.11; 95% confidence interval, 0.07-0.14; P < .001).

At wave 1, associations were found between TD and COVID-related media exposure, prepandemic mental health diagnoses, and prepandemic non–COVID-related stress and trauma. At wave 2, associations were found between TD and COVID-related secondary and financial stressors (P < .001 for all).

In contrast, COVID-related work exposure at wave 1, being 45-59 years old, and living in the Midwest region were negatively associated with TD.

“The sense of the flow of the past into the present, and the present into the future is important for our mental health,” Dr. Holman said. “We need to remember who we have been, how that shaped who we are today, and where we want to go with our lives.”

Staying in the present moment is “good, when you’re doing it mindfully. But you still need to feel you can shape and work toward the future and have some sense of control,” she added.

Dr. Homan also recommended time-perspective therapy, which helps patients with PTSD to “build continuity across time – to understand and learn from the past, live in the present, and move toward the future.”
 

Widespread distortion

In an interview, Ruth Ogden, PhD, a lecturer at Liverpool (England) John Moores University, said the findings “confirm those reported in Europe, South America, and the Middle East, that widespread distortion to time was common during the pandemic and that distortions to time were greatest amongst those most negatively affected by the pandemic.”

The results also support her own recent research in the United Kingdom “suggesting that distortions to time during the pandemic extend to our memory for the length of the pandemic, with most people believing that lockdowns lasted far longer than they actually did,” said Dr. Ogden, who was not involved with Dr. Holman and colleagues’ current study.

“This type of subjective lengthening of the pandemic may reinforce trauma by making the traumatic period seem longer, further damaging health and well-being,” she noted. “As the negative fallouts of the pandemic continue, it is important to establish the long-term effects of time distortions during the pandemic on mental health and well-being.”

The study was funded by U.S. National Science Foundation and the National Institute on Minority Health and Health Disparities. The investigators reported no relevant financial relationships. Dr. Ogden receives funding from the Wellcome Trust.

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

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

Patients who received a first prescription for medicinal cannabis for chronic pain were more likely to have new onset of arrhythmia – bradyarrhythmia, tachyarrhythmia, or a conduction disorder – within 6 months than were similar nonusers, in a new case-control study.

VladK213/Getty Images

There were no between-group differences in the incidence of heart failure or acute coronary syndrome.

The researchers identified 5,071 patients in a national Danish registry who had filled at least one prescription for medicinal cannabis for chronic pain and matched each patient with five patients of the same sex, age range, and type of chronic pain who did not receive this therapy.

The relative risk for arrhythmia was 83% higher in those who used medicinal cannabis than it was in the other patients, study author Nina Nouhravesh, MD, told this news organization in an email.

However, the absolute risks for arrhythmia were slight – a 0.86% risk (95% confidence interval, 0.61%-1.1%) in medicinal cannabis users versus a 0.47% risk (95% CI, 0.38%-0.56%) in those who did not use medicinal cannabis.

“Since medical cannabis is a relatively new drug for a large market of patients with chronic pain, it is important to investigate and report serious side effects,” said Dr. Nouhravesh, from Gentofte University Hospital, Denmark.

The study results, she said, suggest that “there may be a previously unreported risk of arrhythmias following medical cannabis use.”

“Even though the absolute risk difference is small, both patients and physicians should have as much information as possible when weighing up the pros and cons of any treatment,” Dr. Nouhravesh said, adding that “the findings of this study raise concerns for both legal and illegal [cannabis] use worldwide.”

The results will be presented at the annual European Society of Cardiology (ESC) Congress 2022.
 

Too soon to tell?

However, Brian Olshansky, MD, who was not involved with this research, cautions that it is important to consider several study limitations before drawing clinical implications.

“Other data and reports have considered the possibility of arrhythmias in relationship to marijuana use, and the data go in both directions,” Dr. Olshansky, a clinical cardiac electrophysiologist and professor emeritus at University of Iowa Hospitals, Iowa City, pointed out in an email.

“Importantly, arrhythmias, by themselves, are not necessarily consequential,” he stressed. “In any case,” he added, the risks in the current study are “extraordinarily small.”

Sinus bradycardia, sinus tachycardia, and premature atrial or ventricular contractions could be totally benign, he said. On the other hand, arrhythmias may indicate the presence of atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, which are potentially dangerous.

There may be a specific “high risk” group who can develop potentially serious arrhythmias, Dr. Olshansky suggested.

“There is no evidence that any of these patients underwent or required any treatment for their arrhythmia or that stopping or starting the cannabinoids affected the arrhythmia one way or the other,” he said. “In addition, there is no dose/arrhythmia relationship.”

More patients in the medicinal cannabis group than in the nonuser group were also taking opioids (49% vs. 30%), nonsteroidal anti-inflammatory drugs (24% vs. 19%), antiepileptics (35% vs. 23%), or tricyclic antidepressants (11% vs. 4%), he noted.

In summary, according to Dr. Olshansky, “these data pose no obvious health concern and provide no vital knowledge for physicians prescribing cannabis.”

“My concern is that the information will be overblown,” he cautioned. “If the cannabinoid actually has benefit in terms of pain reduction, its use may be mitigated based on the fear of an arrhythmia that may occur – but the risk of an arrhythmia, in any event, is very small and undefined in terms of its seriousness.”
 

Cancer, musculoskeletal, and neurologic pain

For this analysis, the researchers identified 1.8 million patients in Denmark who were diagnosed with chronic pain between 2018 and 2021.

Of those, around 5,000 patients had claimed at least one prescription of medicinal cannabis (dronabinol 29%, cannabinoids 46%, or cannabidiol 25%).

The patients had a median age of 60 years, and 63% were women.

The cannabis users had been prescribed this therapy for musculoskeletal (35%), cancer (18%), neurological (14%), or other (33%) pain, Dr. Nouhravesh said. 

The researchers and Dr. Olshansky have no relevant financial disclosures.  

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

Patients who received a first prescription for medicinal cannabis for chronic pain were more likely to have new onset of arrhythmia – bradyarrhythmia, tachyarrhythmia, or a conduction disorder – within 6 months than were similar nonusers, in a new case-control study.

VladK213/Getty Images

There were no between-group differences in the incidence of heart failure or acute coronary syndrome.

The researchers identified 5,071 patients in a national Danish registry who had filled at least one prescription for medicinal cannabis for chronic pain and matched each patient with five patients of the same sex, age range, and type of chronic pain who did not receive this therapy.

The relative risk for arrhythmia was 83% higher in those who used medicinal cannabis than it was in the other patients, study author Nina Nouhravesh, MD, told this news organization in an email.

However, the absolute risks for arrhythmia were slight – a 0.86% risk (95% confidence interval, 0.61%-1.1%) in medicinal cannabis users versus a 0.47% risk (95% CI, 0.38%-0.56%) in those who did not use medicinal cannabis.

“Since medical cannabis is a relatively new drug for a large market of patients with chronic pain, it is important to investigate and report serious side effects,” said Dr. Nouhravesh, from Gentofte University Hospital, Denmark.

The study results, she said, suggest that “there may be a previously unreported risk of arrhythmias following medical cannabis use.”

“Even though the absolute risk difference is small, both patients and physicians should have as much information as possible when weighing up the pros and cons of any treatment,” Dr. Nouhravesh said, adding that “the findings of this study raise concerns for both legal and illegal [cannabis] use worldwide.”

The results will be presented at the annual European Society of Cardiology (ESC) Congress 2022.
 

Too soon to tell?

However, Brian Olshansky, MD, who was not involved with this research, cautions that it is important to consider several study limitations before drawing clinical implications.

“Other data and reports have considered the possibility of arrhythmias in relationship to marijuana use, and the data go in both directions,” Dr. Olshansky, a clinical cardiac electrophysiologist and professor emeritus at University of Iowa Hospitals, Iowa City, pointed out in an email.

“Importantly, arrhythmias, by themselves, are not necessarily consequential,” he stressed. “In any case,” he added, the risks in the current study are “extraordinarily small.”

Sinus bradycardia, sinus tachycardia, and premature atrial or ventricular contractions could be totally benign, he said. On the other hand, arrhythmias may indicate the presence of atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, which are potentially dangerous.

There may be a specific “high risk” group who can develop potentially serious arrhythmias, Dr. Olshansky suggested.

“There is no evidence that any of these patients underwent or required any treatment for their arrhythmia or that stopping or starting the cannabinoids affected the arrhythmia one way or the other,” he said. “In addition, there is no dose/arrhythmia relationship.”

More patients in the medicinal cannabis group than in the nonuser group were also taking opioids (49% vs. 30%), nonsteroidal anti-inflammatory drugs (24% vs. 19%), antiepileptics (35% vs. 23%), or tricyclic antidepressants (11% vs. 4%), he noted.

In summary, according to Dr. Olshansky, “these data pose no obvious health concern and provide no vital knowledge for physicians prescribing cannabis.”

“My concern is that the information will be overblown,” he cautioned. “If the cannabinoid actually has benefit in terms of pain reduction, its use may be mitigated based on the fear of an arrhythmia that may occur – but the risk of an arrhythmia, in any event, is very small and undefined in terms of its seriousness.”
 

Cancer, musculoskeletal, and neurologic pain

For this analysis, the researchers identified 1.8 million patients in Denmark who were diagnosed with chronic pain between 2018 and 2021.

Of those, around 5,000 patients had claimed at least one prescription of medicinal cannabis (dronabinol 29%, cannabinoids 46%, or cannabidiol 25%).

The patients had a median age of 60 years, and 63% were women.

The cannabis users had been prescribed this therapy for musculoskeletal (35%), cancer (18%), neurological (14%), or other (33%) pain, Dr. Nouhravesh said. 

The researchers and Dr. Olshansky have no relevant financial disclosures.  

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

Patients who received a first prescription for medicinal cannabis for chronic pain were more likely to have new onset of arrhythmia – bradyarrhythmia, tachyarrhythmia, or a conduction disorder – within 6 months than were similar nonusers, in a new case-control study.

VladK213/Getty Images

There were no between-group differences in the incidence of heart failure or acute coronary syndrome.

The researchers identified 5,071 patients in a national Danish registry who had filled at least one prescription for medicinal cannabis for chronic pain and matched each patient with five patients of the same sex, age range, and type of chronic pain who did not receive this therapy.

The relative risk for arrhythmia was 83% higher in those who used medicinal cannabis than it was in the other patients, study author Nina Nouhravesh, MD, told this news organization in an email.

However, the absolute risks for arrhythmia were slight – a 0.86% risk (95% confidence interval, 0.61%-1.1%) in medicinal cannabis users versus a 0.47% risk (95% CI, 0.38%-0.56%) in those who did not use medicinal cannabis.

“Since medical cannabis is a relatively new drug for a large market of patients with chronic pain, it is important to investigate and report serious side effects,” said Dr. Nouhravesh, from Gentofte University Hospital, Denmark.

The study results, she said, suggest that “there may be a previously unreported risk of arrhythmias following medical cannabis use.”

“Even though the absolute risk difference is small, both patients and physicians should have as much information as possible when weighing up the pros and cons of any treatment,” Dr. Nouhravesh said, adding that “the findings of this study raise concerns for both legal and illegal [cannabis] use worldwide.”

The results will be presented at the annual European Society of Cardiology (ESC) Congress 2022.
 

Too soon to tell?

However, Brian Olshansky, MD, who was not involved with this research, cautions that it is important to consider several study limitations before drawing clinical implications.

“Other data and reports have considered the possibility of arrhythmias in relationship to marijuana use, and the data go in both directions,” Dr. Olshansky, a clinical cardiac electrophysiologist and professor emeritus at University of Iowa Hospitals, Iowa City, pointed out in an email.

“Importantly, arrhythmias, by themselves, are not necessarily consequential,” he stressed. “In any case,” he added, the risks in the current study are “extraordinarily small.”

Sinus bradycardia, sinus tachycardia, and premature atrial or ventricular contractions could be totally benign, he said. On the other hand, arrhythmias may indicate the presence of atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, which are potentially dangerous.

There may be a specific “high risk” group who can develop potentially serious arrhythmias, Dr. Olshansky suggested.

“There is no evidence that any of these patients underwent or required any treatment for their arrhythmia or that stopping or starting the cannabinoids affected the arrhythmia one way or the other,” he said. “In addition, there is no dose/arrhythmia relationship.”

More patients in the medicinal cannabis group than in the nonuser group were also taking opioids (49% vs. 30%), nonsteroidal anti-inflammatory drugs (24% vs. 19%), antiepileptics (35% vs. 23%), or tricyclic antidepressants (11% vs. 4%), he noted.

In summary, according to Dr. Olshansky, “these data pose no obvious health concern and provide no vital knowledge for physicians prescribing cannabis.”

“My concern is that the information will be overblown,” he cautioned. “If the cannabinoid actually has benefit in terms of pain reduction, its use may be mitigated based on the fear of an arrhythmia that may occur – but the risk of an arrhythmia, in any event, is very small and undefined in terms of its seriousness.”
 

Cancer, musculoskeletal, and neurologic pain

For this analysis, the researchers identified 1.8 million patients in Denmark who were diagnosed with chronic pain between 2018 and 2021.

Of those, around 5,000 patients had claimed at least one prescription of medicinal cannabis (dronabinol 29%, cannabinoids 46%, or cannabidiol 25%).

The patients had a median age of 60 years, and 63% were women.

The cannabis users had been prescribed this therapy for musculoskeletal (35%), cancer (18%), neurological (14%), or other (33%) pain, Dr. Nouhravesh said. 

The researchers and Dr. Olshansky have no relevant financial disclosures.  

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

Cryolipolysis accounted for a majority of noninvasive cosmetic procedures associated with adverse events, according to an analysis of data from the Manufacturer and User Facility Device Experience (MAUDE).

The number of noninvasive body-contouring procedures performed in the United States increased by fivefold from 2011 to 2019, attributed in part to a combination of improved technology and new medical devices, as well as a “cosmetically savvy consumer base heavily influenced by social media,” wrote Young Lim, MD, PhD, of the department of dermatology, Massachusetts General Hospital, Boston, and coauthors.

However, premarket evaluations of many new medical devices fail to capture rare or delayed onset complications, and consumers and providers may not be fully aware of potential adverse events, they said. The MAUDE database was created by the Food and Drug Administration in 1991 to collect information on device-related deaths, serious injuries, or malfunctions based on reports from manufacturers, patients, and health care providers.

The researchers used the MAUDE database to identify and highlight adverse events associated with noninvasive body contouring technology in order to improve patient safety and satisfaction.

In their report, published in Lasers in Surgery and Medicine, they analyzed 723 medical device reports (MDRs) reported between 2015 and 2021: 660 for noninvasive body contouring, 55 for cellulite treatments, and 8 for muscle stimulation.

“Notably, of the 723 total MDRs between 2015 and 2021, 515 (71.2%) were reported in 2021, with the next highest reported being 64 in 2019 (8.8%),” the researchers wrote.

Overall, paradoxical hyperplasia (PAH) accounted for the majority of adverse reactions in the noninvasive body-contouring category (73.2%). In PAH, patients develop additional adipose tissue in areas treated with cryolipolysis. In this study, all reports of PAH as well as all 47 reported cases of abdominal hernias were attributed to the CoolSculpting device.

For cellulite treatments, the most common MDRs – 11 of 55 – were scars and keloids (20%). The Cellfina subcision technique accounted for 47% (26 of 55) of the MDRs in this category, including 9 of the scar and keloid cases.

Only eight of the MDRs analyzed were in the muscle stimulation category; of these, burns were the most common adverse event and accounted for three of the reports. The other reported AEs were two cases of pain and one report each of electrical shock, urticaria, and arrhythmia.

Patients are increasingly opting for noninvasive cosmetic procedures, but adverse events may be underreported despite the existence of databases such as MAUDE, the researchers wrote in their discussion.

“PAH, first reported in 2014 as an adverse sequelae of cryolipolysis, remains without known pathophysiology, though it proportionately affects men more than women,” they noted. The incidence of PAH varies widely, and the current treatment of choice is power-assisted liposuction, they said, although surgical abdominoplasty may be needed in severe cases.

The findings were limited by several factors including the reliance of the quality of submissions, the selection biases of the MAUDE database, and the potential for underreporting, the researchers noted.

However, “by cataloging the AEs of the growing noninvasive cosmetics market, the MAUDE can educate providers and inform patients to maximize safety and efficacy,” they said.

The size of the database and volume of reports provides a picture that likely reflects overall trends occurring in clinical practice, but in order to be effective, such databases require diligence on the part of manufacturers and clinicians to provide accurate, up-to-date information, the researchers concluded.

More procedures mean more complications

“As the market for minimally and noninvasive cosmetic procedures continues to expand, clinicians will likely encounter a greater number of patients with complications from these procedures,” said Jacqueline Watchmaker, MD, a general and cosmetic dermatologist in Scottsdale, Ariz., in an interview.

“Now more than ever, it is important for providers to understand potential side effects of procedures so that they can adequately counsel patients and optimize patient safety,” and therefore the current study is important at this time, she commented.

Dr. Watchmaker, who was not involved in the study, said that, overall, she was not surprised by the findings. “The adverse events analyzed from the Manufacturer and User Facility Device Experience parallel what is seen in clinical practice,” she said. “I did find it slightly surprising that an overwhelming majority of the medical device reports (515 of 723) were from 2021.” As the authors discuss, the reasons for this increase may include such factors as more flexible pandemic work schedules, pandemic weight gain, and the rise in MedSpas in recent years, she added.

“Some patients mistakenly think that ‘noninvasive’ or ‘minimally invasive’ procedures are risk free,” said Dr. Watchmaker. “However, as this review clearly demonstrates, complications can and do occur with these procedures. It is our job as clinicians to educate our patients on potential adverse events prior to treatment,” she emphasized. Also, she added, it is important for clinicians to report all adverse events to the MAUDE database so the true risks of noninvasive procedures can be more accurately assessed.

As for additional research, “It would be interesting to repeat the same study but to look at other minimally and noninvasive cosmetic devices such as radiofrequency and ultrasound devices,” Dr. Watchmaker noted.

The study received no outside funding. Dr. Lim and his coauthors, Adam Wulkan, MD, of the Lahey Clinic, Burlington, Mass., and Mathew Avram, MD, JD, of Massachusetts General Hospital, had no financial conflicts to disclose. Dr. Watchmaker had no financial conflicts to disclose.
 

Medical device–related adverse events can be reported to the FDA’s MAUDE database here .

Cryolipolysis accounted for a majority of noninvasive cosmetic procedures associated with adverse events, according to an analysis of data from the Manufacturer and User Facility Device Experience (MAUDE).

The number of noninvasive body-contouring procedures performed in the United States increased by fivefold from 2011 to 2019, attributed in part to a combination of improved technology and new medical devices, as well as a “cosmetically savvy consumer base heavily influenced by social media,” wrote Young Lim, MD, PhD, of the department of dermatology, Massachusetts General Hospital, Boston, and coauthors.

However, premarket evaluations of many new medical devices fail to capture rare or delayed onset complications, and consumers and providers may not be fully aware of potential adverse events, they said. The MAUDE database was created by the Food and Drug Administration in 1991 to collect information on device-related deaths, serious injuries, or malfunctions based on reports from manufacturers, patients, and health care providers.

The researchers used the MAUDE database to identify and highlight adverse events associated with noninvasive body contouring technology in order to improve patient safety and satisfaction.

In their report, published in Lasers in Surgery and Medicine, they analyzed 723 medical device reports (MDRs) reported between 2015 and 2021: 660 for noninvasive body contouring, 55 for cellulite treatments, and 8 for muscle stimulation.

“Notably, of the 723 total MDRs between 2015 and 2021, 515 (71.2%) were reported in 2021, with the next highest reported being 64 in 2019 (8.8%),” the researchers wrote.

Overall, paradoxical hyperplasia (PAH) accounted for the majority of adverse reactions in the noninvasive body-contouring category (73.2%). In PAH, patients develop additional adipose tissue in areas treated with cryolipolysis. In this study, all reports of PAH as well as all 47 reported cases of abdominal hernias were attributed to the CoolSculpting device.

For cellulite treatments, the most common MDRs – 11 of 55 – were scars and keloids (20%). The Cellfina subcision technique accounted for 47% (26 of 55) of the MDRs in this category, including 9 of the scar and keloid cases.

Only eight of the MDRs analyzed were in the muscle stimulation category; of these, burns were the most common adverse event and accounted for three of the reports. The other reported AEs were two cases of pain and one report each of electrical shock, urticaria, and arrhythmia.

Patients are increasingly opting for noninvasive cosmetic procedures, but adverse events may be underreported despite the existence of databases such as MAUDE, the researchers wrote in their discussion.

“PAH, first reported in 2014 as an adverse sequelae of cryolipolysis, remains without known pathophysiology, though it proportionately affects men more than women,” they noted. The incidence of PAH varies widely, and the current treatment of choice is power-assisted liposuction, they said, although surgical abdominoplasty may be needed in severe cases.

The findings were limited by several factors including the reliance of the quality of submissions, the selection biases of the MAUDE database, and the potential for underreporting, the researchers noted.

However, “by cataloging the AEs of the growing noninvasive cosmetics market, the MAUDE can educate providers and inform patients to maximize safety and efficacy,” they said.

The size of the database and volume of reports provides a picture that likely reflects overall trends occurring in clinical practice, but in order to be effective, such databases require diligence on the part of manufacturers and clinicians to provide accurate, up-to-date information, the researchers concluded.

More procedures mean more complications

“As the market for minimally and noninvasive cosmetic procedures continues to expand, clinicians will likely encounter a greater number of patients with complications from these procedures,” said Jacqueline Watchmaker, MD, a general and cosmetic dermatologist in Scottsdale, Ariz., in an interview.

“Now more than ever, it is important for providers to understand potential side effects of procedures so that they can adequately counsel patients and optimize patient safety,” and therefore the current study is important at this time, she commented.

Dr. Watchmaker, who was not involved in the study, said that, overall, she was not surprised by the findings. “The adverse events analyzed from the Manufacturer and User Facility Device Experience parallel what is seen in clinical practice,” she said. “I did find it slightly surprising that an overwhelming majority of the medical device reports (515 of 723) were from 2021.” As the authors discuss, the reasons for this increase may include such factors as more flexible pandemic work schedules, pandemic weight gain, and the rise in MedSpas in recent years, she added.

“Some patients mistakenly think that ‘noninvasive’ or ‘minimally invasive’ procedures are risk free,” said Dr. Watchmaker. “However, as this review clearly demonstrates, complications can and do occur with these procedures. It is our job as clinicians to educate our patients on potential adverse events prior to treatment,” she emphasized. Also, she added, it is important for clinicians to report all adverse events to the MAUDE database so the true risks of noninvasive procedures can be more accurately assessed.

As for additional research, “It would be interesting to repeat the same study but to look at other minimally and noninvasive cosmetic devices such as radiofrequency and ultrasound devices,” Dr. Watchmaker noted.

The study received no outside funding. Dr. Lim and his coauthors, Adam Wulkan, MD, of the Lahey Clinic, Burlington, Mass., and Mathew Avram, MD, JD, of Massachusetts General Hospital, had no financial conflicts to disclose. Dr. Watchmaker had no financial conflicts to disclose.
 

Medical device–related adverse events can be reported to the FDA’s MAUDE database here .

Cryolipolysis accounted for a majority of noninvasive cosmetic procedures associated with adverse events, according to an analysis of data from the Manufacturer and User Facility Device Experience (MAUDE).

The number of noninvasive body-contouring procedures performed in the United States increased by fivefold from 2011 to 2019, attributed in part to a combination of improved technology and new medical devices, as well as a “cosmetically savvy consumer base heavily influenced by social media,” wrote Young Lim, MD, PhD, of the department of dermatology, Massachusetts General Hospital, Boston, and coauthors.

However, premarket evaluations of many new medical devices fail to capture rare or delayed onset complications, and consumers and providers may not be fully aware of potential adverse events, they said. The MAUDE database was created by the Food and Drug Administration in 1991 to collect information on device-related deaths, serious injuries, or malfunctions based on reports from manufacturers, patients, and health care providers.

The researchers used the MAUDE database to identify and highlight adverse events associated with noninvasive body contouring technology in order to improve patient safety and satisfaction.

In their report, published in Lasers in Surgery and Medicine, they analyzed 723 medical device reports (MDRs) reported between 2015 and 2021: 660 for noninvasive body contouring, 55 for cellulite treatments, and 8 for muscle stimulation.

“Notably, of the 723 total MDRs between 2015 and 2021, 515 (71.2%) were reported in 2021, with the next highest reported being 64 in 2019 (8.8%),” the researchers wrote.

Overall, paradoxical hyperplasia (PAH) accounted for the majority of adverse reactions in the noninvasive body-contouring category (73.2%). In PAH, patients develop additional adipose tissue in areas treated with cryolipolysis. In this study, all reports of PAH as well as all 47 reported cases of abdominal hernias were attributed to the CoolSculpting device.

For cellulite treatments, the most common MDRs – 11 of 55 – were scars and keloids (20%). The Cellfina subcision technique accounted for 47% (26 of 55) of the MDRs in this category, including 9 of the scar and keloid cases.

Only eight of the MDRs analyzed were in the muscle stimulation category; of these, burns were the most common adverse event and accounted for three of the reports. The other reported AEs were two cases of pain and one report each of electrical shock, urticaria, and arrhythmia.

Patients are increasingly opting for noninvasive cosmetic procedures, but adverse events may be underreported despite the existence of databases such as MAUDE, the researchers wrote in their discussion.

“PAH, first reported in 2014 as an adverse sequelae of cryolipolysis, remains without known pathophysiology, though it proportionately affects men more than women,” they noted. The incidence of PAH varies widely, and the current treatment of choice is power-assisted liposuction, they said, although surgical abdominoplasty may be needed in severe cases.

The findings were limited by several factors including the reliance of the quality of submissions, the selection biases of the MAUDE database, and the potential for underreporting, the researchers noted.

However, “by cataloging the AEs of the growing noninvasive cosmetics market, the MAUDE can educate providers and inform patients to maximize safety and efficacy,” they said.

The size of the database and volume of reports provides a picture that likely reflects overall trends occurring in clinical practice, but in order to be effective, such databases require diligence on the part of manufacturers and clinicians to provide accurate, up-to-date information, the researchers concluded.

More procedures mean more complications

“As the market for minimally and noninvasive cosmetic procedures continues to expand, clinicians will likely encounter a greater number of patients with complications from these procedures,” said Jacqueline Watchmaker, MD, a general and cosmetic dermatologist in Scottsdale, Ariz., in an interview.

“Now more than ever, it is important for providers to understand potential side effects of procedures so that they can adequately counsel patients and optimize patient safety,” and therefore the current study is important at this time, she commented.

Dr. Watchmaker, who was not involved in the study, said that, overall, she was not surprised by the findings. “The adverse events analyzed from the Manufacturer and User Facility Device Experience parallel what is seen in clinical practice,” she said. “I did find it slightly surprising that an overwhelming majority of the medical device reports (515 of 723) were from 2021.” As the authors discuss, the reasons for this increase may include such factors as more flexible pandemic work schedules, pandemic weight gain, and the rise in MedSpas in recent years, she added.

“Some patients mistakenly think that ‘noninvasive’ or ‘minimally invasive’ procedures are risk free,” said Dr. Watchmaker. “However, as this review clearly demonstrates, complications can and do occur with these procedures. It is our job as clinicians to educate our patients on potential adverse events prior to treatment,” she emphasized. Also, she added, it is important for clinicians to report all adverse events to the MAUDE database so the true risks of noninvasive procedures can be more accurately assessed.

As for additional research, “It would be interesting to repeat the same study but to look at other minimally and noninvasive cosmetic devices such as radiofrequency and ultrasound devices,” Dr. Watchmaker noted.

The study received no outside funding. Dr. Lim and his coauthors, Adam Wulkan, MD, of the Lahey Clinic, Burlington, Mass., and Mathew Avram, MD, JD, of Massachusetts General Hospital, had no financial conflicts to disclose. Dr. Watchmaker had no financial conflicts to disclose.
 

Medical device–related adverse events can be reported to the FDA’s MAUDE database here .

In June, Rebecca A. Shatsky, MD, a medical oncologist, turned to Twitter for advice: “What do you do/say when a patient won’t believe you that they have #CANCER. As an oncologist this comes up every now and then and proves very difficult, looking to hear how others have dealt and what works best to help patients here.”

About a dozen people weighed in, offering various thoughts on how to approach these thorny situations. One oncologist suggested revisiting the conversation a few days later, after the patient has more time to process; others suggested sharing the pathology report or images with their patient.

Another person simply noted that “if a [patient] doesn’t want to believe they have cancer, no amount of evidence will change that.”

Based on the initial responses, “it appears there is a paucity of answers sadly,” wrote Dr. Shatsky, a breast cancer specialist at University of California, San Diego.

But for Dr. Shatsky, these incidents spoke to another alarming trend: a rampant mistrust of the medical community that is “becoming MORE common instead of less.”
 

‘Erosion of trust’

Overall, experts say that situations like the one Dr. Shatsky described – patients who don’t believe their cancer diagnosis – occur infrequently.

But denial comes in many forms, and complete disbelief is probably the most extreme. Patients may also downplay the severity of their disease, shy away from hearing bad news, or refuse standard treatment or their doctor’s advice.

Like Dr. Shatsky, these experts say they are also seeing a troubling increase in patients who don’t believe their physicians or don’t trust their recommendations.

“I think there’s an erosion of trust in expertise, in general,” said Ronald M. Epstein, MD, professor of family medicine and psychiatry & oncology at the University of Rochester (N.Y.). “People distrust science more than they did maybe 20 or 30 years ago, or at least that seems to be the case.”

Denial and distrust in cancer care are not new. These responses – along with wishful thinking, distraction, and minimization – are long-established responses among oncology patients. In 1972, Avery D. Weisman, MD, a psychiatrist at Harvard Medical School, Boston, wrote his book “On Dying and Denying,” and ever since, denial and similar responses have been explored in the oncology literature.

Much of this research has focused on the latter stages of illness, but denial can be present at diagnosis as well. One study of patients with breast cancer, carried out nearly 30 years ago, suggested that denial of diagnosis generally occurs early in a patient’s course of illness and decreases over time, but may arise again in the terminal phase of cancer. Another analysis, evaluating this phenomenon across 13 studies, found that the prevalence of denial at diagnosis ranged from 4% to as high as 47%. 

An oncologist delivers somewhere between 10,000 to 30,000 episodes of bad news over the course of a career, so there’s always a chance that a patient will respond in a way that’s on the “spectrum of disbelief,” said Paul Helft, MD, professor of medicine and recently retired director of the ethics center at Indiana University, Indianapolis.

Diane Meier, MD, said denial and disbelief are natural, protective responses to difficult or frightening news.

When patients exhibit denial, Dr. Meier advises patience and time. Physicians can also ask the patient if there’s a person they trust – a family member or faith leader, for example – who could speak on their behalf about possible next steps.

“The main thing is not to find ourselves in opposition to the patient ... or threaten them with what will happen if they don’t listen to us,” said Dr. Meier, a professor of geriatrics and palliative medicine at the Icahn School of Medicine at Mount Sinai, New York.

And physicians should be careful when they feel themselves wanting to argue with or lecture a patient.

“The minute we feel that urge coming on, that’s a signal to us to stop and realize that something is going on inside the patient that we don’t understand,” she said. “Forcing information on a person who is signaling in every way that they don’t want it and can’t handle it is not a recipe for trust or a high-quality relationship.”
 

Refusing expert advice

Jennifer Lycette, MD, has encountered a growing number of patients who don’t believe their disease should be treated the way she or other oncologists recommend. Some patients remain adamant about sticking with alternative medicine or doing nothing, despite growing sicker.

“I’ve even had situations where the tumor might be visible, like growing through the skin, and people still double down that whatever they’re doing is working,” said Dr. Lycette, a hematologist and medical oncologist at the Providence Seaside Cancer Center in Seaside, Ore.

She encourages these patients to get a second opinion and tries to keep an open mind about alternative approaches. If she’s not familiar with something a patient is considering, she’ll research it with them.

But she makes sure to point out any risks associated with these approaches. While some alternative therapies can support patients through standard treatment, she strongly cautions patients against using these therapies in place of standard treatment.

“The bottom line is to keep the lines of communication open,” she said.

Like Dr. Lycette, Dr. Helft has been encountering more patients with alternative health beliefs who rely on people outside of the medical system for elements of their care.

In the past, he used to tell these patients that science is incomplete, and physicians don’t know everything. But he’s changed his tune.

“I’ve taken to just telling them what I believe, which is that the majority of things that they hear and are being sold are almost certainly ineffective and a waste of money,” he said. “I’ve come to accept that people are adults, and they make their own decisions, and sometimes they make decisions that are not the ones that I would make or want them to make.”
 

Delivering bad news

Dr. Helft often sees patients seeking a second or third opinion on their cancer. These patients may not all be in denial about having cancer, but they typically don’t want to hear bad news, which can make treatment a challenge.

To handle these scenarios, Dr. Helft has developed a system of responses for engaging with patients. He borrows an approach described in 2008 where he acknowledges a patient’s emotional distress and tries to understand why they may not want to know more.

For instance, he might tell a patient: “I have formulated an opinion about your situation, but it sounds as if you have heard many negative descriptions previously. I don’t want to burden you with one more if you don’t feel prepared to talk about it.”

Trying to understand why a patient is resistant to hearing about their condition may also help build trust. “If you could help me understand your thinking about why you would rather not talk about prognosis, it will help me know more about how to discuss other serious issues,” is one approach highlighted in the 2008 guide.

Behind the scenes, Dr. Helft will privately assess how much information about a patient’s prognosis is salient to their decision making, especially if the patient appears to misunderstand their prognosis or if there are various options for treatment over the long-term. 

Dr. Helft will also ask patients how much they want to know. Do they want to discuss no options? A few? All and in detail?

This approach implicitly recognizes that the information is highly stressful but avoids being overly blunt, he notes. It can also help steer patients on the right treatment track and minimize poor decision making.

Samantha Winemaker, MD, a palliative care physician in Hamilton, Ont., finds patients often go through an adjustment period after learning about a new diagnosis. The reaction tends to range from needing time to accept the diagnosis as real to jumping in to understand as much as possible.

Dr. Winemaker, who cohosts “The Waiting Room Revolution” podcast that focuses on helping people deal with a serious illness, encourages physicians to be realistic with patients about their prognosis and deliver news with a dose of gentle truth from the start.

“We should invite patients ‘into the know’ as early as possible, while maintaining hope,” she said.

She calls this approach of balancing hope and reality “walking two roads” and said it extends throughout the illness journey. This way, patients are less likely to be surprised if things make a turn for the worse.

“We should never wait until the 11th hour to give someone bad news,” she said.
 

‘We all want to hope’

Dr. Epstein has listened to hundreds of hours of discussion between doctors and patients as part of his research on communication. He often hears doctors initiate difficult conversations by lecturing a patient.

Many physicians mistakenly believe that, if they say something authoritatively, patients will believe it, he said. But the opposite often happens – patients shut down and instinctively distrust the physician.

Dr. Epstein teaches doctors to establish trust before providing difficult information. Even when a patient expresses outlandish ideas about their illness, treat them with dignity and respect, he advised. “If people don’t feel respected, you don’t have a leg to stand on and there’s no point in trying to convince them.”

Patients and physicians often leave conversations with discordant views of what’s ahead. In one study, two-thirds of patients held wildly different views on their prognosis, compared with their doctors, and most had no idea they were at odds with their physician.

In the past, Dr. Epstein has tried to close the gap between his understanding of a patient’s prognosis and the patient’s. But more recently he has become less convinced of the need to do so.

“What I try to do now is focus more on the uncertainty there,” he said. He uses phrases like: “Given that we don’t know how long you will live, I just need to know what you would want me to do if things took a turn for the worse” or “I’m worried that if you don’t have the surgery, you might experience more pain in the future.”

He urged doctors to pay attention to their word choices. Use care with the phrase “response rate” – patients sometimes mistake this to mean that they are being cured. And, instead of telling patients they “must” do something, he says that he worries about consequences for them if they don’t.

He asks patients what they’re hearing from other people in their lives or online. Sometimes patients say that people close to them are encouraging them to stop medical treatment or pursue alternative therapies. When that happens, Dr. Epstein asks to meet with that person to talk to them about his concerns for their loved one.

He also acknowledges calculated uncertainty often exists in medicine. That, he says, leaves open the potential for exceptional circumstances.

“And we all want to hope,” Dr. Epstein said.

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

In June, Rebecca A. Shatsky, MD, a medical oncologist, turned to Twitter for advice: “What do you do/say when a patient won’t believe you that they have #CANCER. As an oncologist this comes up every now and then and proves very difficult, looking to hear how others have dealt and what works best to help patients here.”

About a dozen people weighed in, offering various thoughts on how to approach these thorny situations. One oncologist suggested revisiting the conversation a few days later, after the patient has more time to process; others suggested sharing the pathology report or images with their patient.

Another person simply noted that “if a [patient] doesn’t want to believe they have cancer, no amount of evidence will change that.”

Based on the initial responses, “it appears there is a paucity of answers sadly,” wrote Dr. Shatsky, a breast cancer specialist at University of California, San Diego.

But for Dr. Shatsky, these incidents spoke to another alarming trend: a rampant mistrust of the medical community that is “becoming MORE common instead of less.”
 

‘Erosion of trust’

Overall, experts say that situations like the one Dr. Shatsky described – patients who don’t believe their cancer diagnosis – occur infrequently.

But denial comes in many forms, and complete disbelief is probably the most extreme. Patients may also downplay the severity of their disease, shy away from hearing bad news, or refuse standard treatment or their doctor’s advice.

Like Dr. Shatsky, these experts say they are also seeing a troubling increase in patients who don’t believe their physicians or don’t trust their recommendations.

“I think there’s an erosion of trust in expertise, in general,” said Ronald M. Epstein, MD, professor of family medicine and psychiatry & oncology at the University of Rochester (N.Y.). “People distrust science more than they did maybe 20 or 30 years ago, or at least that seems to be the case.”

Denial and distrust in cancer care are not new. These responses – along with wishful thinking, distraction, and minimization – are long-established responses among oncology patients. In 1972, Avery D. Weisman, MD, a psychiatrist at Harvard Medical School, Boston, wrote his book “On Dying and Denying,” and ever since, denial and similar responses have been explored in the oncology literature.

Much of this research has focused on the latter stages of illness, but denial can be present at diagnosis as well. One study of patients with breast cancer, carried out nearly 30 years ago, suggested that denial of diagnosis generally occurs early in a patient’s course of illness and decreases over time, but may arise again in the terminal phase of cancer. Another analysis, evaluating this phenomenon across 13 studies, found that the prevalence of denial at diagnosis ranged from 4% to as high as 47%. 

An oncologist delivers somewhere between 10,000 to 30,000 episodes of bad news over the course of a career, so there’s always a chance that a patient will respond in a way that’s on the “spectrum of disbelief,” said Paul Helft, MD, professor of medicine and recently retired director of the ethics center at Indiana University, Indianapolis.

Diane Meier, MD, said denial and disbelief are natural, protective responses to difficult or frightening news.

When patients exhibit denial, Dr. Meier advises patience and time. Physicians can also ask the patient if there’s a person they trust – a family member or faith leader, for example – who could speak on their behalf about possible next steps.

“The main thing is not to find ourselves in opposition to the patient ... or threaten them with what will happen if they don’t listen to us,” said Dr. Meier, a professor of geriatrics and palliative medicine at the Icahn School of Medicine at Mount Sinai, New York.

And physicians should be careful when they feel themselves wanting to argue with or lecture a patient.

“The minute we feel that urge coming on, that’s a signal to us to stop and realize that something is going on inside the patient that we don’t understand,” she said. “Forcing information on a person who is signaling in every way that they don’t want it and can’t handle it is not a recipe for trust or a high-quality relationship.”
 

Refusing expert advice

Jennifer Lycette, MD, has encountered a growing number of patients who don’t believe their disease should be treated the way she or other oncologists recommend. Some patients remain adamant about sticking with alternative medicine or doing nothing, despite growing sicker.

“I’ve even had situations where the tumor might be visible, like growing through the skin, and people still double down that whatever they’re doing is working,” said Dr. Lycette, a hematologist and medical oncologist at the Providence Seaside Cancer Center in Seaside, Ore.

She encourages these patients to get a second opinion and tries to keep an open mind about alternative approaches. If she’s not familiar with something a patient is considering, she’ll research it with them.

But she makes sure to point out any risks associated with these approaches. While some alternative therapies can support patients through standard treatment, she strongly cautions patients against using these therapies in place of standard treatment.

“The bottom line is to keep the lines of communication open,” she said.

Like Dr. Lycette, Dr. Helft has been encountering more patients with alternative health beliefs who rely on people outside of the medical system for elements of their care.

In the past, he used to tell these patients that science is incomplete, and physicians don’t know everything. But he’s changed his tune.

“I’ve taken to just telling them what I believe, which is that the majority of things that they hear and are being sold are almost certainly ineffective and a waste of money,” he said. “I’ve come to accept that people are adults, and they make their own decisions, and sometimes they make decisions that are not the ones that I would make or want them to make.”
 

Delivering bad news

Dr. Helft often sees patients seeking a second or third opinion on their cancer. These patients may not all be in denial about having cancer, but they typically don’t want to hear bad news, which can make treatment a challenge.

To handle these scenarios, Dr. Helft has developed a system of responses for engaging with patients. He borrows an approach described in 2008 where he acknowledges a patient’s emotional distress and tries to understand why they may not want to know more.

For instance, he might tell a patient: “I have formulated an opinion about your situation, but it sounds as if you have heard many negative descriptions previously. I don’t want to burden you with one more if you don’t feel prepared to talk about it.”

Trying to understand why a patient is resistant to hearing about their condition may also help build trust. “If you could help me understand your thinking about why you would rather not talk about prognosis, it will help me know more about how to discuss other serious issues,” is one approach highlighted in the 2008 guide.

Behind the scenes, Dr. Helft will privately assess how much information about a patient’s prognosis is salient to their decision making, especially if the patient appears to misunderstand their prognosis or if there are various options for treatment over the long-term. 

Dr. Helft will also ask patients how much they want to know. Do they want to discuss no options? A few? All and in detail?

This approach implicitly recognizes that the information is highly stressful but avoids being overly blunt, he notes. It can also help steer patients on the right treatment track and minimize poor decision making.

Samantha Winemaker, MD, a palliative care physician in Hamilton, Ont., finds patients often go through an adjustment period after learning about a new diagnosis. The reaction tends to range from needing time to accept the diagnosis as real to jumping in to understand as much as possible.

Dr. Winemaker, who cohosts “The Waiting Room Revolution” podcast that focuses on helping people deal with a serious illness, encourages physicians to be realistic with patients about their prognosis and deliver news with a dose of gentle truth from the start.

“We should invite patients ‘into the know’ as early as possible, while maintaining hope,” she said.

She calls this approach of balancing hope and reality “walking two roads” and said it extends throughout the illness journey. This way, patients are less likely to be surprised if things make a turn for the worse.

“We should never wait until the 11th hour to give someone bad news,” she said.
 

‘We all want to hope’

Dr. Epstein has listened to hundreds of hours of discussion between doctors and patients as part of his research on communication. He often hears doctors initiate difficult conversations by lecturing a patient.

Many physicians mistakenly believe that, if they say something authoritatively, patients will believe it, he said. But the opposite often happens – patients shut down and instinctively distrust the physician.

Dr. Epstein teaches doctors to establish trust before providing difficult information. Even when a patient expresses outlandish ideas about their illness, treat them with dignity and respect, he advised. “If people don’t feel respected, you don’t have a leg to stand on and there’s no point in trying to convince them.”

Patients and physicians often leave conversations with discordant views of what’s ahead. In one study, two-thirds of patients held wildly different views on their prognosis, compared with their doctors, and most had no idea they were at odds with their physician.

In the past, Dr. Epstein has tried to close the gap between his understanding of a patient’s prognosis and the patient’s. But more recently he has become less convinced of the need to do so.

“What I try to do now is focus more on the uncertainty there,” he said. He uses phrases like: “Given that we don’t know how long you will live, I just need to know what you would want me to do if things took a turn for the worse” or “I’m worried that if you don’t have the surgery, you might experience more pain in the future.”

He urged doctors to pay attention to their word choices. Use care with the phrase “response rate” – patients sometimes mistake this to mean that they are being cured. And, instead of telling patients they “must” do something, he says that he worries about consequences for them if they don’t.

He asks patients what they’re hearing from other people in their lives or online. Sometimes patients say that people close to them are encouraging them to stop medical treatment or pursue alternative therapies. When that happens, Dr. Epstein asks to meet with that person to talk to them about his concerns for their loved one.

He also acknowledges calculated uncertainty often exists in medicine. That, he says, leaves open the potential for exceptional circumstances.

“And we all want to hope,” Dr. Epstein said.

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

In June, Rebecca A. Shatsky, MD, a medical oncologist, turned to Twitter for advice: “What do you do/say when a patient won’t believe you that they have #CANCER. As an oncologist this comes up every now and then and proves very difficult, looking to hear how others have dealt and what works best to help patients here.”

About a dozen people weighed in, offering various thoughts on how to approach these thorny situations. One oncologist suggested revisiting the conversation a few days later, after the patient has more time to process; others suggested sharing the pathology report or images with their patient.

Another person simply noted that “if a [patient] doesn’t want to believe they have cancer, no amount of evidence will change that.”

Based on the initial responses, “it appears there is a paucity of answers sadly,” wrote Dr. Shatsky, a breast cancer specialist at University of California, San Diego.

But for Dr. Shatsky, these incidents spoke to another alarming trend: a rampant mistrust of the medical community that is “becoming MORE common instead of less.”
 

‘Erosion of trust’

Overall, experts say that situations like the one Dr. Shatsky described – patients who don’t believe their cancer diagnosis – occur infrequently.

But denial comes in many forms, and complete disbelief is probably the most extreme. Patients may also downplay the severity of their disease, shy away from hearing bad news, or refuse standard treatment or their doctor’s advice.

Like Dr. Shatsky, these experts say they are also seeing a troubling increase in patients who don’t believe their physicians or don’t trust their recommendations.

“I think there’s an erosion of trust in expertise, in general,” said Ronald M. Epstein, MD, professor of family medicine and psychiatry & oncology at the University of Rochester (N.Y.). “People distrust science more than they did maybe 20 or 30 years ago, or at least that seems to be the case.”

Denial and distrust in cancer care are not new. These responses – along with wishful thinking, distraction, and minimization – are long-established responses among oncology patients. In 1972, Avery D. Weisman, MD, a psychiatrist at Harvard Medical School, Boston, wrote his book “On Dying and Denying,” and ever since, denial and similar responses have been explored in the oncology literature.

Much of this research has focused on the latter stages of illness, but denial can be present at diagnosis as well. One study of patients with breast cancer, carried out nearly 30 years ago, suggested that denial of diagnosis generally occurs early in a patient’s course of illness and decreases over time, but may arise again in the terminal phase of cancer. Another analysis, evaluating this phenomenon across 13 studies, found that the prevalence of denial at diagnosis ranged from 4% to as high as 47%. 

An oncologist delivers somewhere between 10,000 to 30,000 episodes of bad news over the course of a career, so there’s always a chance that a patient will respond in a way that’s on the “spectrum of disbelief,” said Paul Helft, MD, professor of medicine and recently retired director of the ethics center at Indiana University, Indianapolis.

Diane Meier, MD, said denial and disbelief are natural, protective responses to difficult or frightening news.

When patients exhibit denial, Dr. Meier advises patience and time. Physicians can also ask the patient if there’s a person they trust – a family member or faith leader, for example – who could speak on their behalf about possible next steps.

“The main thing is not to find ourselves in opposition to the patient ... or threaten them with what will happen if they don’t listen to us,” said Dr. Meier, a professor of geriatrics and palliative medicine at the Icahn School of Medicine at Mount Sinai, New York.

And physicians should be careful when they feel themselves wanting to argue with or lecture a patient.

“The minute we feel that urge coming on, that’s a signal to us to stop and realize that something is going on inside the patient that we don’t understand,” she said. “Forcing information on a person who is signaling in every way that they don’t want it and can’t handle it is not a recipe for trust or a high-quality relationship.”
 

Refusing expert advice

Jennifer Lycette, MD, has encountered a growing number of patients who don’t believe their disease should be treated the way she or other oncologists recommend. Some patients remain adamant about sticking with alternative medicine or doing nothing, despite growing sicker.

“I’ve even had situations where the tumor might be visible, like growing through the skin, and people still double down that whatever they’re doing is working,” said Dr. Lycette, a hematologist and medical oncologist at the Providence Seaside Cancer Center in Seaside, Ore.

She encourages these patients to get a second opinion and tries to keep an open mind about alternative approaches. If she’s not familiar with something a patient is considering, she’ll research it with them.

But she makes sure to point out any risks associated with these approaches. While some alternative therapies can support patients through standard treatment, she strongly cautions patients against using these therapies in place of standard treatment.

“The bottom line is to keep the lines of communication open,” she said.

Like Dr. Lycette, Dr. Helft has been encountering more patients with alternative health beliefs who rely on people outside of the medical system for elements of their care.

In the past, he used to tell these patients that science is incomplete, and physicians don’t know everything. But he’s changed his tune.

“I’ve taken to just telling them what I believe, which is that the majority of things that they hear and are being sold are almost certainly ineffective and a waste of money,” he said. “I’ve come to accept that people are adults, and they make their own decisions, and sometimes they make decisions that are not the ones that I would make or want them to make.”
 

Delivering bad news

Dr. Helft often sees patients seeking a second or third opinion on their cancer. These patients may not all be in denial about having cancer, but they typically don’t want to hear bad news, which can make treatment a challenge.

To handle these scenarios, Dr. Helft has developed a system of responses for engaging with patients. He borrows an approach described in 2008 where he acknowledges a patient’s emotional distress and tries to understand why they may not want to know more.

For instance, he might tell a patient: “I have formulated an opinion about your situation, but it sounds as if you have heard many negative descriptions previously. I don’t want to burden you with one more if you don’t feel prepared to talk about it.”

Trying to understand why a patient is resistant to hearing about their condition may also help build trust. “If you could help me understand your thinking about why you would rather not talk about prognosis, it will help me know more about how to discuss other serious issues,” is one approach highlighted in the 2008 guide.

Behind the scenes, Dr. Helft will privately assess how much information about a patient’s prognosis is salient to their decision making, especially if the patient appears to misunderstand their prognosis or if there are various options for treatment over the long-term. 

Dr. Helft will also ask patients how much they want to know. Do they want to discuss no options? A few? All and in detail?

This approach implicitly recognizes that the information is highly stressful but avoids being overly blunt, he notes. It can also help steer patients on the right treatment track and minimize poor decision making.

Samantha Winemaker, MD, a palliative care physician in Hamilton, Ont., finds patients often go through an adjustment period after learning about a new diagnosis. The reaction tends to range from needing time to accept the diagnosis as real to jumping in to understand as much as possible.

Dr. Winemaker, who cohosts “The Waiting Room Revolution” podcast that focuses on helping people deal with a serious illness, encourages physicians to be realistic with patients about their prognosis and deliver news with a dose of gentle truth from the start.

“We should invite patients ‘into the know’ as early as possible, while maintaining hope,” she said.

She calls this approach of balancing hope and reality “walking two roads” and said it extends throughout the illness journey. This way, patients are less likely to be surprised if things make a turn for the worse.

“We should never wait until the 11th hour to give someone bad news,” she said.
 

‘We all want to hope’

Dr. Epstein has listened to hundreds of hours of discussion between doctors and patients as part of his research on communication. He often hears doctors initiate difficult conversations by lecturing a patient.

Many physicians mistakenly believe that, if they say something authoritatively, patients will believe it, he said. But the opposite often happens – patients shut down and instinctively distrust the physician.

Dr. Epstein teaches doctors to establish trust before providing difficult information. Even when a patient expresses outlandish ideas about their illness, treat them with dignity and respect, he advised. “If people don’t feel respected, you don’t have a leg to stand on and there’s no point in trying to convince them.”

Patients and physicians often leave conversations with discordant views of what’s ahead. In one study, two-thirds of patients held wildly different views on their prognosis, compared with their doctors, and most had no idea they were at odds with their physician.

In the past, Dr. Epstein has tried to close the gap between his understanding of a patient’s prognosis and the patient’s. But more recently he has become less convinced of the need to do so.

“What I try to do now is focus more on the uncertainty there,” he said. He uses phrases like: “Given that we don’t know how long you will live, I just need to know what you would want me to do if things took a turn for the worse” or “I’m worried that if you don’t have the surgery, you might experience more pain in the future.”

He urged doctors to pay attention to their word choices. Use care with the phrase “response rate” – patients sometimes mistake this to mean that they are being cured. And, instead of telling patients they “must” do something, he says that he worries about consequences for them if they don’t.

He asks patients what they’re hearing from other people in their lives or online. Sometimes patients say that people close to them are encouraging them to stop medical treatment or pursue alternative therapies. When that happens, Dr. Epstein asks to meet with that person to talk to them about his concerns for their loved one.

He also acknowledges calculated uncertainty often exists in medicine. That, he says, leaves open the potential for exceptional circumstances.

“And we all want to hope,” Dr. Epstein said.

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