MDedge Cardiology

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.

The American Heart Association and the American College of Cardiology have issued a new report on medical ethics and professionalism in cardiovascular medicine.

The report addresses a variety of topics including diversity, equity, inclusion, and belonging; racial, ethnic and gender inequities; conflicts of interest; clinician well-being; data privacy; social justice; and modern health care delivery systems.

The 54-page report is based on the proceedings of the joint 2020 Consensus Conference on Professionalism and Ethics, held Oct. 19 and 20, 2020. It was published online May 11 in Circulation and the Journal of the American College of Cardiology .

The 2020 consensus conference on professionalism and ethics came at a time even more fraught than the eras of the three previous meetings on the same topics, held in 1989, 1997, and 2004, the writing group notes.

“We have seen the COVID-19 pandemic challenge the physical and economic health of the entire country, coupled with a series of national tragedies that have awakened the call for social justice,” conference cochair C. Michael Valentine, MD, said in a news release.

“There is no better time than now to review, evaluate, and take a fresh perspective on medical ethics and professionalism,” said Dr. Valentine, professor of medicine at the Heart and Vascular Center, University of Virginia, Charlottesville.

“We hope this report will provide cardiovascular professionals and health systems with the recommendations and tools they need to address conflicts of interest; racial, ethnic, and gender inequities; and improve diversity, inclusion, and wellness among our workforce,” Dr. Valentine added. “The majority of our members are now employed and must be engaged as the leaders for change in cardiovascular care.”
 

Road map to improve diversity, achieve allyship

The writing committee was made up of a diverse group of cardiologists, internists, and associated health care professionals and laypeople and was organized into five task forces, each addressing a specific topic: conflicts of interest; diversity, equity, inclusion, and belonging; clinician well-being; patient autonomy, privacy, and social justice in health care; and modern health care delivery.

The report serves as a road map to achieve equity, inclusion, and belonging among cardiovascular professionals and calls for ongoing assessment of the professional culture and climate, focused on improving diversity and achieving effective allyship, the writing group says.

The report proposes continuous training to address individual, structural, and systemic racism, sexism, homophobia, classism, and ableism.

It offers recommendations for championing equity in patient care that include an annual review of practice records to look for differences in patient treatment by race, ethnicity, zip code, and primary language.

The report calls for a foundation of training in allyship and antiracism as part of medical school course requirements and experiences: A required course on social justice, race, and racism as part of the first-year curriculum; school programs and professional organizations supporting students, trainees, and members in allyship and antiracism action; and facilitating immersion and partnership with surrounding communities.

“As much as 80% of a person’s health is determined by the social and economic conditions of their environment,” consensus cochair Ivor Benjamin, MD, said in the release.

“To achieve social justice and mitigate health disparities, we must go to the margins and shift our discussions to be inclusive of populations such as rural and marginalized groups from the perspective of health equity lens for all,” said Dr. Benjamin, professor of medicine, Medical College of Wisconsin, Milwaukee.

The report also highlights the need for psychosocial support of the cardiovascular community and recommends that health care organizations prioritize regular assessment of clinicians’ well-being and engagement.

It also recommends addressing the well-being of trainees in postgraduate training programs and calls for an ombudsman program that allows for confidential reporting of mistreatment and access to support.

The report also highlights additional opportunities to:

• improve the efficiency of health information technology, such as electronic health records, and reduce the administrative burden
• identify and assist clinicians who experience mental health conditions, , or 
• emphasize patient autonomy using shared decision-making and patient-centered care that is supportive of the individual patient’s values
• increase privacy protections for patient data used in research
• maintain integrity as new ways of delivering care, such as telemedicine, team-based care approaches, and physician-owned specialty centers emerge
• perform routine audits of electronic health records to promote optimal patient care, as well as ethical medical practice
• expand and make mandatory the reporting of intellectual or associational interests in addition to relationships with industry

The report’s details and recommendations will be presented and discussed Saturday, May 15, at 8:00 AM ET, during ACC.21. The session is titled Diversity and Equity: The Means to Expand Inclusion and Belonging.

The AHA will present a live webinar and six-episode podcast series (available on demand) to highlight the report’s details, dialogue, and actionable steps for cardiovascular and health care professionals, researchers, and educators.

This research had no commercial funding. The list of 40 volunteer committee members and coauthors, including their disclosures, are listed in the original report.

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

The American Heart Association and the American College of Cardiology have issued a new report on medical ethics and professionalism in cardiovascular medicine.

The report addresses a variety of topics including diversity, equity, inclusion, and belonging; racial, ethnic and gender inequities; conflicts of interest; clinician well-being; data privacy; social justice; and modern health care delivery systems.

The 54-page report is based on the proceedings of the joint 2020 Consensus Conference on Professionalism and Ethics, held Oct. 19 and 20, 2020. It was published online May 11 in Circulation and the Journal of the American College of Cardiology .

The 2020 consensus conference on professionalism and ethics came at a time even more fraught than the eras of the three previous meetings on the same topics, held in 1989, 1997, and 2004, the writing group notes.

“We have seen the COVID-19 pandemic challenge the physical and economic health of the entire country, coupled with a series of national tragedies that have awakened the call for social justice,” conference cochair C. Michael Valentine, MD, said in a news release.

“There is no better time than now to review, evaluate, and take a fresh perspective on medical ethics and professionalism,” said Dr. Valentine, professor of medicine at the Heart and Vascular Center, University of Virginia, Charlottesville.

“We hope this report will provide cardiovascular professionals and health systems with the recommendations and tools they need to address conflicts of interest; racial, ethnic, and gender inequities; and improve diversity, inclusion, and wellness among our workforce,” Dr. Valentine added. “The majority of our members are now employed and must be engaged as the leaders for change in cardiovascular care.”
 

Road map to improve diversity, achieve allyship

The writing committee was made up of a diverse group of cardiologists, internists, and associated health care professionals and laypeople and was organized into five task forces, each addressing a specific topic: conflicts of interest; diversity, equity, inclusion, and belonging; clinician well-being; patient autonomy, privacy, and social justice in health care; and modern health care delivery.

The report serves as a road map to achieve equity, inclusion, and belonging among cardiovascular professionals and calls for ongoing assessment of the professional culture and climate, focused on improving diversity and achieving effective allyship, the writing group says.

The report proposes continuous training to address individual, structural, and systemic racism, sexism, homophobia, classism, and ableism.

It offers recommendations for championing equity in patient care that include an annual review of practice records to look for differences in patient treatment by race, ethnicity, zip code, and primary language.

The report calls for a foundation of training in allyship and antiracism as part of medical school course requirements and experiences: A required course on social justice, race, and racism as part of the first-year curriculum; school programs and professional organizations supporting students, trainees, and members in allyship and antiracism action; and facilitating immersion and partnership with surrounding communities.

“As much as 80% of a person’s health is determined by the social and economic conditions of their environment,” consensus cochair Ivor Benjamin, MD, said in the release.

“To achieve social justice and mitigate health disparities, we must go to the margins and shift our discussions to be inclusive of populations such as rural and marginalized groups from the perspective of health equity lens for all,” said Dr. Benjamin, professor of medicine, Medical College of Wisconsin, Milwaukee.

The report also highlights the need for psychosocial support of the cardiovascular community and recommends that health care organizations prioritize regular assessment of clinicians’ well-being and engagement.

It also recommends addressing the well-being of trainees in postgraduate training programs and calls for an ombudsman program that allows for confidential reporting of mistreatment and access to support.

The report also highlights additional opportunities to:

• improve the efficiency of health information technology, such as electronic health records, and reduce the administrative burden
• identify and assist clinicians who experience mental health conditions, , or 
• emphasize patient autonomy using shared decision-making and patient-centered care that is supportive of the individual patient’s values
• increase privacy protections for patient data used in research
• maintain integrity as new ways of delivering care, such as telemedicine, team-based care approaches, and physician-owned specialty centers emerge
• perform routine audits of electronic health records to promote optimal patient care, as well as ethical medical practice
• expand and make mandatory the reporting of intellectual or associational interests in addition to relationships with industry

The report’s details and recommendations will be presented and discussed Saturday, May 15, at 8:00 AM ET, during ACC.21. The session is titled Diversity and Equity: The Means to Expand Inclusion and Belonging.

The AHA will present a live webinar and six-episode podcast series (available on demand) to highlight the report’s details, dialogue, and actionable steps for cardiovascular and health care professionals, researchers, and educators.

This research had no commercial funding. The list of 40 volunteer committee members and coauthors, including their disclosures, are listed in the original report.

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

The American Heart Association and the American College of Cardiology have issued a new report on medical ethics and professionalism in cardiovascular medicine.

The report addresses a variety of topics including diversity, equity, inclusion, and belonging; racial, ethnic and gender inequities; conflicts of interest; clinician well-being; data privacy; social justice; and modern health care delivery systems.

The 54-page report is based on the proceedings of the joint 2020 Consensus Conference on Professionalism and Ethics, held Oct. 19 and 20, 2020. It was published online May 11 in Circulation and the Journal of the American College of Cardiology .

The 2020 consensus conference on professionalism and ethics came at a time even more fraught than the eras of the three previous meetings on the same topics, held in 1989, 1997, and 2004, the writing group notes.

“We have seen the COVID-19 pandemic challenge the physical and economic health of the entire country, coupled with a series of national tragedies that have awakened the call for social justice,” conference cochair C. Michael Valentine, MD, said in a news release.

“There is no better time than now to review, evaluate, and take a fresh perspective on medical ethics and professionalism,” said Dr. Valentine, professor of medicine at the Heart and Vascular Center, University of Virginia, Charlottesville.

“We hope this report will provide cardiovascular professionals and health systems with the recommendations and tools they need to address conflicts of interest; racial, ethnic, and gender inequities; and improve diversity, inclusion, and wellness among our workforce,” Dr. Valentine added. “The majority of our members are now employed and must be engaged as the leaders for change in cardiovascular care.”
 

Road map to improve diversity, achieve allyship

The writing committee was made up of a diverse group of cardiologists, internists, and associated health care professionals and laypeople and was organized into five task forces, each addressing a specific topic: conflicts of interest; diversity, equity, inclusion, and belonging; clinician well-being; patient autonomy, privacy, and social justice in health care; and modern health care delivery.

The report serves as a road map to achieve equity, inclusion, and belonging among cardiovascular professionals and calls for ongoing assessment of the professional culture and climate, focused on improving diversity and achieving effective allyship, the writing group says.

The report proposes continuous training to address individual, structural, and systemic racism, sexism, homophobia, classism, and ableism.

It offers recommendations for championing equity in patient care that include an annual review of practice records to look for differences in patient treatment by race, ethnicity, zip code, and primary language.

The report calls for a foundation of training in allyship and antiracism as part of medical school course requirements and experiences: A required course on social justice, race, and racism as part of the first-year curriculum; school programs and professional organizations supporting students, trainees, and members in allyship and antiracism action; and facilitating immersion and partnership with surrounding communities.

“As much as 80% of a person’s health is determined by the social and economic conditions of their environment,” consensus cochair Ivor Benjamin, MD, said in the release.

“To achieve social justice and mitigate health disparities, we must go to the margins and shift our discussions to be inclusive of populations such as rural and marginalized groups from the perspective of health equity lens for all,” said Dr. Benjamin, professor of medicine, Medical College of Wisconsin, Milwaukee.

The report also highlights the need for psychosocial support of the cardiovascular community and recommends that health care organizations prioritize regular assessment of clinicians’ well-being and engagement.

It also recommends addressing the well-being of trainees in postgraduate training programs and calls for an ombudsman program that allows for confidential reporting of mistreatment and access to support.

The report also highlights additional opportunities to:

• improve the efficiency of health information technology, such as electronic health records, and reduce the administrative burden
• identify and assist clinicians who experience mental health conditions, , or 
• emphasize patient autonomy using shared decision-making and patient-centered care that is supportive of the individual patient’s values
• increase privacy protections for patient data used in research
• maintain integrity as new ways of delivering care, such as telemedicine, team-based care approaches, and physician-owned specialty centers emerge
• perform routine audits of electronic health records to promote optimal patient care, as well as ethical medical practice
• expand and make mandatory the reporting of intellectual or associational interests in addition to relationships with industry

The report’s details and recommendations will be presented and discussed Saturday, May 15, at 8:00 AM ET, during ACC.21. The session is titled Diversity and Equity: The Means to Expand Inclusion and Belonging.

The AHA will present a live webinar and six-episode podcast series (available on demand) to highlight the report’s details, dialogue, and actionable steps for cardiovascular and health care professionals, researchers, and educators.

This research had no commercial funding. The list of 40 volunteer committee members and coauthors, including their disclosures, are listed in the original report.

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 [email protected].

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 [email protected].

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 [email protected].

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.

“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.
 

The use of e-cigarettes is linked to a higher frequency of self-reported wheezing and shortness of breath in adolescents and young adults, according to an online survey. The association was present even after controlling for cigarette and cannabis use.

Previous studies of adolescents and young adults have shown associations between e-cigarette use and wheeze, shortness of breath, and asthma. The Youth Risk Behavior Surveillance (YRBS) survey by the Centers for Disease Control and Prevention and other health agencies, conducted from 2015 to 2017, found that 63.5% of youth who used e-cigarettes also used some combination of cigarettes and cannabis. Combined use was associated with a 55%-65% increased odds of self-reported asthma.

The Population Assessment of Tobacco and Health (PATH) study, which was published in October 2020, had similar findings, though it did not find an association between e-cigarette use alone and wheezing.

“The findings from the current study highlight that we need to keep asking young people about respiratory symptoms, couse of other tobacco products, as well as cannabis use. As more products, including cannabis and various e-cigarette devices, enter the market, assessing respiratory health will be important both where adolescents and young adults receive their health care and in research,” Alayna Tackett, PhD, said in an interview. Dr. Tackett presented the study at the American Thoracic Society’s virtual international conference. She is an assistant professor of preventive medicine at the University of Southern California, Los Angeles.

“I found [the study] very interesting because it seems to be identifying a physiologic response to these e-cigarettes,” said Christopher Pascoe, MD, who was asked to comment. “And they were so young [age 14-21 years]. The fact that these symptoms of wheezing and shortness of breath are coming from people who are this young suggests that there may be chronic problems showing up later with continued use of these devices.”

Dr. Pascoe is an assistant professor of physiology and pathophysiology at the University of Manitoba, Winnipeg, where he also works with the Children’s Hospital Research Institute of Manitoba. His own research examines lung tissue harvested from pneumothorax surgeries in smokers and e-cigarette users to identify markers of inflammation.

He called the research a “good start” at unraveling the impacts of e-cigarettes and smoking, since some people use both products. “The fact that there was still a twofold increase in odds for wheezing, shortness of breath among people who use these e-cigarettes, but weren’t using cannabis and weren’t using cigarettes. I think it’s novel, and it suggests that there is an effect [of e-cigarettes alone].”

The study is based on a self-reported data, which is a significant limitation, especially considering that asthma is often overreported. “Self-report can be fraught with things, but I think it’s an interesting starting point for trying to recruit people who are just e-cigarette users and following them up further,” said Dr. Pascoe.

The researchers surveyed 2,931 individuals aged 14-21 years between Aug. 6 and Aug.30, 2020, with an average age of 18.9 years. Of the respondents, 80% were women and girls, and 75% were White. The high percentage of women and girls was unusual. Dr. Tackett provided no explanation for the atypical demographic but noted that the current study used convenience sampling.

The survey asked about use of e-cigarettes, cigarettes, and cannabis in the past 30 days, as well as asthma diagnosis and respiratory symptoms over the same period. The methodology employed survey management company Lucid, which recruited, collected data from, and provided compensation to participants.

A total of 24% of participants reported asthma, 13% reported wheeze, and 20% reported shortness of breath. Among 1,414 respondents who reported e-cigarette use in the past 30 days, 15% also said they had used cigarettes, and 37% said they had used cannabis.

After controlling for age, birth sex, and race/ethnicity, compared with self-reported never e-cigarette users, there was an association between past 30-day e-cigarette use and self-reported asthma (odds ratio, 1.4; 95% CI, 1.1-1.7), wheeze (OR, 3.1; 95% CI, 2.3-4.2), and shortness of breath (OR, 2.9; 95% CI, 2.3-3.6). After the researchers controlled for past 30-day cigarette cannabis use, the association with asthma was no longer statistically significant (OR, 1.11; 95% CI, 0.87-1.41), but the association with wheeze (OR, 2.3; 95% CI, 1.6-3.0) and shortness of breath (OR, 2.1; 95% CI, 1.6-2.8) remained.

Dr. Tackett noted that wheeze and shortness of breath are only two indicators of respiratory health, and more research needs to be done. Her team is conducting follow-up studies using objective measurement tools such as home-based spirometry in adolescents and young adults who exclusively use e-cigarettes and who have never used e-cigarettes.

“We need to better understand the complex relationships between use of these products and whether multiple product use is associated with worse respiratory outcomes,” said Dr. Tackett.

Dr. Pascoe and Dr. Tackett disclosed no relevant financial relationships.

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

The use of e-cigarettes is linked to a higher frequency of self-reported wheezing and shortness of breath in adolescents and young adults, according to an online survey. The association was present even after controlling for cigarette and cannabis use.

Previous studies of adolescents and young adults have shown associations between e-cigarette use and wheeze, shortness of breath, and asthma. The Youth Risk Behavior Surveillance (YRBS) survey by the Centers for Disease Control and Prevention and other health agencies, conducted from 2015 to 2017, found that 63.5% of youth who used e-cigarettes also used some combination of cigarettes and cannabis. Combined use was associated with a 55%-65% increased odds of self-reported asthma.

The Population Assessment of Tobacco and Health (PATH) study, which was published in October 2020, had similar findings, though it did not find an association between e-cigarette use alone and wheezing.

“The findings from the current study highlight that we need to keep asking young people about respiratory symptoms, couse of other tobacco products, as well as cannabis use. As more products, including cannabis and various e-cigarette devices, enter the market, assessing respiratory health will be important both where adolescents and young adults receive their health care and in research,” Alayna Tackett, PhD, said in an interview. Dr. Tackett presented the study at the American Thoracic Society’s virtual international conference. She is an assistant professor of preventive medicine at the University of Southern California, Los Angeles.

“I found [the study] very interesting because it seems to be identifying a physiologic response to these e-cigarettes,” said Christopher Pascoe, MD, who was asked to comment. “And they were so young [age 14-21 years]. The fact that these symptoms of wheezing and shortness of breath are coming from people who are this young suggests that there may be chronic problems showing up later with continued use of these devices.”

Dr. Pascoe is an assistant professor of physiology and pathophysiology at the University of Manitoba, Winnipeg, where he also works with the Children’s Hospital Research Institute of Manitoba. His own research examines lung tissue harvested from pneumothorax surgeries in smokers and e-cigarette users to identify markers of inflammation.

He called the research a “good start” at unraveling the impacts of e-cigarettes and smoking, since some people use both products. “The fact that there was still a twofold increase in odds for wheezing, shortness of breath among people who use these e-cigarettes, but weren’t using cannabis and weren’t using cigarettes. I think it’s novel, and it suggests that there is an effect [of e-cigarettes alone].”

The study is based on a self-reported data, which is a significant limitation, especially considering that asthma is often overreported. “Self-report can be fraught with things, but I think it’s an interesting starting point for trying to recruit people who are just e-cigarette users and following them up further,” said Dr. Pascoe.

The researchers surveyed 2,931 individuals aged 14-21 years between Aug. 6 and Aug.30, 2020, with an average age of 18.9 years. Of the respondents, 80% were women and girls, and 75% were White. The high percentage of women and girls was unusual. Dr. Tackett provided no explanation for the atypical demographic but noted that the current study used convenience sampling.

The survey asked about use of e-cigarettes, cigarettes, and cannabis in the past 30 days, as well as asthma diagnosis and respiratory symptoms over the same period. The methodology employed survey management company Lucid, which recruited, collected data from, and provided compensation to participants.

A total of 24% of participants reported asthma, 13% reported wheeze, and 20% reported shortness of breath. Among 1,414 respondents who reported e-cigarette use in the past 30 days, 15% also said they had used cigarettes, and 37% said they had used cannabis.

After controlling for age, birth sex, and race/ethnicity, compared with self-reported never e-cigarette users, there was an association between past 30-day e-cigarette use and self-reported asthma (odds ratio, 1.4; 95% CI, 1.1-1.7), wheeze (OR, 3.1; 95% CI, 2.3-4.2), and shortness of breath (OR, 2.9; 95% CI, 2.3-3.6). After the researchers controlled for past 30-day cigarette cannabis use, the association with asthma was no longer statistically significant (OR, 1.11; 95% CI, 0.87-1.41), but the association with wheeze (OR, 2.3; 95% CI, 1.6-3.0) and shortness of breath (OR, 2.1; 95% CI, 1.6-2.8) remained.

Dr. Tackett noted that wheeze and shortness of breath are only two indicators of respiratory health, and more research needs to be done. Her team is conducting follow-up studies using objective measurement tools such as home-based spirometry in adolescents and young adults who exclusively use e-cigarettes and who have never used e-cigarettes.

“We need to better understand the complex relationships between use of these products and whether multiple product use is associated with worse respiratory outcomes,” said Dr. Tackett.

Dr. Pascoe and Dr. Tackett disclosed no relevant financial relationships.

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

The use of e-cigarettes is linked to a higher frequency of self-reported wheezing and shortness of breath in adolescents and young adults, according to an online survey. The association was present even after controlling for cigarette and cannabis use.

Previous studies of adolescents and young adults have shown associations between e-cigarette use and wheeze, shortness of breath, and asthma. The Youth Risk Behavior Surveillance (YRBS) survey by the Centers for Disease Control and Prevention and other health agencies, conducted from 2015 to 2017, found that 63.5% of youth who used e-cigarettes also used some combination of cigarettes and cannabis. Combined use was associated with a 55%-65% increased odds of self-reported asthma.

The Population Assessment of Tobacco and Health (PATH) study, which was published in October 2020, had similar findings, though it did not find an association between e-cigarette use alone and wheezing.

“The findings from the current study highlight that we need to keep asking young people about respiratory symptoms, couse of other tobacco products, as well as cannabis use. As more products, including cannabis and various e-cigarette devices, enter the market, assessing respiratory health will be important both where adolescents and young adults receive their health care and in research,” Alayna Tackett, PhD, said in an interview. Dr. Tackett presented the study at the American Thoracic Society’s virtual international conference. She is an assistant professor of preventive medicine at the University of Southern California, Los Angeles.

“I found [the study] very interesting because it seems to be identifying a physiologic response to these e-cigarettes,” said Christopher Pascoe, MD, who was asked to comment. “And they were so young [age 14-21 years]. The fact that these symptoms of wheezing and shortness of breath are coming from people who are this young suggests that there may be chronic problems showing up later with continued use of these devices.”

Dr. Pascoe is an assistant professor of physiology and pathophysiology at the University of Manitoba, Winnipeg, where he also works with the Children’s Hospital Research Institute of Manitoba. His own research examines lung tissue harvested from pneumothorax surgeries in smokers and e-cigarette users to identify markers of inflammation.

He called the research a “good start” at unraveling the impacts of e-cigarettes and smoking, since some people use both products. “The fact that there was still a twofold increase in odds for wheezing, shortness of breath among people who use these e-cigarettes, but weren’t using cannabis and weren’t using cigarettes. I think it’s novel, and it suggests that there is an effect [of e-cigarettes alone].”

The study is based on a self-reported data, which is a significant limitation, especially considering that asthma is often overreported. “Self-report can be fraught with things, but I think it’s an interesting starting point for trying to recruit people who are just e-cigarette users and following them up further,” said Dr. Pascoe.

The researchers surveyed 2,931 individuals aged 14-21 years between Aug. 6 and Aug.30, 2020, with an average age of 18.9 years. Of the respondents, 80% were women and girls, and 75% were White. The high percentage of women and girls was unusual. Dr. Tackett provided no explanation for the atypical demographic but noted that the current study used convenience sampling.

The survey asked about use of e-cigarettes, cigarettes, and cannabis in the past 30 days, as well as asthma diagnosis and respiratory symptoms over the same period. The methodology employed survey management company Lucid, which recruited, collected data from, and provided compensation to participants.

A total of 24% of participants reported asthma, 13% reported wheeze, and 20% reported shortness of breath. Among 1,414 respondents who reported e-cigarette use in the past 30 days, 15% also said they had used cigarettes, and 37% said they had used cannabis.

After controlling for age, birth sex, and race/ethnicity, compared with self-reported never e-cigarette users, there was an association between past 30-day e-cigarette use and self-reported asthma (odds ratio, 1.4; 95% CI, 1.1-1.7), wheeze (OR, 3.1; 95% CI, 2.3-4.2), and shortness of breath (OR, 2.9; 95% CI, 2.3-3.6). After the researchers controlled for past 30-day cigarette cannabis use, the association with asthma was no longer statistically significant (OR, 1.11; 95% CI, 0.87-1.41), but the association with wheeze (OR, 2.3; 95% CI, 1.6-3.0) and shortness of breath (OR, 2.1; 95% CI, 1.6-2.8) remained.

Dr. Tackett noted that wheeze and shortness of breath are only two indicators of respiratory health, and more research needs to be done. Her team is conducting follow-up studies using objective measurement tools such as home-based spirometry in adolescents and young adults who exclusively use e-cigarettes and who have never used e-cigarettes.

“We need to better understand the complex relationships between use of these products and whether multiple product use is associated with worse respiratory outcomes,” said Dr. Tackett.

Dr. Pascoe and Dr. Tackett disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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.

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.