Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Higher intake of vegetable fats from foods such as olive oil and nuts is associated with a lower risk for stroke, whereas people who eat more animal fats, especially processed red meats, may have a higher stroke risk, observational findings suggest.

camij/thinkstockphotos.com

In a study of more than 117,000 health professionals who were followed for 27 years, those whose diet was in the highest quintile for intake of vegetable fat had a 12% lower risk for stroke, compared with those who consumed the least amount of vegetable fats.

Conversely, having the highest intake of animal fat from nondairy sources was associated with a 16% increased risk of stroke.

Fenglei Wang, PhD, presented these results at the American Heart Association scientific sessions.

“Our findings support the Dietary Guidelines for Americans and dietary recommendations by AHA,” Dr. Wang, a postdoctoral fellow in the department of nutrition at Harvard University’s T.H. Chan School of Public Health in Boston, told this news organization.

“The main sources of vegetable fat have a large overlap with polyunsaturated fat, such as vegetable oils, nuts, walnuts, and peanut butter,” Dr. Wang noted, adding that fish, especially fatty fish, is a main source of polyunsaturated fat and is recommended for cardiovascular health.

“We would recommend that people reduce consumption of red and processed meat, minimize fatty parts of unprocessed meat if consumed, and replace lard or tallow (beef fat) with nontropical vegetable oils, such as olive oil, corn, or soybean oils in cooking, to lower their stroke risk,” she said.

Moreover, although the results from this study of dietary fat are informative, Dr. Wang continued, “there are other dietary factors (fruits, vegetables, salt, alcohol, et cetera), and lifestyle factors (physical activity, smoking, et cetera), that are associated with stroke risk and worthy of attention as well.”

“Many processed meats are high in salt and saturated fat, and low in vegetable fat,” Alice H. Lichtenstein, DSc, an AHA spokesperson who was not involved with this research, noted in a press release.

“Research shows that replacing processed meat with other protein sources, particularly plant sources, is associated with lower death rates,” added Dr. Lichtenstein, the Stanley N. Gershoff professor of nutrition science and policy at Tufts University in Boston, and lead author of the AHA’s 2021 scientific statement, Dietary Guidance to Improve Cardiovascular Health.

“Key features of a heart-healthy diet pattern,” she summarized, “are to balance calorie intake with calorie needs to achieve and maintain a healthy weight; choose whole grains, lean and plant-based protein, and a variety of fruits and vegetables; limit salt, sugar, animal fat, processed foods, and alcohol; and apply this guidance regardless of where the food is prepared or consumed.”
 

Replace processed meat with plant proteins

The focus on stroke in this study “is important” because, traditionally, studies of diet and cardiovascular health have focused on coronary heart disease, Andrew Mente, PhD, who also was not involved in this research, said in an email to this news organization.

“Overall, the take-home message from the study is that replacing processed meat with plant sources of protein in the diet is probably beneficial,” Dr. Mente, associate professor, health research methods, evidence, and impact, Faculty of Health Sciences, McMaster University, Hamilton, Ont., said.

The finding that people who ate the most vegetable fat had a modest 12% lower risk of stroke than those who ate the least vegetable fat “points to protective effects of foods like seeds, nuts, vegetables, and olive oil, which has been shown previously,” he continued.

The highest quintile of total red meat intake was associated with an 8% higher risk for stroke, but this was driven mainly by processed red meat (which was associated with a 12% higher risk for stroke). These findings are “generally consistent with cohort studies showing that processed meat, as with most highly processed foods for that matter, are associated with an increased risk of cardiovascular events,” Dr. Mente noted.

“Surprisingly, dairy products (such as cheese, butter, or milk) in the study were not connected with the risk of stroke,” he added. This finding differs from results of meta-analyses of multiple cohort studies of dairy intake and stroke and the recent large international PURE study, which showed that dairy intake was associated with a lower risk for stroke.

“What is needed to move the field forward,” according to Dr. Mente, “is to employ new methods that use cutting-edge technology to study nutritional biomarkers and health outcomes.”

“When dealing with modest associations as usually encountered in nutrition, it is a challenge to make causal connections based on dietary questionnaires, which are fraught with measurement error,” he added. “The use of novel methods is where the field is headed.”
 

Total dietary fat, different types, and different food sources

Dr. Wang and colleagues investigated how total dietary fat, different types of fat, and fats from different foods were associated with incident stroke in 73,867 women in the 1984-2016 Nurses’ Health Study and 43,269 men who participated in the 1986-2016 Health Professionals Follow-up Study.

The participants had an average age of 50 years, 63% were women, and 97% were White. They replied to food-frequency questionnaires every 4 years.

Total red meat included beef, pork, or lamb (as a main dish or in sandwiches or mixed dishes) as well as processed red meats (such as bacon, sausage, bologna, hot dogs, and salami).

Animal fat sources included meat, beef tallow, lard, and full-fat dairy products, such as full-fat milk and cheese.

The median percentage of total daily calories from different sources of fat ranged from 10% to 20% for vegetable fat, 3% to 10% for dairy fat, and 7% to 17% for nondairy animal fat (for lowest to highest quintiles).

The median percentage of total daily calories from different types of fat ranged from 5% to 8% for polyunsaturated fat, 4% to 7% for n-6 polyunsaturated fat, 9% to 15% for monounsaturated fat, 8% to 14% for saturated fat, and 1% to 2% for trans fat.

During follow-up, there were 6,189 incident strokes, including 2,967 ischemic strokes and 814 hemorrhagic strokes.

The researchers found that intake in the highest quintile of vegetable fat was associated with a lower risk for total stroke, compared with the lowest quintile (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96; P for trend < .001).

Similarly, the highest intake of polyunsaturated fat was also associated with lower total stroke (HR, 0.88; 95% CI, 0.80-0.96; P for trend = .002). 

Highest intake of nondairy animal fat, however, was associated with an increased risk for total stroke (HR, 1.16; 95% CI, 1.05-1.29; P for trend < .001). They observed “similar associations” for ischemic stroke, but the only positive association for nondairy animal fat was with hemorrhagic stroke, the abstract notes.   

The risk for stroke was lower by 9% per serving per day for vegetable oil but increased by 8% and 12%, respectively, per serving of total red meat or processed red meat.

The association for vegetable oil was attenuated after adjustment for vegetable fat or polyunsaturated fat, whereas adjustment for nondairy animal fat rendered the association for total red meat and processed red meat nonsignificant. 

The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Wang has no relevant financial disclosures. Dr. Mente has received research funding from the Dairy Farmers of Canada and the National Dairy Council to analyze data on dairy consumption and health outcomes in the PURE study, which is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, and more than 70 other sources (government and pharmaceutical).

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

Higher intake of vegetable fats from foods such as olive oil and nuts is associated with a lower risk for stroke, whereas people who eat more animal fats, especially processed red meats, may have a higher stroke risk, observational findings suggest.

camij/thinkstockphotos.com

In a study of more than 117,000 health professionals who were followed for 27 years, those whose diet was in the highest quintile for intake of vegetable fat had a 12% lower risk for stroke, compared with those who consumed the least amount of vegetable fats.

Conversely, having the highest intake of animal fat from nondairy sources was associated with a 16% increased risk of stroke.

Fenglei Wang, PhD, presented these results at the American Heart Association scientific sessions.

“Our findings support the Dietary Guidelines for Americans and dietary recommendations by AHA,” Dr. Wang, a postdoctoral fellow in the department of nutrition at Harvard University’s T.H. Chan School of Public Health in Boston, told this news organization.

“The main sources of vegetable fat have a large overlap with polyunsaturated fat, such as vegetable oils, nuts, walnuts, and peanut butter,” Dr. Wang noted, adding that fish, especially fatty fish, is a main source of polyunsaturated fat and is recommended for cardiovascular health.

“We would recommend that people reduce consumption of red and processed meat, minimize fatty parts of unprocessed meat if consumed, and replace lard or tallow (beef fat) with nontropical vegetable oils, such as olive oil, corn, or soybean oils in cooking, to lower their stroke risk,” she said.

Moreover, although the results from this study of dietary fat are informative, Dr. Wang continued, “there are other dietary factors (fruits, vegetables, salt, alcohol, et cetera), and lifestyle factors (physical activity, smoking, et cetera), that are associated with stroke risk and worthy of attention as well.”

“Many processed meats are high in salt and saturated fat, and low in vegetable fat,” Alice H. Lichtenstein, DSc, an AHA spokesperson who was not involved with this research, noted in a press release.

“Research shows that replacing processed meat with other protein sources, particularly plant sources, is associated with lower death rates,” added Dr. Lichtenstein, the Stanley N. Gershoff professor of nutrition science and policy at Tufts University in Boston, and lead author of the AHA’s 2021 scientific statement, Dietary Guidance to Improve Cardiovascular Health.

“Key features of a heart-healthy diet pattern,” she summarized, “are to balance calorie intake with calorie needs to achieve and maintain a healthy weight; choose whole grains, lean and plant-based protein, and a variety of fruits and vegetables; limit salt, sugar, animal fat, processed foods, and alcohol; and apply this guidance regardless of where the food is prepared or consumed.”
 

Replace processed meat with plant proteins

The focus on stroke in this study “is important” because, traditionally, studies of diet and cardiovascular health have focused on coronary heart disease, Andrew Mente, PhD, who also was not involved in this research, said in an email to this news organization.

“Overall, the take-home message from the study is that replacing processed meat with plant sources of protein in the diet is probably beneficial,” Dr. Mente, associate professor, health research methods, evidence, and impact, Faculty of Health Sciences, McMaster University, Hamilton, Ont., said.

The finding that people who ate the most vegetable fat had a modest 12% lower risk of stroke than those who ate the least vegetable fat “points to protective effects of foods like seeds, nuts, vegetables, and olive oil, which has been shown previously,” he continued.

The highest quintile of total red meat intake was associated with an 8% higher risk for stroke, but this was driven mainly by processed red meat (which was associated with a 12% higher risk for stroke). These findings are “generally consistent with cohort studies showing that processed meat, as with most highly processed foods for that matter, are associated with an increased risk of cardiovascular events,” Dr. Mente noted.

“Surprisingly, dairy products (such as cheese, butter, or milk) in the study were not connected with the risk of stroke,” he added. This finding differs from results of meta-analyses of multiple cohort studies of dairy intake and stroke and the recent large international PURE study, which showed that dairy intake was associated with a lower risk for stroke.

“What is needed to move the field forward,” according to Dr. Mente, “is to employ new methods that use cutting-edge technology to study nutritional biomarkers and health outcomes.”

“When dealing with modest associations as usually encountered in nutrition, it is a challenge to make causal connections based on dietary questionnaires, which are fraught with measurement error,” he added. “The use of novel methods is where the field is headed.”
 

Total dietary fat, different types, and different food sources

Dr. Wang and colleagues investigated how total dietary fat, different types of fat, and fats from different foods were associated with incident stroke in 73,867 women in the 1984-2016 Nurses’ Health Study and 43,269 men who participated in the 1986-2016 Health Professionals Follow-up Study.

The participants had an average age of 50 years, 63% were women, and 97% were White. They replied to food-frequency questionnaires every 4 years.

Total red meat included beef, pork, or lamb (as a main dish or in sandwiches or mixed dishes) as well as processed red meats (such as bacon, sausage, bologna, hot dogs, and salami).

Animal fat sources included meat, beef tallow, lard, and full-fat dairy products, such as full-fat milk and cheese.

The median percentage of total daily calories from different sources of fat ranged from 10% to 20% for vegetable fat, 3% to 10% for dairy fat, and 7% to 17% for nondairy animal fat (for lowest to highest quintiles).

The median percentage of total daily calories from different types of fat ranged from 5% to 8% for polyunsaturated fat, 4% to 7% for n-6 polyunsaturated fat, 9% to 15% for monounsaturated fat, 8% to 14% for saturated fat, and 1% to 2% for trans fat.

During follow-up, there were 6,189 incident strokes, including 2,967 ischemic strokes and 814 hemorrhagic strokes.

The researchers found that intake in the highest quintile of vegetable fat was associated with a lower risk for total stroke, compared with the lowest quintile (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96; P for trend < .001).

Similarly, the highest intake of polyunsaturated fat was also associated with lower total stroke (HR, 0.88; 95% CI, 0.80-0.96; P for trend = .002). 

Highest intake of nondairy animal fat, however, was associated with an increased risk for total stroke (HR, 1.16; 95% CI, 1.05-1.29; P for trend < .001). They observed “similar associations” for ischemic stroke, but the only positive association for nondairy animal fat was with hemorrhagic stroke, the abstract notes.   

The risk for stroke was lower by 9% per serving per day for vegetable oil but increased by 8% and 12%, respectively, per serving of total red meat or processed red meat.

The association for vegetable oil was attenuated after adjustment for vegetable fat or polyunsaturated fat, whereas adjustment for nondairy animal fat rendered the association for total red meat and processed red meat nonsignificant. 

The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Wang has no relevant financial disclosures. Dr. Mente has received research funding from the Dairy Farmers of Canada and the National Dairy Council to analyze data on dairy consumption and health outcomes in the PURE study, which is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, and more than 70 other sources (government and pharmaceutical).

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

Higher intake of vegetable fats from foods such as olive oil and nuts is associated with a lower risk for stroke, whereas people who eat more animal fats, especially processed red meats, may have a higher stroke risk, observational findings suggest.

camij/thinkstockphotos.com

In a study of more than 117,000 health professionals who were followed for 27 years, those whose diet was in the highest quintile for intake of vegetable fat had a 12% lower risk for stroke, compared with those who consumed the least amount of vegetable fats.

Conversely, having the highest intake of animal fat from nondairy sources was associated with a 16% increased risk of stroke.

Fenglei Wang, PhD, presented these results at the American Heart Association scientific sessions.

“Our findings support the Dietary Guidelines for Americans and dietary recommendations by AHA,” Dr. Wang, a postdoctoral fellow in the department of nutrition at Harvard University’s T.H. Chan School of Public Health in Boston, told this news organization.

“The main sources of vegetable fat have a large overlap with polyunsaturated fat, such as vegetable oils, nuts, walnuts, and peanut butter,” Dr. Wang noted, adding that fish, especially fatty fish, is a main source of polyunsaturated fat and is recommended for cardiovascular health.

“We would recommend that people reduce consumption of red and processed meat, minimize fatty parts of unprocessed meat if consumed, and replace lard or tallow (beef fat) with nontropical vegetable oils, such as olive oil, corn, or soybean oils in cooking, to lower their stroke risk,” she said.

Moreover, although the results from this study of dietary fat are informative, Dr. Wang continued, “there are other dietary factors (fruits, vegetables, salt, alcohol, et cetera), and lifestyle factors (physical activity, smoking, et cetera), that are associated with stroke risk and worthy of attention as well.”

“Many processed meats are high in salt and saturated fat, and low in vegetable fat,” Alice H. Lichtenstein, DSc, an AHA spokesperson who was not involved with this research, noted in a press release.

“Research shows that replacing processed meat with other protein sources, particularly plant sources, is associated with lower death rates,” added Dr. Lichtenstein, the Stanley N. Gershoff professor of nutrition science and policy at Tufts University in Boston, and lead author of the AHA’s 2021 scientific statement, Dietary Guidance to Improve Cardiovascular Health.

“Key features of a heart-healthy diet pattern,” she summarized, “are to balance calorie intake with calorie needs to achieve and maintain a healthy weight; choose whole grains, lean and plant-based protein, and a variety of fruits and vegetables; limit salt, sugar, animal fat, processed foods, and alcohol; and apply this guidance regardless of where the food is prepared or consumed.”
 

Replace processed meat with plant proteins

The focus on stroke in this study “is important” because, traditionally, studies of diet and cardiovascular health have focused on coronary heart disease, Andrew Mente, PhD, who also was not involved in this research, said in an email to this news organization.

“Overall, the take-home message from the study is that replacing processed meat with plant sources of protein in the diet is probably beneficial,” Dr. Mente, associate professor, health research methods, evidence, and impact, Faculty of Health Sciences, McMaster University, Hamilton, Ont., said.

The finding that people who ate the most vegetable fat had a modest 12% lower risk of stroke than those who ate the least vegetable fat “points to protective effects of foods like seeds, nuts, vegetables, and olive oil, which has been shown previously,” he continued.

The highest quintile of total red meat intake was associated with an 8% higher risk for stroke, but this was driven mainly by processed red meat (which was associated with a 12% higher risk for stroke). These findings are “generally consistent with cohort studies showing that processed meat, as with most highly processed foods for that matter, are associated with an increased risk of cardiovascular events,” Dr. Mente noted.

“Surprisingly, dairy products (such as cheese, butter, or milk) in the study were not connected with the risk of stroke,” he added. This finding differs from results of meta-analyses of multiple cohort studies of dairy intake and stroke and the recent large international PURE study, which showed that dairy intake was associated with a lower risk for stroke.

“What is needed to move the field forward,” according to Dr. Mente, “is to employ new methods that use cutting-edge technology to study nutritional biomarkers and health outcomes.”

“When dealing with modest associations as usually encountered in nutrition, it is a challenge to make causal connections based on dietary questionnaires, which are fraught with measurement error,” he added. “The use of novel methods is where the field is headed.”
 

Total dietary fat, different types, and different food sources

Dr. Wang and colleagues investigated how total dietary fat, different types of fat, and fats from different foods were associated with incident stroke in 73,867 women in the 1984-2016 Nurses’ Health Study and 43,269 men who participated in the 1986-2016 Health Professionals Follow-up Study.

The participants had an average age of 50 years, 63% were women, and 97% were White. They replied to food-frequency questionnaires every 4 years.

Total red meat included beef, pork, or lamb (as a main dish or in sandwiches or mixed dishes) as well as processed red meats (such as bacon, sausage, bologna, hot dogs, and salami).

Animal fat sources included meat, beef tallow, lard, and full-fat dairy products, such as full-fat milk and cheese.

The median percentage of total daily calories from different sources of fat ranged from 10% to 20% for vegetable fat, 3% to 10% for dairy fat, and 7% to 17% for nondairy animal fat (for lowest to highest quintiles).

The median percentage of total daily calories from different types of fat ranged from 5% to 8% for polyunsaturated fat, 4% to 7% for n-6 polyunsaturated fat, 9% to 15% for monounsaturated fat, 8% to 14% for saturated fat, and 1% to 2% for trans fat.

During follow-up, there were 6,189 incident strokes, including 2,967 ischemic strokes and 814 hemorrhagic strokes.

The researchers found that intake in the highest quintile of vegetable fat was associated with a lower risk for total stroke, compared with the lowest quintile (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96; P for trend < .001).

Similarly, the highest intake of polyunsaturated fat was also associated with lower total stroke (HR, 0.88; 95% CI, 0.80-0.96; P for trend = .002). 

Highest intake of nondairy animal fat, however, was associated with an increased risk for total stroke (HR, 1.16; 95% CI, 1.05-1.29; P for trend < .001). They observed “similar associations” for ischemic stroke, but the only positive association for nondairy animal fat was with hemorrhagic stroke, the abstract notes.   

The risk for stroke was lower by 9% per serving per day for vegetable oil but increased by 8% and 12%, respectively, per serving of total red meat or processed red meat.

The association for vegetable oil was attenuated after adjustment for vegetable fat or polyunsaturated fat, whereas adjustment for nondairy animal fat rendered the association for total red meat and processed red meat nonsignificant. 

The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Wang has no relevant financial disclosures. Dr. Mente has received research funding from the Dairy Farmers of Canada and the National Dairy Council to analyze data on dairy consumption and health outcomes in the PURE study, which is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, and more than 70 other sources (government and pharmaceutical).

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

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

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

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

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

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

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

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

[email protected]
 

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

[email protected]
 

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

[email protected]
 

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

Despite objections from the American Psychiatric Association and other national groups, federal regulators are sticking to the Nov. 15 deadline for the modified clozapine risk evaluation and mitigation strategy (REMS) program.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The modifications will require all those who prescribe and dispense clozapine to be recertified. Prescribers and pharmacies who fail to be certified by this date will no longer be able to prescribe/dispense the drug. In addition, clinicians must re-enroll all patients who are currently taking the medication.

Clozapine is used to treat schizophrenia that is not well controlled with standard antipsychotics. It is also prescribed to patients with recurrent suicidal behavior associated with schizophrenia or schizoaffective disorder.

Although it is highly effective in some patients, it also carries serious risks. Specifically, it can decrease the neutrophil count, which can lead to severe neutropenia, serious infections, and death. As a result, those taking the drug must undergo regular absolute neutrophil count (ANC) monitoring. Clozapine REMS is intended to maximize the benefits of the drug and minimize risk.

The U.S. Food and Drug Administration first announced modifications to the program in July. Under the new rules, pharmacies will no longer be permitted to use telecommunication verification, also known as the switch system, to verify safe use conditions. Instead, the authorization to dispense will be obtained either through the contact center or online via the REMS website.

Furthermore, a new patient status form (PFS) will be used to document absolute ANC monitoring for all outpatients and the form must be submitted monthly.

In addition to the APA, opponents of the new recertification rules include the College of Psychiatric and Neurologic Pharmacists, the National Council for Mental Wellbeing, the National Association of State Mental Health Program Directors, the National Alliance on Mental Illness, the American Psychiatric Nurses Association, and the American Pharmacists Association.

No more access to patient data

Among other concerns, the coalition argues the new requirements will make it more difficult for clinicians to access data on patients’ previous clozapine history. Many clinicians depend on these data, which were maintained in the earlier REMS and in previous manufacturer-maintained clozapine monitoring systems.

The FDA told this news organization in a statement that the Clozapine Products Manufacturers’ Group “was not able to incorporate this data into the modified REMS database because of technical reasons. The new REMS contact center will have access to the historical data should a health care provider need the information,” the FDA said.

The FDA could not immediately provide this news organization with more detail on the nature of the “technical reasons” cited as a cause for the new hurdle that prevents clinicians from accessing these previously available data.

In a September letter to the FDA, the coalition pushed back, writing that it is “unreasonable to deny prescribers of this data that they entered. Furthermore, the lack of historical data could result in harm to patients in some circumstances.”

The coalition asked the FDA to intervene and ask the drug’s manufacturers to reinstate prescriber access to the information.

In a response to questions on this issue from this news organization, the FDA said in a written response the historical data had not been lost, but would be maintained “for record-keeping purposes.”

The FDA also said agency officials met on Oct. 10 with members of the professional organizations who authored the letter to hear their concerns about the clozapine REMS program. The CPMG, which has the responsibility for implementing the REMS, was also represented at the meeting, the FDA said.

“Based on concerns raised by stakeholders, the CPMG has recently begun to address some of the concerns raised in the letter including updating the prescriber/prescriber designee relationship and enrollment process to allow for a designee to be affiliated with multiple prescribers,” the FDA told this news organization.

“The recent updates also enable prescriber designees to self-enroll/create credentials, send affiliation requests to prescribers, and attest/perform functions on behalf of prescribers. It is our understanding that the CPMG is disseminating this information to stakeholders,” the agency added.

Bigger burden, bad timing

In an interview, Robert Cotes, MD, who serves as a member of the clinical expert team for Serious Mental Illness Adviser, a joint initiative of the APA and the Substance Abuse and Mental Health Services Administration, said the changes to the clozapine REMS will likely increase the administrative burden on clinicians.

In the letter to the FDA, the APA and other groups in the coalition expressed concern about patient status forms, which are five pages long. The coalition has requested that the FDA develop a form where clinicians can submit monitoring results on multiple patients at one time, with PDF forms presented in a fillable format.

“The concern is that if the workflows become more laborious for people, it could result in treatment interruptions for individuals on clozapine or potentially it may steer prescribers away from using clozapine for people who may need it,” said Dr. Cotes.

Also commenting for this news organization, Raymond C. Love, PharmD, professor and vice chair at the University of Maryland School of Pharmacy, Baltimore, emphasized the poor timing of the switch to a new clozapine REMS.

“Pharmacies are overloaded right now due to COVID tests and influenza and COVID boosters and COVID vaccinations for kids,” making it a tough time to manage the demands of the clozapine REMS re-enrollment, he said.

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

Despite objections from the American Psychiatric Association and other national groups, federal regulators are sticking to the Nov. 15 deadline for the modified clozapine risk evaluation and mitigation strategy (REMS) program.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The modifications will require all those who prescribe and dispense clozapine to be recertified. Prescribers and pharmacies who fail to be certified by this date will no longer be able to prescribe/dispense the drug. In addition, clinicians must re-enroll all patients who are currently taking the medication.

Clozapine is used to treat schizophrenia that is not well controlled with standard antipsychotics. It is also prescribed to patients with recurrent suicidal behavior associated with schizophrenia or schizoaffective disorder.

Although it is highly effective in some patients, it also carries serious risks. Specifically, it can decrease the neutrophil count, which can lead to severe neutropenia, serious infections, and death. As a result, those taking the drug must undergo regular absolute neutrophil count (ANC) monitoring. Clozapine REMS is intended to maximize the benefits of the drug and minimize risk.

The U.S. Food and Drug Administration first announced modifications to the program in July. Under the new rules, pharmacies will no longer be permitted to use telecommunication verification, also known as the switch system, to verify safe use conditions. Instead, the authorization to dispense will be obtained either through the contact center or online via the REMS website.

Furthermore, a new patient status form (PFS) will be used to document absolute ANC monitoring for all outpatients and the form must be submitted monthly.

In addition to the APA, opponents of the new recertification rules include the College of Psychiatric and Neurologic Pharmacists, the National Council for Mental Wellbeing, the National Association of State Mental Health Program Directors, the National Alliance on Mental Illness, the American Psychiatric Nurses Association, and the American Pharmacists Association.

No more access to patient data

Among other concerns, the coalition argues the new requirements will make it more difficult for clinicians to access data on patients’ previous clozapine history. Many clinicians depend on these data, which were maintained in the earlier REMS and in previous manufacturer-maintained clozapine monitoring systems.

The FDA told this news organization in a statement that the Clozapine Products Manufacturers’ Group “was not able to incorporate this data into the modified REMS database because of technical reasons. The new REMS contact center will have access to the historical data should a health care provider need the information,” the FDA said.

The FDA could not immediately provide this news organization with more detail on the nature of the “technical reasons” cited as a cause for the new hurdle that prevents clinicians from accessing these previously available data.

In a September letter to the FDA, the coalition pushed back, writing that it is “unreasonable to deny prescribers of this data that they entered. Furthermore, the lack of historical data could result in harm to patients in some circumstances.”

The coalition asked the FDA to intervene and ask the drug’s manufacturers to reinstate prescriber access to the information.

In a response to questions on this issue from this news organization, the FDA said in a written response the historical data had not been lost, but would be maintained “for record-keeping purposes.”

The FDA also said agency officials met on Oct. 10 with members of the professional organizations who authored the letter to hear their concerns about the clozapine REMS program. The CPMG, which has the responsibility for implementing the REMS, was also represented at the meeting, the FDA said.

“Based on concerns raised by stakeholders, the CPMG has recently begun to address some of the concerns raised in the letter including updating the prescriber/prescriber designee relationship and enrollment process to allow for a designee to be affiliated with multiple prescribers,” the FDA told this news organization.

“The recent updates also enable prescriber designees to self-enroll/create credentials, send affiliation requests to prescribers, and attest/perform functions on behalf of prescribers. It is our understanding that the CPMG is disseminating this information to stakeholders,” the agency added.

Bigger burden, bad timing

In an interview, Robert Cotes, MD, who serves as a member of the clinical expert team for Serious Mental Illness Adviser, a joint initiative of the APA and the Substance Abuse and Mental Health Services Administration, said the changes to the clozapine REMS will likely increase the administrative burden on clinicians.

In the letter to the FDA, the APA and other groups in the coalition expressed concern about patient status forms, which are five pages long. The coalition has requested that the FDA develop a form where clinicians can submit monitoring results on multiple patients at one time, with PDF forms presented in a fillable format.

“The concern is that if the workflows become more laborious for people, it could result in treatment interruptions for individuals on clozapine or potentially it may steer prescribers away from using clozapine for people who may need it,” said Dr. Cotes.

Also commenting for this news organization, Raymond C. Love, PharmD, professor and vice chair at the University of Maryland School of Pharmacy, Baltimore, emphasized the poor timing of the switch to a new clozapine REMS.

“Pharmacies are overloaded right now due to COVID tests and influenza and COVID boosters and COVID vaccinations for kids,” making it a tough time to manage the demands of the clozapine REMS re-enrollment, he said.

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

Despite objections from the American Psychiatric Association and other national groups, federal regulators are sticking to the Nov. 15 deadline for the modified clozapine risk evaluation and mitigation strategy (REMS) program.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The modifications will require all those who prescribe and dispense clozapine to be recertified. Prescribers and pharmacies who fail to be certified by this date will no longer be able to prescribe/dispense the drug. In addition, clinicians must re-enroll all patients who are currently taking the medication.

Clozapine is used to treat schizophrenia that is not well controlled with standard antipsychotics. It is also prescribed to patients with recurrent suicidal behavior associated with schizophrenia or schizoaffective disorder.

Although it is highly effective in some patients, it also carries serious risks. Specifically, it can decrease the neutrophil count, which can lead to severe neutropenia, serious infections, and death. As a result, those taking the drug must undergo regular absolute neutrophil count (ANC) monitoring. Clozapine REMS is intended to maximize the benefits of the drug and minimize risk.

The U.S. Food and Drug Administration first announced modifications to the program in July. Under the new rules, pharmacies will no longer be permitted to use telecommunication verification, also known as the switch system, to verify safe use conditions. Instead, the authorization to dispense will be obtained either through the contact center or online via the REMS website.

Furthermore, a new patient status form (PFS) will be used to document absolute ANC monitoring for all outpatients and the form must be submitted monthly.

In addition to the APA, opponents of the new recertification rules include the College of Psychiatric and Neurologic Pharmacists, the National Council for Mental Wellbeing, the National Association of State Mental Health Program Directors, the National Alliance on Mental Illness, the American Psychiatric Nurses Association, and the American Pharmacists Association.

No more access to patient data

Among other concerns, the coalition argues the new requirements will make it more difficult for clinicians to access data on patients’ previous clozapine history. Many clinicians depend on these data, which were maintained in the earlier REMS and in previous manufacturer-maintained clozapine monitoring systems.

The FDA told this news organization in a statement that the Clozapine Products Manufacturers’ Group “was not able to incorporate this data into the modified REMS database because of technical reasons. The new REMS contact center will have access to the historical data should a health care provider need the information,” the FDA said.

The FDA could not immediately provide this news organization with more detail on the nature of the “technical reasons” cited as a cause for the new hurdle that prevents clinicians from accessing these previously available data.

In a September letter to the FDA, the coalition pushed back, writing that it is “unreasonable to deny prescribers of this data that they entered. Furthermore, the lack of historical data could result in harm to patients in some circumstances.”

The coalition asked the FDA to intervene and ask the drug’s manufacturers to reinstate prescriber access to the information.

In a response to questions on this issue from this news organization, the FDA said in a written response the historical data had not been lost, but would be maintained “for record-keeping purposes.”

The FDA also said agency officials met on Oct. 10 with members of the professional organizations who authored the letter to hear their concerns about the clozapine REMS program. The CPMG, which has the responsibility for implementing the REMS, was also represented at the meeting, the FDA said.

“Based on concerns raised by stakeholders, the CPMG has recently begun to address some of the concerns raised in the letter including updating the prescriber/prescriber designee relationship and enrollment process to allow for a designee to be affiliated with multiple prescribers,” the FDA told this news organization.

“The recent updates also enable prescriber designees to self-enroll/create credentials, send affiliation requests to prescribers, and attest/perform functions on behalf of prescribers. It is our understanding that the CPMG is disseminating this information to stakeholders,” the agency added.

Bigger burden, bad timing

In an interview, Robert Cotes, MD, who serves as a member of the clinical expert team for Serious Mental Illness Adviser, a joint initiative of the APA and the Substance Abuse and Mental Health Services Administration, said the changes to the clozapine REMS will likely increase the administrative burden on clinicians.

In the letter to the FDA, the APA and other groups in the coalition expressed concern about patient status forms, which are five pages long. The coalition has requested that the FDA develop a form where clinicians can submit monitoring results on multiple patients at one time, with PDF forms presented in a fillable format.

“The concern is that if the workflows become more laborious for people, it could result in treatment interruptions for individuals on clozapine or potentially it may steer prescribers away from using clozapine for people who may need it,” said Dr. Cotes.

Also commenting for this news organization, Raymond C. Love, PharmD, professor and vice chair at the University of Maryland School of Pharmacy, Baltimore, emphasized the poor timing of the switch to a new clozapine REMS.

“Pharmacies are overloaded right now due to COVID tests and influenza and COVID boosters and COVID vaccinations for kids,” making it a tough time to manage the demands of the clozapine REMS re-enrollment, he said.

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

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

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

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

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

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

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

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

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

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

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

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

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

Tricuspid valve repair at the time of mitral valve surgery reduces tricuspid regurgitation progression, but at the cost of more than a fivefold increase in permanent pacemakers, results of a new Cardiothoracic Surgical Trials Network study show.

The results were presented during the opening late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

Tricuspid regurgitation (TR) is common among patients undergoing mitral valve surgery, and there’s broad agreement to intervene when a patient has severe TR. There’s uncertainty, however, about the management of moderate or less TR during mitral valve surgery, which is reflected in current guidelines on the basis of observational data, explained coprimary investigator James Gammie, MD, codirector and surgical director of the Johns Hopkins Heart and Vascular Institute, Baltimore. As a result, rates of concomitant tricuspid-mitral surgery range from 5% to 75% at various centers.

To help fill the gap, Dr. Gammie and colleagues screened 5,208 patients at 29 centers in the United States, Canada, and Germany undergoing surgery for degenerative mitral regurgitation, and randomly assigned 401 patients (75% male) to mitral valve surgery alone or with tricuspid annuloplasty.

Patients had either moderate TR (37%) or less than moderate TR with a dilated tricuspid annulus of at least 40 mm or at least 21 mm/m² indexed for body surface area. Importantly, there was a uniform surgical approach using undersized (26-30 mm) rigid nonplanar annuloplasty rings to repair the tricuspid valve, he said.

The study’s primary outcome of treatment failure at 2 years was defined as the composite of death, reoperation for TR, or progression of TR from baseline by 2 grades or severe TR.

The primary endpoint occurred in 10.2% of patients who underwent mitral valve surgery alone and 3.9% who underwent concomitant tricuspid annuloplasty (relative risk, 0.37; 95% confidence interval, 0.16-0.86; P = .02).

The endpoint was driven exclusively by less TR progression in the annuloplasty group, with no TR reoperations in either group, observed Dr. Gammie. At 2 years, just 0.6% of the annuloplasty group had severe TR, compared with 5.6% of the surgery-alone group.

The rate of permanent pacemaker implantations, however, jumped from 2.5% with surgery alone to 14.1% with concomitant tricuspid annuloplasty (rate ratio, 5.75; 95% CI, 2.27-14.60). More than half of pacemakers were placed during the first 2 days after surgery.

There was no between-group difference in 2-year rates of all-cause mortality, major adverse cardiac and cerebrovascular events, readmission, quality of life, or functional status.

Less than moderate TR

In a post hoc analysis stratified by baseline TR severity, treatment failure was significantly less common with surgery plus tricuspid annuloplasty among patients with moderate TR (4.5% vs. 18.1%) but not among those with less than moderate TR and tricuspid annular dilation (3.4% vs. 6.1%).

Although the trial was not powered for the subgroup analysis, “these results call into question the idea that less than moderate TR with annular dilation should be an indication for tricuspid valve repair,” Dr. Gammie told this news organization.

“I did not repair the tricuspid valve in the setting of less than moderate TR before the trial, and my practice won’t change; but it will be based on much better evidence,” he added. “Of course, long-term data from our trial will be of great interest.”

Discussant Joseph Woo, MD, chair of surgery at Stanford (Calif.) University, congratulated the authors on a “landmark trial” that addresses a highly relevant problem without a clear-cut indication.

In the 2020 AHA/American College of Cardiology heart valve disease guideline, tricuspid valve surgery is a class I recommendation when there’s severe TR (stages C and D) and left-sided valve surgery but a class IIa recommendation in patients with progressive TR (stage B) with an annular dilation of at least 40 mm.

“The interesting findings in this study include that moderate TR was only 37% of the enrolled patients, and only 97% of the patients with degenerative MR received a mitral valve repair,” Dr. Woo said. “This level of mitral valve repair is perhaps lower than what we might expect at these centers and lower, certainly, than what the AHA/ACC guidelines recommend for surgery on asymptomatic severe mitral regurgitation.”

Panelist Roxanna Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York said, “What I was struck by is that we, as clinicians, believe that if you fix the mitral valve, maybe the tricuspid regurgitation will improve. And it seems like that is not what’s happening, and I think that’s a big takeaway.”

Session comoderator Joanna Chikwe, MD, head of cardiac surgery at Cedars-Sinai Medical Center, Los Angeles, said, “I think we can all agree that severe tricuspid regurgitation is a disaster for patients, and I think the fact the trial is designed for an additional 5 years’ follow-up will hopefully give us some insights into the clinical impact of severe tricuspid regurgitation.”

For now, “a back of the envelope calculation suggests that, for every 20 patients with moderate tricuspid regurgitation who we repair the tricuspid valve in, we would prevent severe tricuspid valve regurgitation in 1 at the price of pacemakers in 2,” she said.

Dr. Chikwe said in an interview that “transcatheter tricuspid repair is increasingly helping these patients, but if you could avoid it with a technique that doesn’t cause incremental harm beyond, perhaps, the need for pacemakers, then this is helpful data that supports that approach.”

The pacemaker burden is not negligible, she said, but also not surprising to surgeons. “If you look at national practice of mitral-tricuspid surgery, it’s about 15% after that, and it’s simply because the conduction tissue is so close to the tricuspid annulus.”

Pacemaker implantation rates, like those for concomitant tricuspid-mitral surgery, are also highly variable, and in some single-center series only around 2%, Dr. Chikwe said. “So that suggests there are technical approaches that can minimize the pacemaker rate [such as] being extremely careful to avoid suture placement around the area of the conduction tissues.”

For some the trade-off between reduced TR progression and the risk of a permanent pacemaker is worth it. “But the fact that the trial didn’t show a difference in survival, a difference in symptoms or quality of life, might suggest that patients you anticipated were high risk for surgery or didn’t have a longer projected survival aren’t going to benefit from what is quite an aggressive surgical approach,” Dr. Chikwe said.

In an accompanying editorial, Dr. Chikwe and Mario Gaudino, MD, of Weill Cornell Medicine, New York, also point out that the “very dynamic nature of tricuspid regurgitation and wide variability in assessing tricuspid annular dilatation are additional compelling reasons to leave lesser regurgitation alone.”

Julia Grapsa, MD, PhD, Kings College and tricuspid service lead at Guys and St. Thomas NHS, London, also pointed to the need for longer-term follow-up but said increased use of imaging markers is also needed to help pinpoint TR progression in these patients. “For the moment, the results should remind imagers and clinicians to refer patients earlier.”

“As a valvular heart physician, I see more and more patients coming in with significant severe tricuspid regurgitation post–mitral valve surgery and because of the time that’s passed, there’s dysfunction of the right heart, the left heart, and it’s very hard to suggest an operation because they’re at high risk,” she said. “So we’re discussing with these patients whether to do an intervention or medical management.”

“Now, with this study, and the pending longer follow-up by the authors, I’m optimistic that the class II recommendation will be class I in order to help our patients treat tricuspid regurgitation earlier than late,” said Dr. Grapsa, who is also editor-in-chief of JACC: Case Reports.

The study was funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research. Dr. Gammie reports a consultant/stockholder relationship with Edwards Lifesciences. Dr. Grapsa reports no conflicts of interest. Dr. Chikwe reports that as coprincipal investigator/study director of NCT 05051033 (an NHLBI-sponsored Cardiothoracic Surgical Trials Network trial), she collaborates with several of the study authors.
 

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

Tricuspid valve repair at the time of mitral valve surgery reduces tricuspid regurgitation progression, but at the cost of more than a fivefold increase in permanent pacemakers, results of a new Cardiothoracic Surgical Trials Network study show.

The results were presented during the opening late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

Tricuspid regurgitation (TR) is common among patients undergoing mitral valve surgery, and there’s broad agreement to intervene when a patient has severe TR. There’s uncertainty, however, about the management of moderate or less TR during mitral valve surgery, which is reflected in current guidelines on the basis of observational data, explained coprimary investigator James Gammie, MD, codirector and surgical director of the Johns Hopkins Heart and Vascular Institute, Baltimore. As a result, rates of concomitant tricuspid-mitral surgery range from 5% to 75% at various centers.

To help fill the gap, Dr. Gammie and colleagues screened 5,208 patients at 29 centers in the United States, Canada, and Germany undergoing surgery for degenerative mitral regurgitation, and randomly assigned 401 patients (75% male) to mitral valve surgery alone or with tricuspid annuloplasty.

Patients had either moderate TR (37%) or less than moderate TR with a dilated tricuspid annulus of at least 40 mm or at least 21 mm/m² indexed for body surface area. Importantly, there was a uniform surgical approach using undersized (26-30 mm) rigid nonplanar annuloplasty rings to repair the tricuspid valve, he said.

The study’s primary outcome of treatment failure at 2 years was defined as the composite of death, reoperation for TR, or progression of TR from baseline by 2 grades or severe TR.

The primary endpoint occurred in 10.2% of patients who underwent mitral valve surgery alone and 3.9% who underwent concomitant tricuspid annuloplasty (relative risk, 0.37; 95% confidence interval, 0.16-0.86; P = .02).

The endpoint was driven exclusively by less TR progression in the annuloplasty group, with no TR reoperations in either group, observed Dr. Gammie. At 2 years, just 0.6% of the annuloplasty group had severe TR, compared with 5.6% of the surgery-alone group.

The rate of permanent pacemaker implantations, however, jumped from 2.5% with surgery alone to 14.1% with concomitant tricuspid annuloplasty (rate ratio, 5.75; 95% CI, 2.27-14.60). More than half of pacemakers were placed during the first 2 days after surgery.

There was no between-group difference in 2-year rates of all-cause mortality, major adverse cardiac and cerebrovascular events, readmission, quality of life, or functional status.

Less than moderate TR

In a post hoc analysis stratified by baseline TR severity, treatment failure was significantly less common with surgery plus tricuspid annuloplasty among patients with moderate TR (4.5% vs. 18.1%) but not among those with less than moderate TR and tricuspid annular dilation (3.4% vs. 6.1%).

Although the trial was not powered for the subgroup analysis, “these results call into question the idea that less than moderate TR with annular dilation should be an indication for tricuspid valve repair,” Dr. Gammie told this news organization.

“I did not repair the tricuspid valve in the setting of less than moderate TR before the trial, and my practice won’t change; but it will be based on much better evidence,” he added. “Of course, long-term data from our trial will be of great interest.”

Discussant Joseph Woo, MD, chair of surgery at Stanford (Calif.) University, congratulated the authors on a “landmark trial” that addresses a highly relevant problem without a clear-cut indication.

In the 2020 AHA/American College of Cardiology heart valve disease guideline, tricuspid valve surgery is a class I recommendation when there’s severe TR (stages C and D) and left-sided valve surgery but a class IIa recommendation in patients with progressive TR (stage B) with an annular dilation of at least 40 mm.

“The interesting findings in this study include that moderate TR was only 37% of the enrolled patients, and only 97% of the patients with degenerative MR received a mitral valve repair,” Dr. Woo said. “This level of mitral valve repair is perhaps lower than what we might expect at these centers and lower, certainly, than what the AHA/ACC guidelines recommend for surgery on asymptomatic severe mitral regurgitation.”

Panelist Roxanna Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York said, “What I was struck by is that we, as clinicians, believe that if you fix the mitral valve, maybe the tricuspid regurgitation will improve. And it seems like that is not what’s happening, and I think that’s a big takeaway.”

Session comoderator Joanna Chikwe, MD, head of cardiac surgery at Cedars-Sinai Medical Center, Los Angeles, said, “I think we can all agree that severe tricuspid regurgitation is a disaster for patients, and I think the fact the trial is designed for an additional 5 years’ follow-up will hopefully give us some insights into the clinical impact of severe tricuspid regurgitation.”

For now, “a back of the envelope calculation suggests that, for every 20 patients with moderate tricuspid regurgitation who we repair the tricuspid valve in, we would prevent severe tricuspid valve regurgitation in 1 at the price of pacemakers in 2,” she said.

Dr. Chikwe said in an interview that “transcatheter tricuspid repair is increasingly helping these patients, but if you could avoid it with a technique that doesn’t cause incremental harm beyond, perhaps, the need for pacemakers, then this is helpful data that supports that approach.”

The pacemaker burden is not negligible, she said, but also not surprising to surgeons. “If you look at national practice of mitral-tricuspid surgery, it’s about 15% after that, and it’s simply because the conduction tissue is so close to the tricuspid annulus.”

Pacemaker implantation rates, like those for concomitant tricuspid-mitral surgery, are also highly variable, and in some single-center series only around 2%, Dr. Chikwe said. “So that suggests there are technical approaches that can minimize the pacemaker rate [such as] being extremely careful to avoid suture placement around the area of the conduction tissues.”

For some the trade-off between reduced TR progression and the risk of a permanent pacemaker is worth it. “But the fact that the trial didn’t show a difference in survival, a difference in symptoms or quality of life, might suggest that patients you anticipated were high risk for surgery or didn’t have a longer projected survival aren’t going to benefit from what is quite an aggressive surgical approach,” Dr. Chikwe said.

In an accompanying editorial, Dr. Chikwe and Mario Gaudino, MD, of Weill Cornell Medicine, New York, also point out that the “very dynamic nature of tricuspid regurgitation and wide variability in assessing tricuspid annular dilatation are additional compelling reasons to leave lesser regurgitation alone.”

Julia Grapsa, MD, PhD, Kings College and tricuspid service lead at Guys and St. Thomas NHS, London, also pointed to the need for longer-term follow-up but said increased use of imaging markers is also needed to help pinpoint TR progression in these patients. “For the moment, the results should remind imagers and clinicians to refer patients earlier.”

“As a valvular heart physician, I see more and more patients coming in with significant severe tricuspid regurgitation post–mitral valve surgery and because of the time that’s passed, there’s dysfunction of the right heart, the left heart, and it’s very hard to suggest an operation because they’re at high risk,” she said. “So we’re discussing with these patients whether to do an intervention or medical management.”

“Now, with this study, and the pending longer follow-up by the authors, I’m optimistic that the class II recommendation will be class I in order to help our patients treat tricuspid regurgitation earlier than late,” said Dr. Grapsa, who is also editor-in-chief of JACC: Case Reports.

The study was funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research. Dr. Gammie reports a consultant/stockholder relationship with Edwards Lifesciences. Dr. Grapsa reports no conflicts of interest. Dr. Chikwe reports that as coprincipal investigator/study director of NCT 05051033 (an NHLBI-sponsored Cardiothoracic Surgical Trials Network trial), she collaborates with several of the study authors.
 

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

Tricuspid valve repair at the time of mitral valve surgery reduces tricuspid regurgitation progression, but at the cost of more than a fivefold increase in permanent pacemakers, results of a new Cardiothoracic Surgical Trials Network study show.

The results were presented during the opening late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

Tricuspid regurgitation (TR) is common among patients undergoing mitral valve surgery, and there’s broad agreement to intervene when a patient has severe TR. There’s uncertainty, however, about the management of moderate or less TR during mitral valve surgery, which is reflected in current guidelines on the basis of observational data, explained coprimary investigator James Gammie, MD, codirector and surgical director of the Johns Hopkins Heart and Vascular Institute, Baltimore. As a result, rates of concomitant tricuspid-mitral surgery range from 5% to 75% at various centers.

To help fill the gap, Dr. Gammie and colleagues screened 5,208 patients at 29 centers in the United States, Canada, and Germany undergoing surgery for degenerative mitral regurgitation, and randomly assigned 401 patients (75% male) to mitral valve surgery alone or with tricuspid annuloplasty.

Patients had either moderate TR (37%) or less than moderate TR with a dilated tricuspid annulus of at least 40 mm or at least 21 mm/m² indexed for body surface area. Importantly, there was a uniform surgical approach using undersized (26-30 mm) rigid nonplanar annuloplasty rings to repair the tricuspid valve, he said.

The study’s primary outcome of treatment failure at 2 years was defined as the composite of death, reoperation for TR, or progression of TR from baseline by 2 grades or severe TR.

The primary endpoint occurred in 10.2% of patients who underwent mitral valve surgery alone and 3.9% who underwent concomitant tricuspid annuloplasty (relative risk, 0.37; 95% confidence interval, 0.16-0.86; P = .02).

The endpoint was driven exclusively by less TR progression in the annuloplasty group, with no TR reoperations in either group, observed Dr. Gammie. At 2 years, just 0.6% of the annuloplasty group had severe TR, compared with 5.6% of the surgery-alone group.

The rate of permanent pacemaker implantations, however, jumped from 2.5% with surgery alone to 14.1% with concomitant tricuspid annuloplasty (rate ratio, 5.75; 95% CI, 2.27-14.60). More than half of pacemakers were placed during the first 2 days after surgery.

There was no between-group difference in 2-year rates of all-cause mortality, major adverse cardiac and cerebrovascular events, readmission, quality of life, or functional status.

Less than moderate TR

In a post hoc analysis stratified by baseline TR severity, treatment failure was significantly less common with surgery plus tricuspid annuloplasty among patients with moderate TR (4.5% vs. 18.1%) but not among those with less than moderate TR and tricuspid annular dilation (3.4% vs. 6.1%).

Although the trial was not powered for the subgroup analysis, “these results call into question the idea that less than moderate TR with annular dilation should be an indication for tricuspid valve repair,” Dr. Gammie told this news organization.

“I did not repair the tricuspid valve in the setting of less than moderate TR before the trial, and my practice won’t change; but it will be based on much better evidence,” he added. “Of course, long-term data from our trial will be of great interest.”

Discussant Joseph Woo, MD, chair of surgery at Stanford (Calif.) University, congratulated the authors on a “landmark trial” that addresses a highly relevant problem without a clear-cut indication.

In the 2020 AHA/American College of Cardiology heart valve disease guideline, tricuspid valve surgery is a class I recommendation when there’s severe TR (stages C and D) and left-sided valve surgery but a class IIa recommendation in patients with progressive TR (stage B) with an annular dilation of at least 40 mm.

“The interesting findings in this study include that moderate TR was only 37% of the enrolled patients, and only 97% of the patients with degenerative MR received a mitral valve repair,” Dr. Woo said. “This level of mitral valve repair is perhaps lower than what we might expect at these centers and lower, certainly, than what the AHA/ACC guidelines recommend for surgery on asymptomatic severe mitral regurgitation.”

Panelist Roxanna Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York said, “What I was struck by is that we, as clinicians, believe that if you fix the mitral valve, maybe the tricuspid regurgitation will improve. And it seems like that is not what’s happening, and I think that’s a big takeaway.”

Session comoderator Joanna Chikwe, MD, head of cardiac surgery at Cedars-Sinai Medical Center, Los Angeles, said, “I think we can all agree that severe tricuspid regurgitation is a disaster for patients, and I think the fact the trial is designed for an additional 5 years’ follow-up will hopefully give us some insights into the clinical impact of severe tricuspid regurgitation.”

For now, “a back of the envelope calculation suggests that, for every 20 patients with moderate tricuspid regurgitation who we repair the tricuspid valve in, we would prevent severe tricuspid valve regurgitation in 1 at the price of pacemakers in 2,” she said.

Dr. Chikwe said in an interview that “transcatheter tricuspid repair is increasingly helping these patients, but if you could avoid it with a technique that doesn’t cause incremental harm beyond, perhaps, the need for pacemakers, then this is helpful data that supports that approach.”

The pacemaker burden is not negligible, she said, but also not surprising to surgeons. “If you look at national practice of mitral-tricuspid surgery, it’s about 15% after that, and it’s simply because the conduction tissue is so close to the tricuspid annulus.”

Pacemaker implantation rates, like those for concomitant tricuspid-mitral surgery, are also highly variable, and in some single-center series only around 2%, Dr. Chikwe said. “So that suggests there are technical approaches that can minimize the pacemaker rate [such as] being extremely careful to avoid suture placement around the area of the conduction tissues.”

For some the trade-off between reduced TR progression and the risk of a permanent pacemaker is worth it. “But the fact that the trial didn’t show a difference in survival, a difference in symptoms or quality of life, might suggest that patients you anticipated were high risk for surgery or didn’t have a longer projected survival aren’t going to benefit from what is quite an aggressive surgical approach,” Dr. Chikwe said.

In an accompanying editorial, Dr. Chikwe and Mario Gaudino, MD, of Weill Cornell Medicine, New York, also point out that the “very dynamic nature of tricuspid regurgitation and wide variability in assessing tricuspid annular dilatation are additional compelling reasons to leave lesser regurgitation alone.”

Julia Grapsa, MD, PhD, Kings College and tricuspid service lead at Guys and St. Thomas NHS, London, also pointed to the need for longer-term follow-up but said increased use of imaging markers is also needed to help pinpoint TR progression in these patients. “For the moment, the results should remind imagers and clinicians to refer patients earlier.”

“As a valvular heart physician, I see more and more patients coming in with significant severe tricuspid regurgitation post–mitral valve surgery and because of the time that’s passed, there’s dysfunction of the right heart, the left heart, and it’s very hard to suggest an operation because they’re at high risk,” she said. “So we’re discussing with these patients whether to do an intervention or medical management.”

“Now, with this study, and the pending longer follow-up by the authors, I’m optimistic that the class II recommendation will be class I in order to help our patients treat tricuspid regurgitation earlier than late,” said Dr. Grapsa, who is also editor-in-chief of JACC: Case Reports.

The study was funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research. Dr. Gammie reports a consultant/stockholder relationship with Edwards Lifesciences. Dr. Grapsa reports no conflicts of interest. Dr. Chikwe reports that as coprincipal investigator/study director of NCT 05051033 (an NHLBI-sponsored Cardiothoracic Surgical Trials Network trial), she collaborates with several of the study authors.
 

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