Clinical Endocrinology News

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

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

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

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

Although use of some herbal and dietary supplements show statistically greater weight loss compared with placebo, it is not sufficient to benefit health, according to the joint findings of two systematic reviews, which are the first to comprehensively include all available herbal and dietary supplements for weight loss for over 15 years.

Sally Kubetin/MDedge News

“There is currently insufficient evidence to recommend any of the supplements we included in our reviews for weight loss,” stressed lead author Erica Bessell, a PhD candidate from the University of Sydney.

She added that some products with promising results warrant further investigation in well-conducted randomized controlled trials (RCTs) to determine their efficacy and safety.

But, overall, she would like to see a reduction in the number of products on the market without evidence to support their efficacy, “because, as we found, many of the products currently marketed for weight loss just do not work.

“Herbal and dietary supplements might seem like a quick-fix solution to weight problems, but people need to be aware of how little we actually know about them,” she said in an interview. “We would recommend that people trying to lose weight should save their money and seek out evidence-based care instead,” she emphasized.

The research was presented as two posters at this year’s online European Congress on Obesity (ECO). The meeting was presented by the European Association for the Study of Obesity.
 

Herbal and dietary supplement industry booming

Supplements for weight loss are growing in popularity, sustaining a rapidly expanding business sector globally. In the United States, the herbal and dietary supplements industry was estimated to be worth USD $41 billion in 2020, with 15% of Americans having tried a weight loss supplement in their efforts to shed pounds.

In light of this, Ms. Bessell said it is increasingly important to ensure supplements are efficacious and safe: “The popularity of these products underscores the urgency of conducting larger, more rigorous studies to have reasonable assurance of their safety and effectiveness for weight loss.”

Commenting on the study and the wider issues related to the surge in uptake of herbal and dietary supplements, Susan Arentz, PhD, said the evidence is similar to that for other complex interventions that people attempt for weight loss, including for example exercise, in that it is heterogeneous and low quality.

“One outstanding limitation for herbal medicine was the failure of trialists to validate the contents of interventions. Given the chemical variability of plants grown and harvested in different conditions, and the presence of pharmaceuticals and heavy metals found in some supplements ... future investigations of standardized herbal supplements and RCTs of higher methodological quality are needed,” remarked Dr. Arentz, a board member of the Australasian Integrative Medicine Association and researcher at Western Sydney University.

“Also, further RCTs are warranted due to the consumer preferences for natural treatments, especially in health settings with predominant use of traditional medicines and practices,” said Dr. Arentz.   
 

One review for herbal supplements, one for organic compounds

To accommodate the large number of trials investigating supplements for weight loss, the researchers conducted two systematic reviews, together representing 121 randomized placebo-controlled trials. One of the reviews investigated herbal supplements, and the other examined supplements with isolated organic compounds for example, specific fibers or lipids.  

Many of the included trials had been published in the last decade and had not been previously included in an up-to-date systematic review.

Ms. Bessell added that many studies often had a small sample size or were poorly designed, with insufficient information on the composition of supplements, and often featured little data on long-term effectiveness.

The two reviews primarily analyzed efficacy, not safety, because many of the studies did not report adverse effects.

The first review, published last year in Diabetes, Obesity and Metabolism, looked at 54 placebo-controlled randomized trials up to August 2018 on the effect of herbal supplements on weight loss . The study included 4,331 individuals aged 16 years or older who were overweight or obese. To be clinically meaningful, a weight loss of at least 2.5 kg was required over a period of, most often, 12 weeks or less.

Herbal supplements included in the analysis included green tea, Garcinia cambogia and mangosteen (tropical fruits), white kidney bean, ephedra (a stimulant that increases metabolism), African mango, yerba mate (herbal tea made from the leaves and twigs of the Ilex paraguariensis plant), veld grape (commonly used in Indian traditional medicine), licorice root, and East Indian Globe Thistle (used in Ayurvedic medicine).

The second review analyzed 67 randomized trials up to December 2019 that compared the effect of dietary supplements containing naturally occurring isolated organic compounds to placebo for weight loss in 5,194 individuals aged 16 years or older who were overweight or obese.

Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid, and fructans comparing the mean weight difference post intervention between participants receiving the dietary supplement and those on placebo.
 

No clinically significant results

Commenting on the overall results, Ms. Bessell said: “Though most supplements were safe for use in the short term, very few were found to produce clinically meaningful weight loss. Those that were found to result in clinically meaningful weight loss had only been investigated in one or two trials, so we need more research.”

The first review on herbal supplements found that only Phaseolus vulgaris (white kidney bean) resulted in significant weight loss compared with placebo, with an average weight difference of 1.61 kg (3.5 pounds). The result was not clinically meaningful, however.

For isolated organic compounds, significant weight differences compared with placebo were seen for chitosan, with a mean difference of 1.84 kg (4 pounds), glucomannan at 1.27 kg (2.8 pounds), and conjugated linoleic acid at 1.08 kg (2.4 pounds).

Again, none of these findings met the criteria for clinical significance (weight loss of 2.5 kg [5.5 pounds] or more).

In addition, some combination preparations containing African mango, veld grape, East Indian Globe Thistle, and mangosteen showed promising results with a mean weight difference of 1.85 kg (4 pounds), but were investigated in three or fewer trials, often with poor research methodology or reporting, and the findings should be interpreted with caution, the researchers noted.

Other dietary supplements, including modified cellulose – a plant fiber that expands in the stomach to induce a feeling of fullness – and blood orange juice extract, also showed encouraging results but were investigated in one trial and need more evidence before they can be recommended for weight loss, Ms. Bessell added.

She pointed out that some supplements are banned in some countries, such as ephedra (an extract from the plant Ephedra sinica). “This supplement is already banned in many countries because of the risk of serious adverse effects. The possibility of drug interactions may also be present with some other supplements, so health professionals and consumers should be aware of this.”

The isolated organic compounds supplements review was published in the International Journal of Obesity to coincide with the ECO 2021 conference.

Ms. Bessell has declared no relevant conflicts of interests. Dr. Arentz reviewed the systematic review of RCTs of herbal medicine supplements for weight loss published in Diabetes, Obesity and Metabolism.
 

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

Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.

pixologicstudio/Thinkstock

“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an interview.

“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.

The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.  The meeting was presented by the European Association for the Study of Obesity.
 

Tissue samples

Tissue samples were obtained from 38 individuals who were lean and 61 individuals who were obese, and further divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Dr. Catalan elaborated.

Investigators also found upregulated levels of IL-1-beta in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.

Dr. Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.  

“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Dr. Catalan cautioned.

Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Dr. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine – has been associated with increased mortality in colorectal cancer.

“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Dr. Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.  

Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Dr. Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Dr. Catalan observed.

The researchers speculated that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1-beta is currently an important area of research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1-beta antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1-beta receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1-beta signaling, Dr. Catalan pointed out.

Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Dr. Catalan speculated.

“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers said.
 

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

Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.

pixologicstudio/Thinkstock

“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an interview.

“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.

The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.  The meeting was presented by the European Association for the Study of Obesity.
 

Tissue samples

Tissue samples were obtained from 38 individuals who were lean and 61 individuals who were obese, and further divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Dr. Catalan elaborated.

Investigators also found upregulated levels of IL-1-beta in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.

Dr. Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.  

“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Dr. Catalan cautioned.

Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Dr. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine – has been associated with increased mortality in colorectal cancer.

“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Dr. Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.  

Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Dr. Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Dr. Catalan observed.

The researchers speculated that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1-beta is currently an important area of research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1-beta antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1-beta receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1-beta signaling, Dr. Catalan pointed out.

Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Dr. Catalan speculated.

“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers said.
 

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

Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers, according to new research.

pixologicstudio/Thinkstock

“Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules,” Victoria Catalan, PhD, Navarre Institute of Health Research, Pamplona, Spain, explained in an interview.

“So inflammasomes are not only implicated in obesity-associated colon cancer but their role may be more relevant in patients with obesity,” she added.

The new research was presented during the recent European Congress on Obesity, held virtually because of the pandemic.  The meeting was presented by the European Association for the Study of Obesity.
 

Tissue samples

Tissue samples were obtained from 38 individuals who were lean and 61 individuals who were obese, and further divided into those with or without colon cancer.

A new finding from the study was that both obesity and colon cancer increase gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue (VAT), “suggesting that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development,” Dr. Catalan elaborated.

Investigators also found upregulated levels of IL-1-beta in VAT from individuals who were obese as well as those with colon cancer, an observation that strengthens the hypothesis that inflammasome-dependent production of these cytokines may influence colon tumorigenesis, she added.

Dr. Catalan noted that her team has previously shown that blocking the expression of NLRP3 reduces VAT inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.  

“Whether obesity has an impact on colon cancer through the enhancement of inflammation or via a direct mechanism is largely unclear, and the role of inflammasomes in cancer development is still controversial,” Dr. Catalan cautioned.

Nevertheless, the study showed that tissue samples from patients with colon cancer were associated with reduced expression of NLRP6 and IL-18. Dr. Catalan explained that NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation. The same protein is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine – has been associated with increased mortality in colorectal cancer.

“Thus, reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier,” Dr. Catalan suggested. The same experiment revealed that gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, were similarly reduced in VAT in individuals who were obese as well as those with colon cancer.  

Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer, Dr. Catalan noted. But it has also been recently shown that normal levels of adiponectin inhibit colorectal cancer cell growth. “It is very important to take into account that inflammasomes have contrasting roles in tumorigenesis, demonstrating both detrimental and beneficial effects,” Dr. Catalan observed.

The researchers speculated that NLRP3 agonists may enhance immune function and help reverse the immunosuppressive microenvironment promoted by VAT inflammation. For instance, activation of IL-18 signaling by inflammasomes regulates intestinal tissue repair following the development of colon cancer by triggering the process of re-epithelialization. Development of NLRP3 antagonists that can block the signaling pathway of IL-1-beta is currently an important area of research.

Similarly, the recombinant IL-1 receptor antagonist anakinra (Kineret, Amgen), the neutralizing IL-1-beta antibody canakinumab (Ilaris, Novartis), and the soluble decoy IL-1-beta receptor rilonacept (Arcalyst, Regeneron) are all being evaluated as a strategy to block IL-1-beta signaling, Dr. Catalan pointed out.

Various NLRP3 inflammasome inhibitors are also being developed. “Pharmacological inhibitors of the NLRP3 pathway could offer a [viable] treatment option in a wide array of chronic and autoinflammatory diseases for which no adequate therapies currently exist,” Dr. Catalan speculated.

“Strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer,” the researchers said.
 

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

As has been dominating the headlines, the Centers for Disease Control and Prevention recently released updated public health guidance for those who are fully vaccinated against COVID-19. This guidance was issued on May 13, 2021, and has potentially provided some relief to those who are fully vaccinated, though some are concerned and confused about the implications of this guidance.

This new guidance applies to those who are fully vaccinated as indicated by 2 weeks after the second dose in a 2-dose series or 2 weeks after a single-dose vaccine. Those who meet these criteria no longer need to wear a mask or physically distance themselves from others in both indoor and outdoor settings. For those not fully vaccinated, masking and social distancing should continue to be practiced.

The new guidance indicates that quarantine after a known exposure is no longer necessary.

Unless required by local, state, or territorial health authorities, testing is no longer required following domestic travel for fully vaccinated individuals. A negative test is still required prior to boarding an international flight to the United States and testing 3-5 days after arrival is still recommended. Self-quarantine is no longer required after international travel for fully vaccinated individuals.

The new guidance recommends that individuals who are fully vaccinated not participate in routine screening programs when feasible. Finally, if an individual has tested positive for COVID-19, regardless of vaccination status, that person should isolate and not visit public or private settings for a minimum of ten days.¹

Updated guidance for health care facilities

In addition to changes for the general public in all settings, the CDC updated guidance for health care facilities on April 27, 2021. These updated guidelines allow for communal dining and visitation for fully vaccinated patients and their visitors. The guidelines indicate that fully vaccinated health care personnel (HCP) do not require quarantine after exposure to patients who have tested positive for COVID-19 as long as the HCP remains asymptomatic. They should, however, continue to utilize personal protective equipment as previously recommended. HCPs are able to be in break and meeting rooms unmasked if all HCPs are vaccinated.²

There are some important caveats to these updated guidelines. They do not apply to those who have immunocompromising conditions, including those using immunosuppressant agents. They also do not apply to locations subject to federal, state, local, tribal, or territorial laws, rules, and regulations, including local business and workplace guidance.

Those who work or reside in correction or detention facilities and homeless shelters are also still required to test after known exposures. Masking is still required by all travelers on all forms of public transportation into and within the United States.

Most importantly, the guidelines apply only to those who are fully vaccinated. Finally, no vaccine is perfect. As such, anyone who experiences symptoms indicative of COVID-19, regardless of vaccination status, should obtain viral testing and isolate themselves from others.^1,2

Pros and cons to new guidance

Both sets of updated guidelines are a great example of public health guidance that is changing as the evidence is gathered and changes. This guidance is also a welcome encouragement that the vaccines are effective at decreasing transmission of this virus that has upended our world.

These guidelines leave room for change as evidence is gathered on emerging novel variants. There are, however, a few remaining concerns.

My first concern is for those who are not yet able to be vaccinated, including children under the age of 12. For families with members who are not fully vaccinated, they may have first heard the headlines of “you do not have to mask” to then read the fine print that remains. When truly following these guidelines, many social situations in both the public and private setting should still include both masking and social distancing.

There is no clarity on how these guidelines are enforced. Within the guidance, it is clear that individuals’ privacy is of utmost importance. In the absence of knowledge, that means that the assumption should be that all are not yet vaccinated. Unless there is a way to reliably demonstrate vaccination status, it would likely still be safer to assume that there are individuals who are not fully vaccinated within the setting.

Finally, although this is great news surrounding the efficacy of the vaccine, some are concerned that local mask mandates that have already started to be lifted will be completely removed. As there is still a large portion of the population not yet fully vaccinated, it seems premature for local, state, and territorial authorities to lift these mandates.
 

How to continue exercising caution

With the outstanding concerns, I will continue to mask in settings, particularly indoors, where I do not definitely know that everyone is vaccinated. I will continue to do this to protect my children and my patients who are not yet vaccinated, and my patients who are immunosuppressed for whom we do not yet have enough information.

I will continue to advise my patients to be thoughtful about the risk for themselves and their families as well.

There has been more benefit to these public health measures then just decreased transmission of COVID-19. I hope that this year has reinforced within us the benefits of masking and self-isolation in the cases of any contagious illnesses.

Although I am looking forward to the opportunities to interact in person with more colleagues and friends, I think we should continue to do this with caution and thoughtfulness. We must be prepared for the possibility of vaccines having decreased efficacy against novel variants as well as eventually the possibility of waning immunity. If these should occur, we need to be prepared for additional recommendation changes and tightening of restrictions.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

References

1. Centers for Disease Control and Prevention. Interim Public Health Recommendations for Fully Vaccinated People. U.S. Department of Health & Human Services, May 13, 2021.

2. Centers for Disease Control and Prevention. Updated Healthcare Infection Prevention and Control Recommendations in Response to COVID-19 Vaccination. U.S. Department of Health and Human Services, April 27, 2021.

As has been dominating the headlines, the Centers for Disease Control and Prevention recently released updated public health guidance for those who are fully vaccinated against COVID-19. This guidance was issued on May 13, 2021, and has potentially provided some relief to those who are fully vaccinated, though some are concerned and confused about the implications of this guidance.

This new guidance applies to those who are fully vaccinated as indicated by 2 weeks after the second dose in a 2-dose series or 2 weeks after a single-dose vaccine. Those who meet these criteria no longer need to wear a mask or physically distance themselves from others in both indoor and outdoor settings. For those not fully vaccinated, masking and social distancing should continue to be practiced.

The new guidance indicates that quarantine after a known exposure is no longer necessary.

Unless required by local, state, or territorial health authorities, testing is no longer required following domestic travel for fully vaccinated individuals. A negative test is still required prior to boarding an international flight to the United States and testing 3-5 days after arrival is still recommended. Self-quarantine is no longer required after international travel for fully vaccinated individuals.

The new guidance recommends that individuals who are fully vaccinated not participate in routine screening programs when feasible. Finally, if an individual has tested positive for COVID-19, regardless of vaccination status, that person should isolate and not visit public or private settings for a minimum of ten days.¹

Updated guidance for health care facilities

In addition to changes for the general public in all settings, the CDC updated guidance for health care facilities on April 27, 2021. These updated guidelines allow for communal dining and visitation for fully vaccinated patients and their visitors. The guidelines indicate that fully vaccinated health care personnel (HCP) do not require quarantine after exposure to patients who have tested positive for COVID-19 as long as the HCP remains asymptomatic. They should, however, continue to utilize personal protective equipment as previously recommended. HCPs are able to be in break and meeting rooms unmasked if all HCPs are vaccinated.²

There are some important caveats to these updated guidelines. They do not apply to those who have immunocompromising conditions, including those using immunosuppressant agents. They also do not apply to locations subject to federal, state, local, tribal, or territorial laws, rules, and regulations, including local business and workplace guidance.

Those who work or reside in correction or detention facilities and homeless shelters are also still required to test after known exposures. Masking is still required by all travelers on all forms of public transportation into and within the United States.

Most importantly, the guidelines apply only to those who are fully vaccinated. Finally, no vaccine is perfect. As such, anyone who experiences symptoms indicative of COVID-19, regardless of vaccination status, should obtain viral testing and isolate themselves from others.^1,2

Pros and cons to new guidance

Both sets of updated guidelines are a great example of public health guidance that is changing as the evidence is gathered and changes. This guidance is also a welcome encouragement that the vaccines are effective at decreasing transmission of this virus that has upended our world.

These guidelines leave room for change as evidence is gathered on emerging novel variants. There are, however, a few remaining concerns.

My first concern is for those who are not yet able to be vaccinated, including children under the age of 12. For families with members who are not fully vaccinated, they may have first heard the headlines of “you do not have to mask” to then read the fine print that remains. When truly following these guidelines, many social situations in both the public and private setting should still include both masking and social distancing.

There is no clarity on how these guidelines are enforced. Within the guidance, it is clear that individuals’ privacy is of utmost importance. In the absence of knowledge, that means that the assumption should be that all are not yet vaccinated. Unless there is a way to reliably demonstrate vaccination status, it would likely still be safer to assume that there are individuals who are not fully vaccinated within the setting.

Finally, although this is great news surrounding the efficacy of the vaccine, some are concerned that local mask mandates that have already started to be lifted will be completely removed. As there is still a large portion of the population not yet fully vaccinated, it seems premature for local, state, and territorial authorities to lift these mandates.
 

How to continue exercising caution

With the outstanding concerns, I will continue to mask in settings, particularly indoors, where I do not definitely know that everyone is vaccinated. I will continue to do this to protect my children and my patients who are not yet vaccinated, and my patients who are immunosuppressed for whom we do not yet have enough information.

I will continue to advise my patients to be thoughtful about the risk for themselves and their families as well.

There has been more benefit to these public health measures then just decreased transmission of COVID-19. I hope that this year has reinforced within us the benefits of masking and self-isolation in the cases of any contagious illnesses.

Although I am looking forward to the opportunities to interact in person with more colleagues and friends, I think we should continue to do this with caution and thoughtfulness. We must be prepared for the possibility of vaccines having decreased efficacy against novel variants as well as eventually the possibility of waning immunity. If these should occur, we need to be prepared for additional recommendation changes and tightening of restrictions.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

References

1. Centers for Disease Control and Prevention. Interim Public Health Recommendations for Fully Vaccinated People. U.S. Department of Health & Human Services, May 13, 2021.

2. Centers for Disease Control and Prevention. Updated Healthcare Infection Prevention and Control Recommendations in Response to COVID-19 Vaccination. U.S. Department of Health and Human Services, April 27, 2021.

As has been dominating the headlines, the Centers for Disease Control and Prevention recently released updated public health guidance for those who are fully vaccinated against COVID-19. This guidance was issued on May 13, 2021, and has potentially provided some relief to those who are fully vaccinated, though some are concerned and confused about the implications of this guidance.

This new guidance applies to those who are fully vaccinated as indicated by 2 weeks after the second dose in a 2-dose series or 2 weeks after a single-dose vaccine. Those who meet these criteria no longer need to wear a mask or physically distance themselves from others in both indoor and outdoor settings. For those not fully vaccinated, masking and social distancing should continue to be practiced.

The new guidance indicates that quarantine after a known exposure is no longer necessary.

Unless required by local, state, or territorial health authorities, testing is no longer required following domestic travel for fully vaccinated individuals. A negative test is still required prior to boarding an international flight to the United States and testing 3-5 days after arrival is still recommended. Self-quarantine is no longer required after international travel for fully vaccinated individuals.

The new guidance recommends that individuals who are fully vaccinated not participate in routine screening programs when feasible. Finally, if an individual has tested positive for COVID-19, regardless of vaccination status, that person should isolate and not visit public or private settings for a minimum of ten days.¹

Updated guidance for health care facilities

In addition to changes for the general public in all settings, the CDC updated guidance for health care facilities on April 27, 2021. These updated guidelines allow for communal dining and visitation for fully vaccinated patients and their visitors. The guidelines indicate that fully vaccinated health care personnel (HCP) do not require quarantine after exposure to patients who have tested positive for COVID-19 as long as the HCP remains asymptomatic. They should, however, continue to utilize personal protective equipment as previously recommended. HCPs are able to be in break and meeting rooms unmasked if all HCPs are vaccinated.²

There are some important caveats to these updated guidelines. They do not apply to those who have immunocompromising conditions, including those using immunosuppressant agents. They also do not apply to locations subject to federal, state, local, tribal, or territorial laws, rules, and regulations, including local business and workplace guidance.

Those who work or reside in correction or detention facilities and homeless shelters are also still required to test after known exposures. Masking is still required by all travelers on all forms of public transportation into and within the United States.

Most importantly, the guidelines apply only to those who are fully vaccinated. Finally, no vaccine is perfect. As such, anyone who experiences symptoms indicative of COVID-19, regardless of vaccination status, should obtain viral testing and isolate themselves from others.^1,2

Pros and cons to new guidance

Both sets of updated guidelines are a great example of public health guidance that is changing as the evidence is gathered and changes. This guidance is also a welcome encouragement that the vaccines are effective at decreasing transmission of this virus that has upended our world.

These guidelines leave room for change as evidence is gathered on emerging novel variants. There are, however, a few remaining concerns.

My first concern is for those who are not yet able to be vaccinated, including children under the age of 12. For families with members who are not fully vaccinated, they may have first heard the headlines of “you do not have to mask” to then read the fine print that remains. When truly following these guidelines, many social situations in both the public and private setting should still include both masking and social distancing.

There is no clarity on how these guidelines are enforced. Within the guidance, it is clear that individuals’ privacy is of utmost importance. In the absence of knowledge, that means that the assumption should be that all are not yet vaccinated. Unless there is a way to reliably demonstrate vaccination status, it would likely still be safer to assume that there are individuals who are not fully vaccinated within the setting.

Finally, although this is great news surrounding the efficacy of the vaccine, some are concerned that local mask mandates that have already started to be lifted will be completely removed. As there is still a large portion of the population not yet fully vaccinated, it seems premature for local, state, and territorial authorities to lift these mandates.
 

How to continue exercising caution

With the outstanding concerns, I will continue to mask in settings, particularly indoors, where I do not definitely know that everyone is vaccinated. I will continue to do this to protect my children and my patients who are not yet vaccinated, and my patients who are immunosuppressed for whom we do not yet have enough information.

I will continue to advise my patients to be thoughtful about the risk for themselves and their families as well.

There has been more benefit to these public health measures then just decreased transmission of COVID-19. I hope that this year has reinforced within us the benefits of masking and self-isolation in the cases of any contagious illnesses.

Although I am looking forward to the opportunities to interact in person with more colleagues and friends, I think we should continue to do this with caution and thoughtfulness. We must be prepared for the possibility of vaccines having decreased efficacy against novel variants as well as eventually the possibility of waning immunity. If these should occur, we need to be prepared for additional recommendation changes and tightening of restrictions.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

References

1. Centers for Disease Control and Prevention. Interim Public Health Recommendations for Fully Vaccinated People. U.S. Department of Health & Human Services, May 13, 2021.

2. Centers for Disease Control and Prevention. Updated Healthcare Infection Prevention and Control Recommendations in Response to COVID-19 Vaccination. U.S. Department of Health and Human Services, April 27, 2021.

Have you ever had a nightmare you’re running late? Recently I dreamt I was seeing patients on a ship, a little cruiser like the ones that give you tours of Boston Harbor, with low ceilings and narrow iron stairs. My nurse stood where what would have been the coffee and danish window. My first patient was a newborn (this was a nightmare, in case you forgot) who was enormous. She had a big belly and spindly legs that hung off the table. Uniform, umbilicated papules and pustules covered her body. At the sight of her, terror ripped through me – no clue. I rushed to the doctor lounge (nice the ship had one) and flipped channels on a little TV mounted on the ceiling. Suddenly, my nurse burst in, she was frantic because dozens of angry adults and crying children were crammed in the hallway. Apparently, I had been watching TV for hours and my whole clinic was now backed up.

Running-late dreams are common and usually relate to real life. For us, the clinic has been busy lately. Vaccinated patients are returning after a year with their skin cancers that have flourished and psoriasis covering them like kudzu. Staying on time has been difficult. Yet, despite the challenge, some of my colleagues manage easily. Why are they always on time? I talked to a few to get insight. In particular, they “see the floor” better than other docs and therefore make continual adjustments to stay on pace. At its essence, they are using super-powers of observation to make decisions. It reminded me of a podcast about court awareness and great passers in basketball like the Charlotte Hornets’ LaMelo Ball and NBA great, Bill Bradley.

Bradley had an extraordinary ability to know where all the players were, and where they would be, at any given moment. He spent years honing this skill, noticing details in store windows as he stared straight ahead walking down a street. It’s reported his peripheral vision extended 5%-15% wider than average and he used it to gather more information and to process it more quickly. As a result he made outstanding decisions and fast, ultimately earning a spot in the Hall of Fame in Springfield.

Hall of Fame clinicians similarly take in a wider view than others and process that information quickly. They know how much time they have spent in the room, sense the emotional needs of the patient and anticipate the complexity of the problem. They quickly get to the critical questions and examinations that will make the diagnosis. They know the experience and skill of their medical assistant. They know the level of difficulty and even the temperament of patients who lie ahead on the schedule. All this is processed and used in moment-to-moment decision making. Do I sit down or stand up now? Can I excise this today, or reschedule? Do I ask another question? Do I step out of this room and see another in parallel while this biopsy is set up? And always, do I dare ask about grandkids or do I politely move on?

By broadening out their vision, they optimize their clinic, providing the best possible service, whether the day is busy or slow. I found their economy of motion also means they are less exhausted at the end of the day. I bet if when they dream of being on a ship, they’re sipping a Mai Tai, lounging on the deck.

For more on Bill Bradley and becoming more observant about your surroundings, you might appreciate the following:

www.newyorker.com/magazine/1965/01/23/a-sense-of-where-you-are and freakonomics.com/podcast/nsq-mindfulness/

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

Have you ever had a nightmare you’re running late? Recently I dreamt I was seeing patients on a ship, a little cruiser like the ones that give you tours of Boston Harbor, with low ceilings and narrow iron stairs. My nurse stood where what would have been the coffee and danish window. My first patient was a newborn (this was a nightmare, in case you forgot) who was enormous. She had a big belly and spindly legs that hung off the table. Uniform, umbilicated papules and pustules covered her body. At the sight of her, terror ripped through me – no clue. I rushed to the doctor lounge (nice the ship had one) and flipped channels on a little TV mounted on the ceiling. Suddenly, my nurse burst in, she was frantic because dozens of angry adults and crying children were crammed in the hallway. Apparently, I had been watching TV for hours and my whole clinic was now backed up.

Running-late dreams are common and usually relate to real life. For us, the clinic has been busy lately. Vaccinated patients are returning after a year with their skin cancers that have flourished and psoriasis covering them like kudzu. Staying on time has been difficult. Yet, despite the challenge, some of my colleagues manage easily. Why are they always on time? I talked to a few to get insight. In particular, they “see the floor” better than other docs and therefore make continual adjustments to stay on pace. At its essence, they are using super-powers of observation to make decisions. It reminded me of a podcast about court awareness and great passers in basketball like the Charlotte Hornets’ LaMelo Ball and NBA great, Bill Bradley.

Bradley had an extraordinary ability to know where all the players were, and where they would be, at any given moment. He spent years honing this skill, noticing details in store windows as he stared straight ahead walking down a street. It’s reported his peripheral vision extended 5%-15% wider than average and he used it to gather more information and to process it more quickly. As a result he made outstanding decisions and fast, ultimately earning a spot in the Hall of Fame in Springfield.

Hall of Fame clinicians similarly take in a wider view than others and process that information quickly. They know how much time they have spent in the room, sense the emotional needs of the patient and anticipate the complexity of the problem. They quickly get to the critical questions and examinations that will make the diagnosis. They know the experience and skill of their medical assistant. They know the level of difficulty and even the temperament of patients who lie ahead on the schedule. All this is processed and used in moment-to-moment decision making. Do I sit down or stand up now? Can I excise this today, or reschedule? Do I ask another question? Do I step out of this room and see another in parallel while this biopsy is set up? And always, do I dare ask about grandkids or do I politely move on?

By broadening out their vision, they optimize their clinic, providing the best possible service, whether the day is busy or slow. I found their economy of motion also means they are less exhausted at the end of the day. I bet if when they dream of being on a ship, they’re sipping a Mai Tai, lounging on the deck.

For more on Bill Bradley and becoming more observant about your surroundings, you might appreciate the following:

www.newyorker.com/magazine/1965/01/23/a-sense-of-where-you-are and freakonomics.com/podcast/nsq-mindfulness/

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

Have you ever had a nightmare you’re running late? Recently I dreamt I was seeing patients on a ship, a little cruiser like the ones that give you tours of Boston Harbor, with low ceilings and narrow iron stairs. My nurse stood where what would have been the coffee and danish window. My first patient was a newborn (this was a nightmare, in case you forgot) who was enormous. She had a big belly and spindly legs that hung off the table. Uniform, umbilicated papules and pustules covered her body. At the sight of her, terror ripped through me – no clue. I rushed to the doctor lounge (nice the ship had one) and flipped channels on a little TV mounted on the ceiling. Suddenly, my nurse burst in, she was frantic because dozens of angry adults and crying children were crammed in the hallway. Apparently, I had been watching TV for hours and my whole clinic was now backed up.

Running-late dreams are common and usually relate to real life. For us, the clinic has been busy lately. Vaccinated patients are returning after a year with their skin cancers that have flourished and psoriasis covering them like kudzu. Staying on time has been difficult. Yet, despite the challenge, some of my colleagues manage easily. Why are they always on time? I talked to a few to get insight. In particular, they “see the floor” better than other docs and therefore make continual adjustments to stay on pace. At its essence, they are using super-powers of observation to make decisions. It reminded me of a podcast about court awareness and great passers in basketball like the Charlotte Hornets’ LaMelo Ball and NBA great, Bill Bradley.

Bradley had an extraordinary ability to know where all the players were, and where they would be, at any given moment. He spent years honing this skill, noticing details in store windows as he stared straight ahead walking down a street. It’s reported his peripheral vision extended 5%-15% wider than average and he used it to gather more information and to process it more quickly. As a result he made outstanding decisions and fast, ultimately earning a spot in the Hall of Fame in Springfield.

Hall of Fame clinicians similarly take in a wider view than others and process that information quickly. They know how much time they have spent in the room, sense the emotional needs of the patient and anticipate the complexity of the problem. They quickly get to the critical questions and examinations that will make the diagnosis. They know the experience and skill of their medical assistant. They know the level of difficulty and even the temperament of patients who lie ahead on the schedule. All this is processed and used in moment-to-moment decision making. Do I sit down or stand up now? Can I excise this today, or reschedule? Do I ask another question? Do I step out of this room and see another in parallel while this biopsy is set up? And always, do I dare ask about grandkids or do I politely move on?

By broadening out their vision, they optimize their clinic, providing the best possible service, whether the day is busy or slow. I found their economy of motion also means they are less exhausted at the end of the day. I bet if when they dream of being on a ship, they’re sipping a Mai Tai, lounging on the deck.

For more on Bill Bradley and becoming more observant about your surroundings, you might appreciate the following:

www.newyorker.com/magazine/1965/01/23/a-sense-of-where-you-are and freakonomics.com/podcast/nsq-mindfulness/

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

“Vaccines have been the bright light of this extraordinary challenge that we’ve gone through,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases.

In an address for the opening ceremony of the American Thoracic Society’s virtual international conference, Dr. Fauci emphasized the role of basic and clinical research and government support for science in helping turn the tide of the COVID-19 pandemic.

“A few weeks ago, I wrote an editorial in Science, because there was some misunderstanding about how and why we were able to go from a realization of a new pathogen in January of 2020, to getting doses of vaccines in the arms of individuals – a highly efficacious vaccine – 11 months later. Truly, an unprecedented accomplishment,” he said.

“But as I said in the editorial, the speed and efficiency with which these highly efficacious vaccines were developed, and their potential for saving millions of lives, are due to an extraordinary multidisciplinary effort, involving basic, preclinical, and clinical science that had been underway – out of the spotlight – for decades and decades before the unfolding of the COVID-19 pandemic, a fact that very few people really appreciate: namely, the importance of investment in biomedical research.”
 

The general addresses the troops

Perhaps no other audience is so well suited to receive Dr. Fauci’s speech as those who are currently attending (virtually) the ATS conference, including researchers who scrutinize the virus from every angle to describe its workings and identify its vulnerabilities, epidemiologists who study viral transmission and look for ways to thwart it, public health workers who fan out to communities across the country to push vaccine acceptance, and clinicians who specialize in critical care and pulmonary medicine, many of whom staff the respiratory floors and intensive care units where the most severely ill patients are treated.

Speaking about the lessons learned and challenges remaining from the COVID-19 pandemic, Dr. Fauci briefly reviewed the epidemiology, virology and transmission, diagnostics, and clinical course of SARS-CoV-2 infections and the therapeutics and vaccines for COVID-19.
 

Epidemiology

The pandemic began in December 2019 with recognition of a novel type of pneumonia in the Wuhan District of Central China, Dr. Fauci noted.

“Very quickly thereafter, in the first week of January 2020, the Chinese identified a new strain of coronavirus as [the] source of the outbreak. Fast forward to where we are right now: We have experienced and are experiencing the most devastating pandemic of a respiratory illness in the last 102 years, with already approximately 160 million individuals having been infected – and this is clearly a gross undercounting – and also 3.3 million deaths, again, very likely an undercounting,” he said.

According to the Centers for Disease Control and Prevention, as of May 9, 2021, there were approximately 32.5 million cases of COVID-19 and 578,520 deaths in the United States. Those cases and deaths occurred largely in three surges in the United States, in early spring, early summer, and late fall of 2020.
 

Virology and transmission

SARS-CoV-2 is a beta-coronavirus in the same subgenus as SARS-CoV-1 and some bat coronaviruses, Dr. Fauci explained. The viral genome is large, about 30,000 kilobases, and it has four structural proteins, most importantly the S or “spike” protein that allows the virus to attach to and fuse with cell membranes by binding to the ACE2 receptor on tissues in the upper and lower respiratory tract, gastrointestinal tract, cardiovascular system, and other organ systems.

The virus is transmitted mainly through exposure to respiratory droplets within 6 feet of an infected person, or sometimes through droplets or particles that remain in the air over time and various distances.

Contact with contaminated surfaces, once feared as a means of transmission, is now understood to be less common.

The virus has been detected in stool, blood, semen, and ocular secretions, although the role of transmission through these sources is still unknown.

“Some very interesting characteristics of this virus, really quite unique compared to other viruses, certainly other respiratory viruses, is [that] about a third to 40% of people who are infected never develop any symptoms,” Dr. Fauci said. “Importantly, and very problematic to what we do to contain it – particularly with regard to identification, isolation, and contract tracing – between 50% and 60% of the transmissions occur either from someone who will never develop symptoms, or someone in the presymptomatic phase of disease.”

The fundamentals of preventing acquisition and transmission are as familiar to most Americans now as the Pledge of Allegiance: universal mask wearing, physical distancing, avoiding crowds and congregate settings, preference for outdoor over indoor settings, and frequent hand washing, he noted.
 

Diagnostics

Tests for SARS-CoV-2 infection fall into three basic categories: molecular tests such as polymerase chain reaction (PCR) that are highly specific and highly sensitive for actual infections, antigen tests that detect the viral protein rather than the nucleic acids, and antibody tests to detect serum proteins made in response to viral infection.

Antigen testing is used largely for broader surveillance of groups of individuals to detect viral penetrance within that group, Dr. Fauci noted.
 

Clinical course

The clinical course of COVID-19 has some interesting characteristics but is not substantially different from a flu-like syndrome, Dr. Fauci said.

Symptoms and signs common to both types of infections include fever, cough, fatigue, anorexia, dyspnea, and myalgias, but the loss of smell and/or taste preceding the onset of respiratory symptoms is a unique feature of COVID-19.

Dr. Fauci cited data on more than 44,000 individuals with confirmed COVID-19 in China that showed that a large majority (81%) of cases were mild or moderate in nature, but 14% of patients experienced severe disease, and 5% were critically ill. The case-fatality rate in this study was 2.3%.

People at increased risk for severe disease include older adults and those of any age with certain comorbidities.

Manifestations of severe COVID-19 infections in adults can include neurological disorders, hyperinflammation, acute respiratory distress syndrome, cardiac dysfunction, hypercoagulability, and acute kidney injury.

In children, COVID-19 has been associated with a multisystem inflammatory syndrome (MIS-C) similar to Kawasaki disease.

In a substantial number of cases, the effects of COVID-19 can linger for 6 months or longer, Dr. Fauci said, pointing to a study from the University of Washington in Seattle.

Investigators there found that approximately 30% of patients enrolled at their center reported persistent symptoms for as long as 9 months after the initial illness, with fatigue as the most commonly reported symptom. One-third of outpatients with mild disease also reported persistent symptoms.
 

Therapeutics

Therapeutics that are either approved by the Food and Drug Administration, have emergency use authorization, or are in clinical trials for early or moderate disease include remdesivir (Veklury, Gilead Sciences), monoclonal antibodies, convalescent plasma, antiviral agents, hyperimmune globulin, anticoagulants, and immunomodulators.

Options for moderate to severe to advanced disease include dexamethasone, baricitinib (Olumiant, Eli Lilly and Company) plus remdesivir, and immunomodulators such as infliximab (Remicade, Janssen Biotech), and biosimilars.
 

Vaccines

Finally, Dr. Fauci reviewed the current state of vaccines, including the three with emergency use authorization from the FDA as of this writing: two nucleic acid, messenger RNA-based (mRNA) vaccines from Moderna and Pfizer/BioNTech, and an adenoviral vector-based vaccine from Johnson & Johnson.

Other vaccines in development or in use elsewhere in the world include recombinant protein and adjuvant approaches by GlaxoSmithKline and Sanofi (in a phase 2 clinical trial launched in February 2021) and by Novavax.

The three vaccines in use in the United States were highly efficacious in both clinical trials, with efficacy of about 95% for the mRNA vaccines and 67% for the Johnson & Johnson vaccine.

The real-world performance of these vaccines has been even more impressive, however.

For example, the Johnson & Johnson vaccine had 72% efficacy at preventing moderate to severe COVID 19 in the United States, 68% in Brazil, and 64% in South Africa, and 85% efficacy against severe disease across all regions studied, Dr. Fauci said.

He cited a study of 22,234 employees of the University of Texas Southwestern Medical Center in Dallas who were vaccinated under a program started on Dec. 15, 2020. The COVID-19 infection rate among these vaccinated employees was 0.05%.

Dr. Fauci recounted the experience in Israel, where the highly transmissible B.1.1.7 strain of SARS-CoV-2 is predominant. A chart of the progress shows clearly that as the vaccine doses delivered steadily increased, the number of COVID-19 cases began a precipitous decline.
 

Horse race

Fittingly for a speech presented on the day that the Preakness Stakes – the second leg in thoroughbred racing’s Triple Crown – was run, Dr. Fauci closed with a cartoon showing two racehorses, labeled “SARS-CoV-2” and “Vaccines,” nearly neck-and-neck, but with vaccines having a slight lead.

“We are in a race against the virus. The vaccines, and the virus: If we vaccinate the overwhelming proportion of our population, we will without a doubt be able to crush the outbreak in the same way as we have done with other viral-borne diseases like measles, smallpox, and polio.

“So, the message is: Get vaccinated,” he concluded.
 

“Vaccines have been the bright light of this extraordinary challenge that we’ve gone through,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases.

In an address for the opening ceremony of the American Thoracic Society’s virtual international conference, Dr. Fauci emphasized the role of basic and clinical research and government support for science in helping turn the tide of the COVID-19 pandemic.

“A few weeks ago, I wrote an editorial in Science, because there was some misunderstanding about how and why we were able to go from a realization of a new pathogen in January of 2020, to getting doses of vaccines in the arms of individuals – a highly efficacious vaccine – 11 months later. Truly, an unprecedented accomplishment,” he said.

“But as I said in the editorial, the speed and efficiency with which these highly efficacious vaccines were developed, and their potential for saving millions of lives, are due to an extraordinary multidisciplinary effort, involving basic, preclinical, and clinical science that had been underway – out of the spotlight – for decades and decades before the unfolding of the COVID-19 pandemic, a fact that very few people really appreciate: namely, the importance of investment in biomedical research.”
 

The general addresses the troops

Perhaps no other audience is so well suited to receive Dr. Fauci’s speech as those who are currently attending (virtually) the ATS conference, including researchers who scrutinize the virus from every angle to describe its workings and identify its vulnerabilities, epidemiologists who study viral transmission and look for ways to thwart it, public health workers who fan out to communities across the country to push vaccine acceptance, and clinicians who specialize in critical care and pulmonary medicine, many of whom staff the respiratory floors and intensive care units where the most severely ill patients are treated.

Speaking about the lessons learned and challenges remaining from the COVID-19 pandemic, Dr. Fauci briefly reviewed the epidemiology, virology and transmission, diagnostics, and clinical course of SARS-CoV-2 infections and the therapeutics and vaccines for COVID-19.
 

Epidemiology

The pandemic began in December 2019 with recognition of a novel type of pneumonia in the Wuhan District of Central China, Dr. Fauci noted.

“Very quickly thereafter, in the first week of January 2020, the Chinese identified a new strain of coronavirus as [the] source of the outbreak. Fast forward to where we are right now: We have experienced and are experiencing the most devastating pandemic of a respiratory illness in the last 102 years, with already approximately 160 million individuals having been infected – and this is clearly a gross undercounting – and also 3.3 million deaths, again, very likely an undercounting,” he said.

According to the Centers for Disease Control and Prevention, as of May 9, 2021, there were approximately 32.5 million cases of COVID-19 and 578,520 deaths in the United States. Those cases and deaths occurred largely in three surges in the United States, in early spring, early summer, and late fall of 2020.
 

Virology and transmission

SARS-CoV-2 is a beta-coronavirus in the same subgenus as SARS-CoV-1 and some bat coronaviruses, Dr. Fauci explained. The viral genome is large, about 30,000 kilobases, and it has four structural proteins, most importantly the S or “spike” protein that allows the virus to attach to and fuse with cell membranes by binding to the ACE2 receptor on tissues in the upper and lower respiratory tract, gastrointestinal tract, cardiovascular system, and other organ systems.

The virus is transmitted mainly through exposure to respiratory droplets within 6 feet of an infected person, or sometimes through droplets or particles that remain in the air over time and various distances.

Contact with contaminated surfaces, once feared as a means of transmission, is now understood to be less common.

The virus has been detected in stool, blood, semen, and ocular secretions, although the role of transmission through these sources is still unknown.

“Some very interesting characteristics of this virus, really quite unique compared to other viruses, certainly other respiratory viruses, is [that] about a third to 40% of people who are infected never develop any symptoms,” Dr. Fauci said. “Importantly, and very problematic to what we do to contain it – particularly with regard to identification, isolation, and contract tracing – between 50% and 60% of the transmissions occur either from someone who will never develop symptoms, or someone in the presymptomatic phase of disease.”

The fundamentals of preventing acquisition and transmission are as familiar to most Americans now as the Pledge of Allegiance: universal mask wearing, physical distancing, avoiding crowds and congregate settings, preference for outdoor over indoor settings, and frequent hand washing, he noted.
 

Diagnostics

Tests for SARS-CoV-2 infection fall into three basic categories: molecular tests such as polymerase chain reaction (PCR) that are highly specific and highly sensitive for actual infections, antigen tests that detect the viral protein rather than the nucleic acids, and antibody tests to detect serum proteins made in response to viral infection.

Antigen testing is used largely for broader surveillance of groups of individuals to detect viral penetrance within that group, Dr. Fauci noted.
 

Clinical course

The clinical course of COVID-19 has some interesting characteristics but is not substantially different from a flu-like syndrome, Dr. Fauci said.

Symptoms and signs common to both types of infections include fever, cough, fatigue, anorexia, dyspnea, and myalgias, but the loss of smell and/or taste preceding the onset of respiratory symptoms is a unique feature of COVID-19.

Dr. Fauci cited data on more than 44,000 individuals with confirmed COVID-19 in China that showed that a large majority (81%) of cases were mild or moderate in nature, but 14% of patients experienced severe disease, and 5% were critically ill. The case-fatality rate in this study was 2.3%.

People at increased risk for severe disease include older adults and those of any age with certain comorbidities.

Manifestations of severe COVID-19 infections in adults can include neurological disorders, hyperinflammation, acute respiratory distress syndrome, cardiac dysfunction, hypercoagulability, and acute kidney injury.

In children, COVID-19 has been associated with a multisystem inflammatory syndrome (MIS-C) similar to Kawasaki disease.

In a substantial number of cases, the effects of COVID-19 can linger for 6 months or longer, Dr. Fauci said, pointing to a study from the University of Washington in Seattle.

Investigators there found that approximately 30% of patients enrolled at their center reported persistent symptoms for as long as 9 months after the initial illness, with fatigue as the most commonly reported symptom. One-third of outpatients with mild disease also reported persistent symptoms.
 

Therapeutics

Therapeutics that are either approved by the Food and Drug Administration, have emergency use authorization, or are in clinical trials for early or moderate disease include remdesivir (Veklury, Gilead Sciences), monoclonal antibodies, convalescent plasma, antiviral agents, hyperimmune globulin, anticoagulants, and immunomodulators.

Options for moderate to severe to advanced disease include dexamethasone, baricitinib (Olumiant, Eli Lilly and Company) plus remdesivir, and immunomodulators such as infliximab (Remicade, Janssen Biotech), and biosimilars.
 

Vaccines

Finally, Dr. Fauci reviewed the current state of vaccines, including the three with emergency use authorization from the FDA as of this writing: two nucleic acid, messenger RNA-based (mRNA) vaccines from Moderna and Pfizer/BioNTech, and an adenoviral vector-based vaccine from Johnson & Johnson.

Other vaccines in development or in use elsewhere in the world include recombinant protein and adjuvant approaches by GlaxoSmithKline and Sanofi (in a phase 2 clinical trial launched in February 2021) and by Novavax.

The three vaccines in use in the United States were highly efficacious in both clinical trials, with efficacy of about 95% for the mRNA vaccines and 67% for the Johnson & Johnson vaccine.

The real-world performance of these vaccines has been even more impressive, however.

For example, the Johnson & Johnson vaccine had 72% efficacy at preventing moderate to severe COVID 19 in the United States, 68% in Brazil, and 64% in South Africa, and 85% efficacy against severe disease across all regions studied, Dr. Fauci said.

He cited a study of 22,234 employees of the University of Texas Southwestern Medical Center in Dallas who were vaccinated under a program started on Dec. 15, 2020. The COVID-19 infection rate among these vaccinated employees was 0.05%.

Dr. Fauci recounted the experience in Israel, where the highly transmissible B.1.1.7 strain of SARS-CoV-2 is predominant. A chart of the progress shows clearly that as the vaccine doses delivered steadily increased, the number of COVID-19 cases began a precipitous decline.
 

Horse race

Fittingly for a speech presented on the day that the Preakness Stakes – the second leg in thoroughbred racing’s Triple Crown – was run, Dr. Fauci closed with a cartoon showing two racehorses, labeled “SARS-CoV-2” and “Vaccines,” nearly neck-and-neck, but with vaccines having a slight lead.

“We are in a race against the virus. The vaccines, and the virus: If we vaccinate the overwhelming proportion of our population, we will without a doubt be able to crush the outbreak in the same way as we have done with other viral-borne diseases like measles, smallpox, and polio.

“So, the message is: Get vaccinated,” he concluded.
 

“Vaccines have been the bright light of this extraordinary challenge that we’ve gone through,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases.

In an address for the opening ceremony of the American Thoracic Society’s virtual international conference, Dr. Fauci emphasized the role of basic and clinical research and government support for science in helping turn the tide of the COVID-19 pandemic.

“A few weeks ago, I wrote an editorial in Science, because there was some misunderstanding about how and why we were able to go from a realization of a new pathogen in January of 2020, to getting doses of vaccines in the arms of individuals – a highly efficacious vaccine – 11 months later. Truly, an unprecedented accomplishment,” he said.

“But as I said in the editorial, the speed and efficiency with which these highly efficacious vaccines were developed, and their potential for saving millions of lives, are due to an extraordinary multidisciplinary effort, involving basic, preclinical, and clinical science that had been underway – out of the spotlight – for decades and decades before the unfolding of the COVID-19 pandemic, a fact that very few people really appreciate: namely, the importance of investment in biomedical research.”
 

The general addresses the troops

Perhaps no other audience is so well suited to receive Dr. Fauci’s speech as those who are currently attending (virtually) the ATS conference, including researchers who scrutinize the virus from every angle to describe its workings and identify its vulnerabilities, epidemiologists who study viral transmission and look for ways to thwart it, public health workers who fan out to communities across the country to push vaccine acceptance, and clinicians who specialize in critical care and pulmonary medicine, many of whom staff the respiratory floors and intensive care units where the most severely ill patients are treated.

Speaking about the lessons learned and challenges remaining from the COVID-19 pandemic, Dr. Fauci briefly reviewed the epidemiology, virology and transmission, diagnostics, and clinical course of SARS-CoV-2 infections and the therapeutics and vaccines for COVID-19.
 

Epidemiology

The pandemic began in December 2019 with recognition of a novel type of pneumonia in the Wuhan District of Central China, Dr. Fauci noted.

“Very quickly thereafter, in the first week of January 2020, the Chinese identified a new strain of coronavirus as [the] source of the outbreak. Fast forward to where we are right now: We have experienced and are experiencing the most devastating pandemic of a respiratory illness in the last 102 years, with already approximately 160 million individuals having been infected – and this is clearly a gross undercounting – and also 3.3 million deaths, again, very likely an undercounting,” he said.

According to the Centers for Disease Control and Prevention, as of May 9, 2021, there were approximately 32.5 million cases of COVID-19 and 578,520 deaths in the United States. Those cases and deaths occurred largely in three surges in the United States, in early spring, early summer, and late fall of 2020.
 

Virology and transmission

SARS-CoV-2 is a beta-coronavirus in the same subgenus as SARS-CoV-1 and some bat coronaviruses, Dr. Fauci explained. The viral genome is large, about 30,000 kilobases, and it has four structural proteins, most importantly the S or “spike” protein that allows the virus to attach to and fuse with cell membranes by binding to the ACE2 receptor on tissues in the upper and lower respiratory tract, gastrointestinal tract, cardiovascular system, and other organ systems.

The virus is transmitted mainly through exposure to respiratory droplets within 6 feet of an infected person, or sometimes through droplets or particles that remain in the air over time and various distances.

Contact with contaminated surfaces, once feared as a means of transmission, is now understood to be less common.

The virus has been detected in stool, blood, semen, and ocular secretions, although the role of transmission through these sources is still unknown.

“Some very interesting characteristics of this virus, really quite unique compared to other viruses, certainly other respiratory viruses, is [that] about a third to 40% of people who are infected never develop any symptoms,” Dr. Fauci said. “Importantly, and very problematic to what we do to contain it – particularly with regard to identification, isolation, and contract tracing – between 50% and 60% of the transmissions occur either from someone who will never develop symptoms, or someone in the presymptomatic phase of disease.”

The fundamentals of preventing acquisition and transmission are as familiar to most Americans now as the Pledge of Allegiance: universal mask wearing, physical distancing, avoiding crowds and congregate settings, preference for outdoor over indoor settings, and frequent hand washing, he noted.
 

Diagnostics

Tests for SARS-CoV-2 infection fall into three basic categories: molecular tests such as polymerase chain reaction (PCR) that are highly specific and highly sensitive for actual infections, antigen tests that detect the viral protein rather than the nucleic acids, and antibody tests to detect serum proteins made in response to viral infection.

Antigen testing is used largely for broader surveillance of groups of individuals to detect viral penetrance within that group, Dr. Fauci noted.
 

Clinical course

The clinical course of COVID-19 has some interesting characteristics but is not substantially different from a flu-like syndrome, Dr. Fauci said.

Symptoms and signs common to both types of infections include fever, cough, fatigue, anorexia, dyspnea, and myalgias, but the loss of smell and/or taste preceding the onset of respiratory symptoms is a unique feature of COVID-19.

Dr. Fauci cited data on more than 44,000 individuals with confirmed COVID-19 in China that showed that a large majority (81%) of cases were mild or moderate in nature, but 14% of patients experienced severe disease, and 5% were critically ill. The case-fatality rate in this study was 2.3%.

People at increased risk for severe disease include older adults and those of any age with certain comorbidities.

Manifestations of severe COVID-19 infections in adults can include neurological disorders, hyperinflammation, acute respiratory distress syndrome, cardiac dysfunction, hypercoagulability, and acute kidney injury.

In children, COVID-19 has been associated with a multisystem inflammatory syndrome (MIS-C) similar to Kawasaki disease.

In a substantial number of cases, the effects of COVID-19 can linger for 6 months or longer, Dr. Fauci said, pointing to a study from the University of Washington in Seattle.

Investigators there found that approximately 30% of patients enrolled at their center reported persistent symptoms for as long as 9 months after the initial illness, with fatigue as the most commonly reported symptom. One-third of outpatients with mild disease also reported persistent symptoms.
 

Therapeutics

Therapeutics that are either approved by the Food and Drug Administration, have emergency use authorization, or are in clinical trials for early or moderate disease include remdesivir (Veklury, Gilead Sciences), monoclonal antibodies, convalescent plasma, antiviral agents, hyperimmune globulin, anticoagulants, and immunomodulators.

Options for moderate to severe to advanced disease include dexamethasone, baricitinib (Olumiant, Eli Lilly and Company) plus remdesivir, and immunomodulators such as infliximab (Remicade, Janssen Biotech), and biosimilars.
 

Vaccines

Finally, Dr. Fauci reviewed the current state of vaccines, including the three with emergency use authorization from the FDA as of this writing: two nucleic acid, messenger RNA-based (mRNA) vaccines from Moderna and Pfizer/BioNTech, and an adenoviral vector-based vaccine from Johnson & Johnson.

Other vaccines in development or in use elsewhere in the world include recombinant protein and adjuvant approaches by GlaxoSmithKline and Sanofi (in a phase 2 clinical trial launched in February 2021) and by Novavax.

The three vaccines in use in the United States were highly efficacious in both clinical trials, with efficacy of about 95% for the mRNA vaccines and 67% for the Johnson & Johnson vaccine.

The real-world performance of these vaccines has been even more impressive, however.

For example, the Johnson & Johnson vaccine had 72% efficacy at preventing moderate to severe COVID 19 in the United States, 68% in Brazil, and 64% in South Africa, and 85% efficacy against severe disease across all regions studied, Dr. Fauci said.

He cited a study of 22,234 employees of the University of Texas Southwestern Medical Center in Dallas who were vaccinated under a program started on Dec. 15, 2020. The COVID-19 infection rate among these vaccinated employees was 0.05%.

Dr. Fauci recounted the experience in Israel, where the highly transmissible B.1.1.7 strain of SARS-CoV-2 is predominant. A chart of the progress shows clearly that as the vaccine doses delivered steadily increased, the number of COVID-19 cases began a precipitous decline.
 

Horse race

Fittingly for a speech presented on the day that the Preakness Stakes – the second leg in thoroughbred racing’s Triple Crown – was run, Dr. Fauci closed with a cartoon showing two racehorses, labeled “SARS-CoV-2” and “Vaccines,” nearly neck-and-neck, but with vaccines having a slight lead.

“We are in a race against the virus. The vaccines, and the virus: If we vaccinate the overwhelming proportion of our population, we will without a doubt be able to crush the outbreak in the same way as we have done with other viral-borne diseases like measles, smallpox, and polio.

“So, the message is: Get vaccinated,” he concluded.
 

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

mzoler@mdedge.com

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

mzoler@mdedge.com

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

mzoler@mdedge.com

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Renal denervation’s comeback as a potential treatment for patients with drug-resistant hypertension rolls on.

Renal denervation with ultrasound energy produced a significant, median 4.5–mm Hg incremental drop in daytime, ambulatory, systolic blood pressure, compared with sham-treatment after 2 months follow-up in a randomized study of 136 patients with drug-resistant hypertension maintained on a standardized, single-pill, triple-drug regimen during the study.

Courtesy American College of Cardiology

The results “confirm that ultrasound renal denervation can lower blood pressure across a spectrum of hypertension,” concluded Ajay J. Kirtane, MD, at the annual scientific sessions of the American College of Cardiology. Renal denervation procedures involve percutaneously placing an endovascular catheter bilaterally inside a patient’s renal arteries and using brief pulses of energy to ablate neurons involved in blood pressure regulation.

A former ‘hot concept’

“Renal denervation was a hot concept a number of years ago, but had been tested only in studies without a sham control,” and initial testing using sham controls failed to show a significant benefit from the intervention, noted Deepak L. Bhatt, MD, an interventional cardiologist and professor of medicine at Harvard Medical School in Boston who was not involved with the study. The significant reductions in systolic blood pressure reported with renal denervation, compared with control patients in this study, “are believable” because of inclusion of a true control cohort, he added. “This really exciting finding puts renal denervation squarely back on the map,” commented Dr. Bhatt during a press briefing.

Dr. Bhatt added that, while the median 4.5–mm Hg incremental reduction in daytime, ambulatory, systolic blood pressure, compared with control patients – the study’s primary endpoint – may seem modest, “in the world of hypertension it’s a meaningful reduction” that, if sustained over the long term, would be expected to produce meaningful cuts in adverse cardiovascular events such as heart failure, stroke, and MI.

“The question is whether the effects are durable,” highlighted Dr. Bhatt, who helped lead the first sham-controlled trial of renal denervation, SYMPLICITY HTN-3, which failed to show a significant blood pressure reduction, compared with controls using radiofrequency energy to ablate renal nerves. A more recent study that used a different radiofrequency catheter and sham controls showed a significant effect on reducing systolic blood pressure in the SPYRAL HTN-OFF MED Pivotal trial, which by design did not maintain patients on any antihypertensive medications following their renal denervation procedure.

Dr. Kirtane noted that, although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure.

Concurrently with his report the results also appeared in an article posted online (Lancet. 2021 May 16;doi: 10.1016/S0140-6736(21)00788-1).

Denervation coupled with a single, daily three-drug pill

The RADIANCE-HTN TRIO study ran at 53 centers in the United States and Europe, and randomized 136 adults with an office-measured blood pressure of at least 140/90 mm Hg despite being on a stable regimen of at least three antihypertensive drugs including a diuretic. The enrolled cohort averaged 52 years of age and had an average office-measured pressure of about 162/104 mm Hg despite being on an average of four agents, although only about a third of enrolled patients were on treatment with a mineralocorticoid-receptor antagonist (MRA) such as spironolactone.

At the time of enrollment and 4 weeks before their denervation procedure, all patients switched to a uniform drug regimen of a single, daily, oral pill containing the calcium channel blocker amlodipine, the angiotensin receptor blocker valsartan or olmesartan, and the diuretic hydrochlorothiazide with no other drug treatment allowed except for unusual, prespecified clinical circumstances. All patients remained on this drug regimen for the initial 2-month follow-up period unless their blood pressure exceeded 180/110 mm Hg during in-office measurement.

The denervation treatment was well tolerated, although patients reported brief, transient, and “minor” pain associated with the procedure that did not affect treatment blinding or have any lingering consequences, said Dr. Kirtane, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York.

A reason to use energy delivery by ultrasound rather than by radiofrequency to ablate nerves in the renal arteries is that the ultrasound approach exerts a more uniform effect, allowing effective treatment delivery without need for catheter repositioning into more distal branches of the renal arteries, said Dr. Kirtane, who is also an interventional cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

But each method has its advantages, he added.

He also conceded that additional questions need to be addressed regarding which patients are most appropriate for renal denervation. “We need to figure out in which patients we can apply a device-based treatment,” Dr. Kirtane said during the press briefing. Patients with what appears to be drug-resistant hypertension often do not receive treatment with a MRA because of adverse effects, and many of these patients are not usually assessed for primary aldosteronism.

In SYMPLICITY HTN-3, “about half the patients who were seemingly eligible became ineligible” when they started treatment with a MRA, noted Dr. Bhatt. “A little spironolactone can go a long way” toward resolving treatment-resistant hypertension in many patients, he said.

RADIANCE-HTN TRIO was sponsored by ReCor Medical, the company developing the tested ultrasound catheter. Dr. Kirtane has received travel expenses and meals from ReCor Medical and several other companies, and Columbia has received research funding from ReCor Medical and several other companies related to research he has conducted. Dr. Bhatt has no relationship with ReCor Medical. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an advisor to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies.

mzoler@mdedge.com

Renal denervation’s comeback as a potential treatment for patients with drug-resistant hypertension rolls on.

Renal denervation with ultrasound energy produced a significant, median 4.5–mm Hg incremental drop in daytime, ambulatory, systolic blood pressure, compared with sham-treatment after 2 months follow-up in a randomized study of 136 patients with drug-resistant hypertension maintained on a standardized, single-pill, triple-drug regimen during the study.

Courtesy American College of Cardiology

The results “confirm that ultrasound renal denervation can lower blood pressure across a spectrum of hypertension,” concluded Ajay J. Kirtane, MD, at the annual scientific sessions of the American College of Cardiology. Renal denervation procedures involve percutaneously placing an endovascular catheter bilaterally inside a patient’s renal arteries and using brief pulses of energy to ablate neurons involved in blood pressure regulation.

A former ‘hot concept’

“Renal denervation was a hot concept a number of years ago, but had been tested only in studies without a sham control,” and initial testing using sham controls failed to show a significant benefit from the intervention, noted Deepak L. Bhatt, MD, an interventional cardiologist and professor of medicine at Harvard Medical School in Boston who was not involved with the study. The significant reductions in systolic blood pressure reported with renal denervation, compared with control patients in this study, “are believable” because of inclusion of a true control cohort, he added. “This really exciting finding puts renal denervation squarely back on the map,” commented Dr. Bhatt during a press briefing.

Dr. Bhatt added that, while the median 4.5–mm Hg incremental reduction in daytime, ambulatory, systolic blood pressure, compared with control patients – the study’s primary endpoint – may seem modest, “in the world of hypertension it’s a meaningful reduction” that, if sustained over the long term, would be expected to produce meaningful cuts in adverse cardiovascular events such as heart failure, stroke, and MI.

“The question is whether the effects are durable,” highlighted Dr. Bhatt, who helped lead the first sham-controlled trial of renal denervation, SYMPLICITY HTN-3, which failed to show a significant blood pressure reduction, compared with controls using radiofrequency energy to ablate renal nerves. A more recent study that used a different radiofrequency catheter and sham controls showed a significant effect on reducing systolic blood pressure in the SPYRAL HTN-OFF MED Pivotal trial, which by design did not maintain patients on any antihypertensive medications following their renal denervation procedure.

Dr. Kirtane noted that, although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure.

Concurrently with his report the results also appeared in an article posted online (Lancet. 2021 May 16;doi: 10.1016/S0140-6736(21)00788-1).

Denervation coupled with a single, daily three-drug pill

The RADIANCE-HTN TRIO study ran at 53 centers in the United States and Europe, and randomized 136 adults with an office-measured blood pressure of at least 140/90 mm Hg despite being on a stable regimen of at least three antihypertensive drugs including a diuretic. The enrolled cohort averaged 52 years of age and had an average office-measured pressure of about 162/104 mm Hg despite being on an average of four agents, although only about a third of enrolled patients were on treatment with a mineralocorticoid-receptor antagonist (MRA) such as spironolactone.

At the time of enrollment and 4 weeks before their denervation procedure, all patients switched to a uniform drug regimen of a single, daily, oral pill containing the calcium channel blocker amlodipine, the angiotensin receptor blocker valsartan or olmesartan, and the diuretic hydrochlorothiazide with no other drug treatment allowed except for unusual, prespecified clinical circumstances. All patients remained on this drug regimen for the initial 2-month follow-up period unless their blood pressure exceeded 180/110 mm Hg during in-office measurement.

The denervation treatment was well tolerated, although patients reported brief, transient, and “minor” pain associated with the procedure that did not affect treatment blinding or have any lingering consequences, said Dr. Kirtane, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York.

A reason to use energy delivery by ultrasound rather than by radiofrequency to ablate nerves in the renal arteries is that the ultrasound approach exerts a more uniform effect, allowing effective treatment delivery without need for catheter repositioning into more distal branches of the renal arteries, said Dr. Kirtane, who is also an interventional cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

But each method has its advantages, he added.

He also conceded that additional questions need to be addressed regarding which patients are most appropriate for renal denervation. “We need to figure out in which patients we can apply a device-based treatment,” Dr. Kirtane said during the press briefing. Patients with what appears to be drug-resistant hypertension often do not receive treatment with a MRA because of adverse effects, and many of these patients are not usually assessed for primary aldosteronism.

In SYMPLICITY HTN-3, “about half the patients who were seemingly eligible became ineligible” when they started treatment with a MRA, noted Dr. Bhatt. “A little spironolactone can go a long way” toward resolving treatment-resistant hypertension in many patients, he said.

RADIANCE-HTN TRIO was sponsored by ReCor Medical, the company developing the tested ultrasound catheter. Dr. Kirtane has received travel expenses and meals from ReCor Medical and several other companies, and Columbia has received research funding from ReCor Medical and several other companies related to research he has conducted. Dr. Bhatt has no relationship with ReCor Medical. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an advisor to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies.

mzoler@mdedge.com

Renal denervation’s comeback as a potential treatment for patients with drug-resistant hypertension rolls on.

Renal denervation with ultrasound energy produced a significant, median 4.5–mm Hg incremental drop in daytime, ambulatory, systolic blood pressure, compared with sham-treatment after 2 months follow-up in a randomized study of 136 patients with drug-resistant hypertension maintained on a standardized, single-pill, triple-drug regimen during the study.

Courtesy American College of Cardiology

The results “confirm that ultrasound renal denervation can lower blood pressure across a spectrum of hypertension,” concluded Ajay J. Kirtane, MD, at the annual scientific sessions of the American College of Cardiology. Renal denervation procedures involve percutaneously placing an endovascular catheter bilaterally inside a patient’s renal arteries and using brief pulses of energy to ablate neurons involved in blood pressure regulation.

A former ‘hot concept’

“Renal denervation was a hot concept a number of years ago, but had been tested only in studies without a sham control,” and initial testing using sham controls failed to show a significant benefit from the intervention, noted Deepak L. Bhatt, MD, an interventional cardiologist and professor of medicine at Harvard Medical School in Boston who was not involved with the study. The significant reductions in systolic blood pressure reported with renal denervation, compared with control patients in this study, “are believable” because of inclusion of a true control cohort, he added. “This really exciting finding puts renal denervation squarely back on the map,” commented Dr. Bhatt during a press briefing.

Dr. Bhatt added that, while the median 4.5–mm Hg incremental reduction in daytime, ambulatory, systolic blood pressure, compared with control patients – the study’s primary endpoint – may seem modest, “in the world of hypertension it’s a meaningful reduction” that, if sustained over the long term, would be expected to produce meaningful cuts in adverse cardiovascular events such as heart failure, stroke, and MI.

“The question is whether the effects are durable,” highlighted Dr. Bhatt, who helped lead the first sham-controlled trial of renal denervation, SYMPLICITY HTN-3, which failed to show a significant blood pressure reduction, compared with controls using radiofrequency energy to ablate renal nerves. A more recent study that used a different radiofrequency catheter and sham controls showed a significant effect on reducing systolic blood pressure in the SPYRAL HTN-OFF MED Pivotal trial, which by design did not maintain patients on any antihypertensive medications following their renal denervation procedure.

Dr. Kirtane noted that, although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure.

Concurrently with his report the results also appeared in an article posted online (Lancet. 2021 May 16;doi: 10.1016/S0140-6736(21)00788-1).

Denervation coupled with a single, daily three-drug pill

The RADIANCE-HTN TRIO study ran at 53 centers in the United States and Europe, and randomized 136 adults with an office-measured blood pressure of at least 140/90 mm Hg despite being on a stable regimen of at least three antihypertensive drugs including a diuretic. The enrolled cohort averaged 52 years of age and had an average office-measured pressure of about 162/104 mm Hg despite being on an average of four agents, although only about a third of enrolled patients were on treatment with a mineralocorticoid-receptor antagonist (MRA) such as spironolactone.

At the time of enrollment and 4 weeks before their denervation procedure, all patients switched to a uniform drug regimen of a single, daily, oral pill containing the calcium channel blocker amlodipine, the angiotensin receptor blocker valsartan or olmesartan, and the diuretic hydrochlorothiazide with no other drug treatment allowed except for unusual, prespecified clinical circumstances. All patients remained on this drug regimen for the initial 2-month follow-up period unless their blood pressure exceeded 180/110 mm Hg during in-office measurement.

The denervation treatment was well tolerated, although patients reported brief, transient, and “minor” pain associated with the procedure that did not affect treatment blinding or have any lingering consequences, said Dr. Kirtane, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York.

A reason to use energy delivery by ultrasound rather than by radiofrequency to ablate nerves in the renal arteries is that the ultrasound approach exerts a more uniform effect, allowing effective treatment delivery without need for catheter repositioning into more distal branches of the renal arteries, said Dr. Kirtane, who is also an interventional cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

But each method has its advantages, he added.

He also conceded that additional questions need to be addressed regarding which patients are most appropriate for renal denervation. “We need to figure out in which patients we can apply a device-based treatment,” Dr. Kirtane said during the press briefing. Patients with what appears to be drug-resistant hypertension often do not receive treatment with a MRA because of adverse effects, and many of these patients are not usually assessed for primary aldosteronism.

In SYMPLICITY HTN-3, “about half the patients who were seemingly eligible became ineligible” when they started treatment with a MRA, noted Dr. Bhatt. “A little spironolactone can go a long way” toward resolving treatment-resistant hypertension in many patients, he said.

RADIANCE-HTN TRIO was sponsored by ReCor Medical, the company developing the tested ultrasound catheter. Dr. Kirtane has received travel expenses and meals from ReCor Medical and several other companies, and Columbia has received research funding from ReCor Medical and several other companies related to research he has conducted. Dr. Bhatt has no relationship with ReCor Medical. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an advisor to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies.

mzoler@mdedge.com

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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